Phase II Study of Redirected Autologous T Cells Engineered to Contain Anti-CD19 Attached to TCR and 4-1BB Signaling Domains in Patients With Chemotherapy Resistant or RefractoryAcute Lymphoblastic Leukemia
Phase: PHASE2
Conditions: Patients With B Cell ALL, Relapsed or Refractory, With no Available Curative Treatment Options
Sponsor: University of Pennsylvania

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 1 of 1 0 8  
V ersi o n V 1 2. 0 4 -1 4 -2 0 1 7   
C O N F I D E N TIA L  
T his d oc u me nt is c o nfi de nti al a n d t he pr o pe rt y of t he U ni ve rsit y of Pe n ns yl v a ni a.  N o p art of it m a y be tr a ns mitte d, 
re pr o d uce d, p u blis he d, or use d b y ot he r pers o ns wit h o ut pri or w ritte n a ut h oriz ati o n fr o m t he st u d y s p o ns or.  
U niversity of Pe n nsylv a ni a  
 
 
P H A S E II S T U D Y O F  R E DI R E C T E D A U T O L O G O U S T  C E L L S E N GI N E E R E D T O 
C O N T AI N A N TI - C D 1 9 A T T A C H E D T O T C R  A N D  4- 1 B B  S I G N A LI N G D O M AI N S 
IN P A TI E N T S W I T H C H E M O T H E R A P Y R E SI S T A N T O R R E F R A C T O R Y A C U T E 
L Y M P H O B L A S TI C L E U K E MI A  
 
P ri nci p al I n vesti g at or:  
N oelle Frey, M D, M S  
De p art me nt of Me dici ne  
Perel m a n Sc h o ol of Me dici ne  
P hil a del p hi a, Pe n nsylv a ni a 1 9 1 0 4  
Re g ul at or y S p o ns or:  
U niversity of Pe n nsylv a ni a  
F u n di n g Or g a niz ati o n : 
 
 
 
 
 
 
 
 
 
N ov artis P h ar m ace utic als C or p  
O ne He alt h Pl az a  
E ast H a n over, NJ 0 7 9 3 6  
 
 
 
 
S p o ns or Cell M a n uf act uri n g - 
U ni versit y of Pe n ns yl v a ni a : 
 
C orrel ati ve L a b or at or y 
Te a m : 
 
 
 
  
Bi ost atistici a n:  
 
St u d y P r o d uct: 
C D 1 9 re direc te d a ut ol o g o us T cells ( C A R T-1 9 T Cells)  
P r ot oc ol N u m ber s: 
 
I N D N u m ber: 
 
 
 
 
 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 2 of 1 0 8  
V ersi o n V 1 2. 0 4 -1 4 -2 0 1 7   
C O N F I D E N TIA L  
T his d oc u me nt is c o nfi de nti al a n d t he pr o pe rt y of t he U ni ve rsit y of Pe n ns yl v a ni a.  N o p art of it m a y be tr a ns mitte d, 
re pr o d uce d, p u blis he d, or use d b y ot he r pers o ns wit h o ut pri or w ritte n a ut h oriz ati o n fr o m t he st u d y s p o ns or.  
D ate  
A me n de d:  
0 7 -2 3 -1 3  
0 8 -2 3 -1 3  
0 9 -3 0 -1 3  
0 5 -0 9 -1 4  
0 6 -1 9 -1 4  
1 1 -2 1 -1 4  
0 1 -2 0 -1 5  
0 5 -0 5 -1 5  
0 6 -1 2 -1 5  
0 9 -0 7 -1 5  
0 2 -1 6 -1 6  
0 4 -1 4 -1 7  
 
 
   
Me dic al M o nit or  
 
 
 
 
  
                              
  
  
  
 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 3 of 1 0 8  
V ersi o n V 1 2. 0 4 -1 4 -2 0 1 7   
C O N FI D E N TI A L  
T his d oc u me nt is c o nfi de nti al a n d t he pr o pe rt y of t he U ni ve rsit y of Pe n ns yl v a ni a.  N o p art of it m a y be tr a ns mitte d, 
re pr o d uce d, p u blis he d, or use d b y ot he r pers o ns wit h o ut pri or w ritte n a ut h oriz ati o n fr o m t he st u d y s p o ns or.  
T A B L E O F C O N T E N T S 
LI S T O F A B B R E VI A TI O N S .................................................................................................................... 5 
S T U D Y S U M M A R Y A N D S T U D Y S C H E M A ........................................................................................ 7 
1.  
I N T R O D U C TI O N ......................................................................................................................... 1 0  
1. 1.  
B ac k gr o u n d ........................................................................................................................... 1 0  
1. 2.  
I n vesti gati o nal A ge nt ............................................................................................................ 1 1  
1. 3.  
Precli nical Data ..................................................................................................................... 1 3  
1. 4.  
Pre vi o us Cli nical Data wit h C A R T- 1 9 cells ......................................................................... 1 3  
1. 5.  
D ose Rati o nale a n d Ris k/ Be nefits ......................................................................................... 1 6  
2.  
S T U D Y O B J E C TI V E S A N D E N D P OI N T S ................................................................................ 2 3  
3.  
S T U D Y D E SI G N ............................................................................................................................ 2 4  
3. 1.  
Ge neral Desi g n ...................................................................................................................... 2 4  
3. 2.  
Pri mar y Efficac y N o n- E val ua ble P atie nts ............................................................................. 2 7  
3. 3.  
Retreat me nt C o h ort ............................................................................................................... 2 7  
4.  
P A TI E N T S E L E C TI O N A N D WI T H D R A W A L ........................................................................ 2 9  
4. 1.  
I ncl usi o n Criteria ................................................................................................................... 2 9  
4. 2.  
E xcl usi o n Criteria .................................................................................................................. 3 0  
4. 3.  
P atie nt Recr uit me nt a n d Scree ni n g ....................................................................................... 3 1  
4. 4.  
Earl y Wit h dra wal of P atie nts ................................................................................................ 3 1  
5.  
S T U D Y D R U G ............................................................................................................................... 3 3  
5. 1.  
Descri pti o n ............................................................................................................................ 3 3  
5. 2.  
P atie nt Eli gi bilit y t o Recei ve C A R T- 1 9 Tra ns d uce d T Cells ................................................ 3 3  
5. 3.  
Treat me nt Re gi me n ............................................................................................................... 3 4  
5. 4.  
Pre p arati o n a n d A d mi nistrati o n of St u d y Dr u g ..................................................................... 3 4  
5. 5.  
I nf usi o n of C A R T- 1 9 Pr o d uct ............................................................................................... 3 6  
5. 6.  
C o nc o mita nt T hera p y ............................................................................................................ 3 6  
6.  
S T U D Y P R O C E D U R E S ............................................................................................................... 3 6  
6. 1.  
Scree ni n g a n d E nr oll me nt Assess me nts ................................................................................ 5 3  
6. 2.  
A p heresis a n d T est e x pa nsi o n ............................................................................................... 5 4  
6. 3.  
Assess me nt T y pes ................................................................................................................. 5 4  
6. 4.  
P atie nt E nr oll me nt ................................................................................................................. 6 0  
6. 5.  
A p heresis Visit Pr oce d ure ..................................................................................................... 6 0  
6. 6.  
C yt ore d ucti ve c he m ot hera p y ................................................................................................. 6 1  
6. 7.  
C A R T- 1 9 I nf usi o n ................................................................................................................ 6 1  
6. 8.  
Da y 2 8: F oll o w U p ................................................................................................................ 6 2  
6. 9.  
M o nt hl y E val uati o ns 2 t o 6 M o nt hs P ost I nf usi o n ................................................................ 6 2  
6. 1 0.  Q uarterl y E val uati o ns f or u p t o 1 Year P ost I nf usi o n ........................................................... 6 2  
6. 1 1.  Sec o n dar y F oll o w- u p  ............................................................................................................ 6 3  
6. 1 2.  L o n g-ter m F oll o w- u p Pr ot oc ol .............................................................................................. 6 3  
6. 1 3.  Re -treat me nt C o h ort Pr oce d ures ........................................................................................... 6 3  
6. 1 4.  Efficac y Assess me nts ............................................................................................................ 6 5  
6. 1 5.  A L L Res p o nse Criteria ......................................................................................................... 6 7  
7.  
S T A TI S TI C A L P L A N ................................................................................................................... 6 9  
7. 1.  
Desi g n O ver vie w ................................................................................................................... 6 9  
7. 2.  
Sa m ple Size J ustificati o n ...................................................................................................... 6 9  
7. 3.  
A nal ysis Sets ......................................................................................................................... 7 0  

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 4 of 1 0 8  
V ersi o n V 1 2. 0 4 -1 4 -2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
7. 4.  
A nal ysis of Pri mar y O bj ecti ve .............................................................................................. 7 0  
7. 5.  
A nal ysis of Sec o n dar y Efficac y O bj ecti ves .......................................................................... 7 1  
7. 6.  
A nal ysis of Sec o n dar y Safet y o bj ecti ves .............................................................................. 7 2  
7. 7.  
A nal ysis of Ot her Sec o n dar y O bj ecti ves ............................................................................... 7 3  
7. 8.  
Retreat me nt C o h ort A nal ysis ................................................................................................ 7 3  
7. 9.  
M o nit ori n g of Safet y ............................................................................................................. 7 3  
8.  
S A F E T Y A N D A D V E R S E E V E N T S ........................................................................................... 7 4  
8. 1.  
Defi niti o ns ............................................................................................................................. 7 4  
8. 2.  
Rec or di n g of A d verse E ve nts ................................................................................................ 7 6  
8. 3.  
Re p orti n g of Seri o us A d verse E ve nts ................................................................................... 8 0  
8. 4.  
T o xicit y Ma na ge me nt, St o p pi n g R ules a n d St u d y T er mi nati o n ........................................... 8 4  
8. 5.  
Pr ot oc ol E xce pti o ns a n d De vi ati o ns ...................................................................................... 9 1  
8. 6.  
Me dical M o nit ori n g .............................................................................................................. 9 2  
9.  
D A T A H A N D LI N G A N D R E C O R D K E E PI N G ......................................................................... 9 3  
9. 1.  
C o nfi de ntialit y ...................................................................................................................... 9 3  
9. 2.  
S o urce D oc u me nts ................................................................................................................ 9 4  
9. 3.  
Case Re p ort F or ms ................................................................................................................ 9 4  
1 0.  
S T U D Y M O NI T O RI N G, A U DI TI N G, A N D I N S P E C TI N G ..................................................... 9 5  
1 0. 1.  Site M o nit ori n g ..................................................................................................................... 9 5  
1 0. 2.  A u diti n g a n d I ns pecti n g ........................................................................................................ 9 5  
1 1.  
E T HI C A L C O N SI D E R A TI O N S .................................................................................................. 9 5  
1 2.  
S T U D Y FI N A N C E S ....................................................................................................................... 9 6  
1 2. 1.  F u n di n g S o urce ..................................................................................................................... 9 6  
1 2. 2.  C o nflict of I nterest ................................................................................................................ 9 6  
1 2. 3.  P atie nt Sti pe n ds or P a y me nts ................................................................................................ 9 6  
1 2. 4.  St u d y Disc o nti n uati o n ........................................................................................................... 9 6  
1 3.  
P U B LI C A TI O N P L A N ................................................................................................................. 9 6  
1 4.  
R E F E R E N C E LI S T ....................................................................................................................... 9 7  
A p pe n di x 1.  Ne w Y or k He a rt Ass oci ati o n ( N Y H A) F u ncti o n al Cl assific ati o n ................................ 1 0 6  
A p pe n di x 2.  Cl assific ati o n of Gr aft- Vers us- H ost- Dise ase .................................................................. 1 0 7  
 
 
 
 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 5 of 1 0 8  
V ersi o n V 1 2. 0 4 -1 4 -2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
LI S T O F A B B R E VI A TI O N S 
 
A L L  
ac ute l y m p h o blastic le u ke mia  
A P C  
a nti ge n prese nti n g cell  
a A P C  
artificial A P C  
A E  
a d verse e ve nt  
 
B -A L L  
B li nea ge ac ute l e u ke mia  
B -cell A L L 
B cell ac ute l y m p h o blastic le u ke mia  
C A R  
c hi meric a nti ge n rece pt or  
C A R T -1 9 cells  
C D 1 9 re direct e d a ut ol o g o us T cells  
C CI  
Ce nter f or Cell ular I m m u n ot hera pies  
C H O P  
C hil dre n’s H os pital of P hila del p hia  
CI R  
c hi meric i m m u ne rece pt or, i nterc ha n gea ble wit h C A R 
C F R  
c o de of fe deral re g ul ati o ns  
C L L  
chr o nic l y m p h o bl astic le u ke mia  
C M V  
C yt o m e gal o vir us  
C N S  
ce ntral ner v o us s yste m  
C R  
c o m plete re missi o n  
C Ri  
c o m plete re missi o n wit h i nc o m plete bl o o d c o u nt r ec o ver y  
C R F  
case rep ort f or m  
C R P  
C -reacti ve pr otei n 
C R S  
c yt o ki ne rele ase s y n dr o m e  
C S F  
cere bral s pi nal fl ui d  
C T C A E  
c o m m o n t o xicit y criteri a  of a d verse e ve nts  
C T R C  
cli nical a n d tra nslati o nal researc h ce nter  
C T sca n  
c o m p ute d t o m o gra p h y sca n  
C T L  
c yt ot o xic T l y m p h oc yte  
C V P F  
cli nical cell a n d vacci ne pr o d ucti o n facilit y  
C T L  
c yt ot o xic T l y m p h oc yte  
C D 1 3 7  
4 -1 B B c osti m ulat or y m olec ule  
D F S  
disease free s ur vi v al  
D O R  
d urati o n of res p o ns e  
D S M B  
data safet y a n d m o nit ori n g b oar d  
D S M C  
data safet y a n d m o nit ori n g c o m mittee  
E C O G  
Ea ster n C o o perati ve O nc ol o g y Gr o u p 
E F S  
e ve nt  free s ur vi val 
F A S  
f ull a nal ysis set 
F D A  
f o o d a n d dr u g a d mi nistrati o n 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 6 of 1 0 8  
V ersi o n V 1 2. 0 4 -1 4 -2 0 1 7   
 
C O N F I D E N TIA L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
FI S H  
fl u oresce nt i n sit u h y bri dizati o n 
G C P  
g o o d cli nic al practices  
G M P  
g o o d ma n ufact uri n g practices  
G V H D  
graft vers us h ost disease  
H A M A  
h u ma n a nti -m uri ne a nti b o d y  
H S C T  
he mat o p oietic ste m cell tra ns pla ntati o n  
I B C 
I nstit uti o nal Bi osafet y C o m mittee 
I R B 
I nstit uti o nal Re vie w B oar d 
M A S  
macr o p ha ge acti vati o n s y n dr o me  
M R D  
mi ni mal resi d ual disease  
M RI  
ma g n etic res o n a nce i ma gi n g  
N C C N  
Nati o n al C o m pre he nsi ve Ca ncer Net w or k  
O R R  
o verall re missi o n rate  
O S  
o verall s ur vi val  
P B M C  
peri p heral bl o o d m o n o n uclear cells  
P D  
pr o gressi ve dise ase  
P K  
p har mac o ki netics  
P R  
partial re missi o n  
Q o L  
q ualit y of life  
R A C  
NI H Office of Bi otec h n ol o g y Rec o m bi na n t D N A A d vis or y C o m mittee 
R C R/ L  
re plicati o n c o m pete nt le nti vir us 
R F S  
rela pse free s ur vi val 
S A E  
seri o us a d vers e e v e nt 
sc F v 
si n gle c h ai n F v fra g me nt 
S C T  
ste m cell tra ns pla nt 
T C R  
T cell rece pt or  
T C R -
si g nali n g d o mai n f o u n d i n t he i ntracell ular re gi o n of t he T C R zeta, ga m ma 
a n d e psil o n c hai ns  
T C S L  
Tra nslati o nal a n d C orrelati ve St u dies La b orat or y  
T L S  
t u m or l ysis s y n dr o me 
U Pe n n  
U ni versit y of Pe n ns yl v a nia  
V β  
a rearra n ge d T cell s pecific ge ne t hat ca n be use d t o deter mi ne cl o nalit y of a  
T cell p o p ulati o n  
V S V -G  
Vesic ular St o matitis Vir us, Gl yc o pr otei n  
W B C  
w hite bl o o d cell  
 
 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 7 of 1 0 8  
V ersi o n V 1 2. 0 4 -1 4 -2 0 1 7   
 
C O N F I D E N TIA L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
S T U D Y S U M M A R Y A N D S T U D Y S C H E M A 
Title  
P h ase II St u d y Of Re directe d A ut ol o g o us T Cells E n gi neere d T o 
C o nt ai n A nti -C D 1 9 Att ac he d T o T C R  A n d 4 -1 B B Si g n ali n g D o m ai ns 
I n P atie nts Wit h C he m ot her a p y Resist a nt Or Refr act or y Ac ute 
L y m p h o bl astic Le u ke mi a  
S h ort Title  
C D 1 9 re direct e d a ut ol o g o us T cells f or A L L  
Pr ot oc ol N u m bers  
 
 
P hase  
P hase 2  
Met h o d ol o g y  
T his is a si n g le ce nter, si n gle ar m, o pe n-l a bel p hase II st u d y t o deter mi ne 
t he effic ac y a n d safet y of a ut ol o g o us T cells e x pressi n g C D 1 9 c hi meric 
a nti ge n rece pt ors e x pressi n g ta n de m  T C Rζ a n d 4 -1 B B ( T C Rζ/ 4 -1 B B) 
c o-sti m ulat or y d o mai ns (referre d t o as “ C A R T-1 9 ” cells) i n a d ult patie nts 
wit h rela pse d or refract or y B -cell ac ute l y m p h o blastic le u ke mia.  
 
T his pr ot oc ol als o all o ws f or retr eat me nt of a n y s u bject w h o recei ve d 
C A R T -1 9 T -cells an d  has s u bse q ue ntl y rela pse d  wit h C D 1 9 + disease .   
St u d y D urati o n  
T he d urati o n of acti ve pr ot oc ol i nter ve nti o n is a p pr o xi matel y 1 2 -1 5 
m o nt hs fr o m scree ni n g visit. T he pr ot oc ol will re q uire a p pr o xi matel y 
2 4 -3 0  m o nt hs t o c o m plete e nr oll me nt.  
St u d y C e nter(s ) 
Si n gle -ce nter  
O bjecti ves  
 Pri m ar y O bjecti ve  
E val uate t he efficac y of C A R T -1 9 t hera p y as me as ure d b y c o m plet e 
re missi o n rates w hic h i ncl u des c o m plete re missi o n ( C R) a n d C R wit h 
i nc o m plete bl o o d c o u nt rec o ver y ( C Ri) at Da y 2 8 (see Secti o n 6. 15  f or 
res p o nse defi niti o ns).  
 
Sec o n d ar y O bjecti ves:  
1.  E val uate best o verall res p o nse rate.  
2.  E val uate o verall s ur vi val ( O S), d urati o n of re missi o n ( D O R), rela ps e 
free s ur vi val ( R F S), a n d e ve nt free s ur vi val ( E F S). 
3.  Descri be ca use of deat h ( C O D) w he n a p pr o priate.  
4.  Descri be re s p o nse i n ter ms of mi ni mal resi d ual disease ( M R D) 
ne gati ve a n d p ositi ve testi n g usi n g fl o w c yt o metr y (sta n dar d) a n d 
q ua ntitati ve m olec ular tec h n ol o gies ( dee p s e q ue n ci n g).  
5.  E val uate ma n ufact uri n g feasi bilit y of C A R T -1 9.  
6.  Assess safet y a n d t olera bilit y of C A R T -1 9.  
7.  C haracterize t he i n viv o cell ular p har mac o ki netic ( P K) pr ofile (le v els, 
persiste nce, tr affi c ki n g) of C A R T -1 9 cells i n tar get tiss ues ( bl o o d, b o ne 
marr o w, cere bral s pi nal fl ui d a n d ot her tiss ues if a vaila ble).  
8.  Descri be t h e i nci de nce of i m m u n o ge nicit y t o C A R T -1 9, a n d assess 
c orrel ati o n f or i m m u n o ge nicit y wit h l oss of detecta ble C A R T -1 9 (l oss 
of e n graft me nt).  
9.  F or patie nts treate d f or rela pse after all o ge nei c S C T, descri be t he ris ks 
of G V H D.  

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 8 of 1 0 8  
V ersi o n V 1 2. 0 4 -1 4 -2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
1 0.  E val uate bi oacti vit y of C A R T -1 9 cells.  
1 1.  Descri be Patie nt Re p orte d O utc o mes  
1 2.  Assess safet y a n d effi cac y of re -i nf usi o n of C A R T-1 9 cells i n 
pre vi o usl y tr eate d patie nts  
N u m b er of Patie nts  
3 0  e val ua ble s u bjects 
 
Dia g n osis a n d M ai n  
I n cl usi o n Criteria 
I n cl usi o n criteria are d esi g ne d t o i ncl u d e a d ult patie nts a ge d > 1 8 wit h  
B c ell A L L, rela ps e d or refract or y, wit h n o a vaila ble c urati ve tr eat me nt 
o pti o ns (s uc h as a ut ol o g o us or all o ge neic ste m cell tra ns pla ntati o n) w h o 
ha ve li mite d pr o g n osis wit h c urre ntl y a vaila ble t h era pies.  
St u d y Pr o d uct, D ose,  
R o ute, Re gi me n  
C A R T -1 9 cells tra ns d uce d wit h a le nti viral vect or t o e x press a nti -C D 1 9  
sc F v T C R: 4 1 B B a d mi nistere d b y i. v. i nf usi o n.   
 T he first 6 s u bjects recei ve d 1 t o 5 x 1 0 8 tra ns d uce d C A R T cells  
via a si n gle i. v. i nf usi o n .    
 T he ne xt 6  s u bjects recei ved  1 t o 5 x 1 0 7 tra ns d uce d C A R T cells  
via a si n gle i. v. i nf usi o n . 
 T he ne xt 3  s u bjects recei ved  1 t o 5 x 1 0 7 tra ns d uce d C A R T cells 
via s plit d osi n g: 1 0 % o n Da y 1, 3 0 % o n Da y 2, 6 0 % o n Da y 3.  
 T he re mai ni n g s u bjects will recei ve 1 t o 5 x 1 0 8 tra ns d uce d C A R 
T cells via s plit d osi n g: 1 0 % o n Da y 1, 3 0 % o n Da y 2, 6 0 % o n 
Da y  3.  
 
Retreat me nt C o h ort : 
T he tar get d ose f or t his retreat me nt c o h ort will be 1 -5 x 1 0 8 tra ns d uce d 
C A R T cells via s plit d osi n g: 1 0 % o n Da y 1, 3 0 % o n Da y 2, 6 0 % o n 
Da y  3.   S u bjects ma y recei ve eit her m uri ne or h u ma nize d C A R T -1 9 as 
part of t his retreat me nt c o h ort.   F or retreat me nt, prefere nce will be f or 
s u bjects t o recei v e h u ma nize d C A R T-1 9 . If n ot d eter mi ne d t o be feasi ble 
a n d/ or a s u bject h as a d diti o nal cr y o pres er ve d m uri ne C A R T -1 9 d oses 
a vaila ble, t he y will recei ve retr ea t me nt wit h m uri ne C A R T-1 9.    
D urati o n of  
a d mi nistrati o n  
Base d o n t h e t otal v ol u me t o be i nf use d a n d t h e rec o m me n de d i nf usi o n rate 
of 1 0 -2 0 m L per mi n ute  
Refere n ce t hera p y  
N o ne. T his pr ot oc ol will be offere d t o patie nts wit h u n met me dical nee ds 
f or w hic h t here are n o effecti ve t hera pies k n o w n at t his ti me. 
Statistical  
Met h o d ol o g y  
A t otal of 3 0  e val ua ble p atie nts will be treate d.  T h e pri mar y o bjecti ve i n 
t his st u d y is t o deter mi ne o verall c o m plete re missi o n rate ( O R R) at Da y 
2 8. T he t w o -si de d e x act Cl o p per-Pears o n 9 5 % c o nfi de nce i nter vals ( CI) 
f or 2 8-da y O R R will be c o m p ute d.   T he half -wi dt h  of t he 9 5 % e x act 
c o nfi de nce i nter val f or O R R will be n o lar ger t ha n 1 9 %  f or a c o h ort of 
siz e 3 0 a n d n o lar ger t ha n 2 6 % f or a c o h ort of siz e 1 5. 
 
F or t he sec o n dar y effic ac y o bjecti ves, pr o p orti o n of patie nts wit h a best 
o verall disease res p o nse of C R or C Ri, pr o p orti o n of patie nts ac hie vi n g 
C R or C Ri bef ore or at  M o nt h 6, a n d t he pr o p orti o n of patie nts wit h a 
mi ni mal resi d ual disease ( M R D) ne gati ve b o n e marr o w as deter mi n e d 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 9 of 1 0 8  
V ersi o n V 1 2. 0 4 -1 4 -2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
acc or di n g t o Secti o n 6. 1 4  will be c o m p ute d al o n g wit h a t w o -si de d 9 5 % 
e x act CI. Sec o n d ar y ti me t o e ve nt e n d p oi nts i ncl u d e o verall s ur vi val 
( O S), d urati o n of re missi o n ( D O R), rel a pse free s ur vi val ( R F S), a n d 
e ve nt free s ur vi val ( E F S). Ka pla n -Mei er met h o d  will be use d . Me dia n 
s ur vi val ti me a n d t he ass ociate d 9 5 % c o nfi de nce i nter vals will be 
prese nte d if a p pr o priat e d.  I n ci de nce a n d se v erit y of A Es, a n d c h a n ges i n 
la b orat or y val u es a n d vital si g ns fr o m b aseli ne will be s u m marize d a n d 
ta b ulate d. Descri pti ve statistics will be calc ulate d f or c orrelati ve 
e n d p oi nts, ma n ufact uri n g feasi bilit y e n d p oi nt, a n d patie nt re p orte d 
o utc o mes. E x pl orat or y s u bset a nal yses of s afet y a n d efficac y f or 
s pecific d osi n g-gr o u ps [e. g. fracti o nat e d 1 -5 x 1 0 8 ( N = 1 5)] will be 
c o nsi dere d.  
 
Safet y a n d efficac y a n al yses f or s u bjects i n t he retreat me nt c o h ort will 
be e x pl orat or y a n d use d t o ge n erat e h y p ot heses f or f ut ure st u dies.  
Feasi bilit y e n d p oi nts will be a nal yz e d usi n g all patie nts w h o are 
e val uate d f or cell e x pa nsi o n.  
 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 1 0  of 1 0 8 
V ersi o n V 1 2. 0 4 -1 4 -2 0 1 7   
C O N FI D E N TI A L  
T his d oc u me nt is c o nfi de nti al a n d t he pr o pe rt y of t he U ni ve rsit y of Pe n ns yl v a ni a.  N o p art of it m a y be tr a ns mitte d, 
re pr o d uce d, p u blis he d, or use d b y ot he r pers o ns wit h o ut pri or w ritte n a ut h oriz ati o n fr o m t he st u d y s p o ns or.  
1.  I N T R O D U C TI O N 
1. 1. B a c k gr o u n d 
C D 1 9 p ositi ve he mat ol o gic mali g na n cies. B cell mali g na n cies c o m prise a heter o ge n e o us gr o u p of 
ne o plas ms i ncl u di n g a vast maj orit y of n o n- H o d g ki n's l y m p h o mas ( N H L), as well as ac ute 
l y m p h o blastic le u ke mias ( A L L) a n d c hr o ni c l y m p h oc ytic le u ke mias ( C L L). A n esti mate d 8 7, 0 0 0 
ne w cas es of le u ke mia a n d n o n- H o d g ki n’s l y m p h o mas are dia g n ose d i n t he U S a n n uall y 1, a n d 
m ost of t hese are of B cell ori gi n.  C urre nt treat me nts f or B cell 
mali g na ncies i ncl u de 
c he m ot hera p y, ra di ati o n t hera p y, b o n e marr o w tra ns pla ntati o n, a n d peri p heral bl o o d ste m cell 
tra ns pla ntati o n. Des pite t hese treat me nt m o dalities, m ost patie nts will re mai n i nc ura ble. 
 
B li nea ge ac ut e le u ke mia ( B- A L L) is res p o nsi ve t o c he m ot hera p y, h o we ver t he a bilit y t o 
u nif or ml y era di cate t he disease h as n ot bee n ac hie ve d as a b o ut 6 5 % of a d ults a n d 2 0 % of c hil dre n 
ha ve diseas e rec urre nce 2, 3. I m pr o v e d res p o ns e rates ha v e t h us far o nl y bee n ac hie ve d wit h 
i nte nsifie d c yt ot o xic c he m ot hera p y, res ulti n g i n s u bsta ntial m or bi dit y. A d o pti ve i m m u n ot hera p y 
wit h all o ge n eic d o n or l e u k oc yt es has p ote nt a nti-l e u ke mic effects, h o we ver t he be nefit is c o nfi ne d 
lar gel y t o patie nts wit h m yel oi d le u k e mias, as B- A L L has a d ura ble re missi o n rate of l ess t ha n 
1 0 % 4, a n d ofte n at t he c ost of s u bsta ntial m or bi dit y d ue t o graft vers us h ost disease ( G V H D)5, 6. 
 
A d o pti ve i m m u n ot hera p y.  A d o pti ve tra nsfer is a ter m c oi ne d b y Me d a war 7 t o st u d y all o graft 
rejecti o n, a n d t he ter m a d o pti ve i m m u n ot hera p y de n otes t he tra nsfer of i m m u n oc o m pete nt cells 
f or t he treat me nt of ca ncer or i nfecti o us disease8. A d o pti ve i m m u n ot hera p y a p pears t o be t he m ost 
r o b ust f or m of i m m u n ot hera p y f or treat me nt of esta blis he d t u m ors9, as p o werf ul effects ha ve bee n 
n ote d i n patie nts wit h metastatic mela n o ma after t he a d o pti ve tra nsfer of t u m or i nfiltrati n g 
l y m p h oc ytes a n d ge ne m o difie d peri p heral bl o o d T cells1 0.  H o we ver, se veral pr o ble ms re mai n t o 
be s ol ve d bef ore t his t hera p y b ec o mes r o uti ne; see re vie ws f or details 1 1 -1 3. 
 
C D 1 9 as a t hera pe utic tar get f or le u ke mia a n d l y m p h o ma. C D 1 9 is a 9 5 k Da gl yc o pr otei n prese nt 
o n B cells fr o m earl y de v el o p me nt u ntil differe ntiati o n i nt o plas ma cells 1 4 -1 6. It is a me m ber of t he 
i m m u n o gl o b uli n (I g) s u perfa mil y a n d a c o m p o ne nt of a cell s urface si g nal tra ns d ucti o n c o m ple x 
t hat re g ul ates si g nal tra ns d ucti o n t hr o u g h t he B cell rece pt or1 4, 1 7, 1 8. Mice lac ki n g C D 1 9 ha ve a 
decrease d n u m ber of B cells i n peri p heral l y m p h oi d tiss ues, a decrease d B cell res p o nse t o oral 
vacci nes a n d mit o ge ns, a n d decrease d ser u m I g le vels 1 4, 1 9. E x pressi o n of C D 1 9 is restricte d t o B 
li nea ge cells a n d is n ot e x presse d b y pl uri p ote nt bl o o d ste m cells2 0. C D 1 9 is als o e x presse d b y 
m ost B cell l y m p h o mas, ma ntle cell l y m p h o ma, A L Ls, C L Ls, hair y cell le u ke mias, a n d a s u bset 
of ac ute m yel o ge n o us le u ke mias 1 5, 2 1, 2 2. C D 1 9 t h us re prese nts a hi g hl y attracti ve tar get f or 
i m m u n ot hera p y2 0. F urt h er m ore, C D 1 9 is n ot pr ese nt o n m ost n or mal tiss ues, ot her t h a n n or mal B 
cells, i ncl u di n g pl uri p ote nt bl o o d ste m cells 2 0, w hic h ma kes C D 1 9 a relati vel y s afe tar get 
prese nti n g a mi ni mal ris k of a ut oi m m u ne dise ase or irre versi ble m yel ot o xicit y. A nti- C D 1 9 
a nti b o dies a n d sc F vs eit her nati ve or c o nj u gat e d t o ra di ois ot o pes or t o xi ns are c urre ntl y b ei n g 
de vel o pe d a n d ha v e de m o nstrate d pr o mise i n b ot h m o use m o dels 2 3 -2 7  a n d h u ma n a n d n o n- h u m a n 
pri mates 2 8 -3 8. 
 
E n gi ne ere d T cells wit h re directe d s pecifi cit y: c hi meric a nti ge n rece pt ors ( C A Rs). As s h o w n i n 
Fi g ure 1- 1 , t he C A R a p pr oac h uses ge n eticall y pr o gra m me d, p atie nt- deri ve d l y m p h o c ytes 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 1 1  of 1 0 8 
V ersi o n V 1 2. 0 4 -1 4 -2 0 1 7   
 
C O N F I D E N TIA L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
tra nsfect e d wit h c hi meric rece pt or ge nes t o c o m bi ne t he 
effect or f u ncti o ns of T l y m p h oc ytes wit h t he hi g h s pecificit y 
a nti b o d y rec o g niti o n of pre defi n e d s urface a nti ge ns i n  a  n o n-
M H C  restrict e d ma n ner
3 9, 4 0. I n pri n ci ple, u ni vers al tar geti n g 
vect ors ca n be c o nstr ucte d beca us e t he C A R’s s c F v re gi o n 
bi n ds t o nati ve cell s urface e pit o pes a n d b y pass es t he nee d f or 
s pecific a nti ge n pr ocessi n g. T he s c F v re gi o n is e n gi neere d f or 
t u m or bi n di n g f u ncti o n a n d c o ntai ns t he VH a n d V L c h ai ns 
j oi ne d b y a pe pti de li n ker of a b o ut 1 5 resi d ues i n le n gt h4 1. 
First ge nerati o n C A Rs c o ntai n a mi ni mal T cell rece pt or 
( T C R) si g nali n g d o mai n c o nsisti n g of 
T C Rζ. Sec o n d 
ge n erati o n C A Rs c o ntai n d o u ble c osti m ulat or y si g nali n g 
d o mai ns s uc h as C D 2 8 a n d T C Rζ or 4- 1 B B a n d T C Rζ. T hir d 
ge n erati o n 
C A Rs c o ntai n tri ple c osti m ulat or y 
m o d ules 
c o m prise d of C D 2 8, 4- 1 B B, a n d T C Rζ. See re vie ws of C A Rs 
f or details1 1, 4 2- 4 5.  
 
Rati o nale t o e val uate C A R T- 1 9 i n patie nts wit h c he m ot hera p y resista nt or refract or y a d ult A L L. 
O utc o me re mai ns p o or f or a d ult patie nts wit h rela pse d or r efract or y (r/r), B cell ac ute 
l y m p h o blastic le u ke mia ( B cell A L L). Treat me nt o pti o ns f or r/r B-cell A L L i ncl u de f urt h er 
treat me nt wit h s al va ge c he m ot hera p y, a 2 n d all o ge n eic h e mat o p oietic ste m cell tra ns pl a ntati o n 
( H S C T) or s u p p orti ve care. F or t his p o p ulati o n, 5 yr o verall s ur vi v al ( O S) after rel a pse is esti mate d 
at 7 % 4 6.  F or t he s mall mi n orit y of p atie nts wit h rel a pse d A L L w h o h a ve a d o n or i de ntifie d a n d g o 
o n t o tra ns pla nt, O S is esti mate d at 2 3 % a n d t h ose patie nts w h o recei v e c h e m ot hera p y o nl y is 4 %.  
T heref ore, t he ris k: be nefit rati o f or a n o vel t hera p y wit h t he p ot e ntial t o i n d uce re missi o n i n A L L 
is q uite fa v ora ble. 
 
M ore o ver, i n o n g oi n g cli nical trials wit h C A R T- 1 9, T cells e x pressi n g a sec o n d ge n erati o n C A R 
wit h a n a nti- C D 1 9 sc F v a n d 4- 1 B B a n d T C R si g n ali n g d o mai ns, i n patie nts wit h B-cell A L L a n d 
C L L ( b ot h C D 1 9 e x pressi n g B cell mali g na nci es) s h o w t hat C A R T- 1 9 t h era p y h as p ote nt a nti-
t u m or acti vit y i n pe di atric a n d a d ult p atie nts4 7, 4 8 ( descri be d i n d etail i n Secti o n 1. 4). Ei g htee n a d ult 
C L L s u bjects are e v al ua ble as of A pril 2 0 1 3 a n d i n cl u de: 5 C R, 6 P R, a n d 7  N R t o gi ve a n o verall 
res p o nse rate of 1 1/ 1 8 ( 6 1 %). Of t he ni n e e val u a ble pe diatric B cell A L L pati e nts, 7 C R, 1 P R a n d 
1 N R ha ve bee n re p orte d f or a n o v erall res p o nse rate of 8/ 9 ( 8 9 %).  T he o ne a d ult A L L patie nt 
treate d re mai ns i n C R after 2 m o nt hs of f oll o w u p a n d has g o n e o n t o ha ve a n all o ge neic S C T; of 
n ote, he was c o nsi dere d pre vi o usl y i neli gi ble f or all o ge n eic S C T bef ore C A R T 1 9 cell i nf usi o n 
beca use of his refract or y disease.  
 
F or A L L patie nts, t here is little be nefit fr o m all o ge neic S C T wit h rela pse d a n d acti ve diseas e a n d 
ma n y ce nters, d o n ot offer patie nts i n t his sit uati o n tra ns pla ntati o n beca use of f utilit y. T heref ore, 
a n y b e nefit t hat ma y b e s ee n wit h C A R T- 1 9 cells will ha ve a maj or i m pact f or patie nts.  
1. 2. I n v e sti g ati o n al A g e nt 
T he i n vesti gati o nal a ge nt i n t his pr ot oc ol is C A R T- 1 9 cells.   A ut ol o g o us T cells will be e n gi neere d 
usi n g a le nti viral vect or t o e x press a n e xtracell ular si n gle c h ai n a nti b o d y (sc F v) wit h s pecificit y 
f or C D 1 9. T his will be e x pecte d t o re direct s pecificit y of t he tra ns d u ce d T cells f or cells t hat 
 
Fi g.  1 -1 .  C A R d e s ig n.  B i s pe ci fic  T  
c ell s a r e c re a te d  b y t h e  in tro d u c tio n  o f 
g e n e s  e n c o d in g  C A R p ro te in s  th a t 
re c o g ni z e t a rg e t s u rfa c e  a n tig e n s in a n  
M H C -i n d e pe n d e n t fa s h i o n. 
 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 1 2  of 1 0 8 
V ersi o n V 1 2. 0 4 -1 4 -2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
e x press C D 1 9, a m olec ul e t hat is restri cte d i n e x pressi o n o n t he s urface of t he mali g n a nt cells a n d 
o n n or mal B cells. I n a d diti o n t o t he C D 1 9 sc F v, t he cells will be tr a ns d uce d t o e x press a n 
i ntracell ular ta n d e m si g n ali n g d o mai n c o m prise d of 4- 1 B B a n d T C Rζ si g n ali n g m o d ules.  Cli nical 
gra de C D 1 9 T C Rζ/ 4- 1 B B le nti viral v ect or will be ma n ufact ure d at t he C hil dre n’s H os pital of 
P hila del p hia ( C H O P) a n d Cit y of H o pe Ce nter f or A p plie d Tec h n ol o g y De v el o p me nt. T he 
e xtracell ular si n gle c h a n ge a nti b o d y (sc F v) wit h s pecificit y f or C D 1 9 is deri ve d fr o m a m o use 
m o n ocl o nal a nti b o d y usi n g h y bri d o ma cell li ne F M C 6 3 descri be d i n Nic h ols o n et al.
4 9 or will be 
a h u ma nize d versi o n of t hat s e q ue n ce de vel o pe d b y N o vartis Bi o me dical I nstit utes of Researc h. 
T he h u ma nize d versi o n will o nl y b e use d i n t he retreat me nt c o h ort. T he si g nali n g d o mai ns are 
e ntirel y of t he nati ve h u ma n se q ue nces 5 0, 5 1.   
 
T he C A R T- 1 9 cells will be ma n ufact ure d i n t he Cli nical Cell a n d Vacci ne Pr o d ucti o n Facilit y at 
t he U ni versit y of Pe n ns yl va nia. At t he e n d of cell c ult ures, t he cells are cr y o preser ve d i n i nf usi ble 
cr y o me dia. T he i nf usi o n ba g/s yri n ge will c o ntai n a n ali q u ot ( v ol u me d e pe n de nt u p o n d os e) of 
cr y o me dia c o ntai ni n g t he f oll o wi n g i nf usi ble gra de rea ge nts ( % v/ v): 3 1. 2 5 %   plas mal yte-
A, 3 1. 2 5 % de xtr ose ( 5 %), 0. 4 5 % Na Cl, 7. 5 % D M S O, 1 % de xtra n 4 0, 5 % h u ma n ser u m al b u mi n.   
 
Mec ha nis m of acti o n. Re directe d T cells ha ve bee n s h o w n i n e x peri me ntal m o dels t o bi n d t o cells 
t hat e x press t he tar get a nti ge n. O ver t he p ast deca de, C A Rs direct e d a gai nst a wi de v ariet y of 
t u m or a nti ge ns ha ve bee n de vel o pe d5 2, 5 3. T here are s e veral p ote ntial li mitati o ns t o t he C A R T 
cells: 1) t he t u m or m ust e x press t he tar get a nti ge n o n t he cell s urface; 2) lar ge a m o u nts of s he d or 
s ol u ble a nti ge n c o ul d i n hi bit t he C A R T cells; 3) t he c hi meric rece pt or ma y be i m m u n o ge nic, 
res ulti n g i n t he eli mi nati o n of t he re dir ecte d T cells b y t he h ost i m m u ne s yste m. 
 
A bs or pti o n, distri b uti o n a n d meta b olis m. L y m p h oc yt es ha ve c o m ple x traffic ki n g a n d s ur vi val 
ki netics, a n d after a d o pti ve tra nsf er se veral fates ha ve b ee n d e m o nstrate d: 1) mar gi nati o n; 2) e xit 
fr o m t he peri p heral bl o o d traffic ki n g t o l y m p h oi d tiss ues; a n d 3) deat h b y a p o pt osis. F oll o wi n g a n 
i ntra ve n o us d ose, retr o virall y m o difie d a n d a d o pti vel y tra nsferre d T cells ha ve bee n s h o w n t o 
persist i n t he circ ulati o n f or at least 1 0 years i n i m m u n o deficie nt S CI D patie nts d ue t o t he 
re plicati ve c o m p ete nce of T cells5 4. H u ma n C D 8 C T Ls ha ve a n eli mi nati o n half-life fr o m t he 
peri p heral bl o o d of a b o ut 8 da ys, a n d t his i ncreas es t o a b o ut 1 6 d a ys w he n l o w d oses of I L- 2 are 
gi ve n 5 5. I n p atie nts wit h HI V i nfecti o n, it was deter mi ne d t hat t he mea n half-life of l e nti virall y 
m o difie d C D 4 T cells i n t he circ ulati o n of 5 patie nts f oll o wi n g a si n gl e i nf usi o n was 2 3. 5 ( ± 7. 7) 
da ys i n p atie nts.  A d o pti vel y  tr a nsferre d  h u ma n  T  cells  ha ve  bee n  s h o w n  t o  traffi c  t o  t u m or  
a n d sec o n dar y l y m p h oi d tiss ues 5 5 -5 8. 
 
Dr u g i nteracti o ns. C A R T- 1 9 cells are e x pecte d t o retai n ma n y of t he pr o perties of nat ur al T cells. 
As s uc h, t he y will be e x pecte d t o be s usce pti ble t o i m m u n os u p pressi ve a ge nts s uc h as 
c ortic oster oi ds, i m m u n o p hili ns s uc h as c ycl os p ori n e a n d tacr oli m us, met h otr e x ate, m yc o p h e n olate 
m ofetil, m T O R i n hi bit ors s uc h as ra pa m yci n, ale mt uz u ma b, dacliz u ma b, o nta k. L y m p h oc ytes are 
es peciall y s usce pti ble t o c yt ot o xic a n d c he m ot hera pe utic a ge nts t hat are c o m m o nl y a d mi nistere d 
f or he mat ol o gic mali g na ncies s uc h as c ycl o p h os p ha mi de a n d fl u dara bi ne. 
 
I m m u ne eli mi nati o n. A n i m p orta nt c o nsi derati o n is t hat t he C A R c a n be i m m u n o ge nic, eit her 
beca use f orei g n se q ue n ces s uc h as a nti bi otic selecti o n ge n es or m o use a nti b o d y s e q ue nces are 
e x presse d, or beca use of n o vel e pit o pes t hat are creat e d at t he f usi o n j oi nt of h u ma n si g n ali n g 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 1 3  of 1 0 8 
V ersi o n V 1 2. 0 4 -1 4 -2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
d o mai ns t hat are n ot n or mall y j u xta p ose d. I m m u n o ge ni cit y of t he C A R ca n lea d t o t he rejecti o n 
of t he a d o pti vel y tr a nsferre d T cells. T he basis f or t his s u p p ositi o n is t hat h u ma n retr o virall y-
m o difie d C T Ls e x pressi n g a f usi o n pr otei n c o nsisti n g of h y gr o m yci n: H S V t h y mi di ne ki nase were 
eli mi nate d b y h ost C T Ls i n patie nts wit h a d v a n ce d HI V i nf ecti o n 5 9; i m p orta ntl y, t his i m m u ne 
me diate d eli mi nati o n was n ot acc o m pa nie d b y a d verse eff ects a n d re q uire d 6 t o 8 wee ks t o occ ur.  
It is i m p orta nt t o n ote t hat it is p ossi ble t he C A R T- 1 9 T cells ma y be rejecte d i n patie nts. 
 
Rati o nale f or l y m p h o de pleti o n. A d o pti ve i m m u n ot hera p y strat e gies ma y b e a ble t o ca pitalize o n 
h o me ostatic T cell pr oliferati o n 6 0, a rece nt fi n di n g t hat nai ve T cells be gi n t o pr oliferat e a n d 
differe ntiat e i nt o me m or y-li ke T cells w he n t otal n u m bers of nai ve T cells are re d u ce d b el o w a 
certai n t hres h ol d 6 1, 6 2. L y m p h o de pleti o n eli mi nates re g ulat or y T-cells a n d ot her c o m peti n g 
ele me nts of t h e i m m u ne s yste m t hat act as “c yt o ki ne si n ks”, e n h a nci n g t h e a vaila bilit y of c yt o ki nes 
s uc h as I L- 7 a n d I L- 1 5 6 3. T his h y p ot h esis has bee n teste d cli nicall y i n patie nts wit h metastatic 
mela n o ma refract or y of c o n ve nti o nal treat me nts 5 6. T he patie nts recei v e d a l y m p h o d e pleti n g 
c o n diti o ni n g re gi me n c o nsisti n g of c ycl o p h os p ha mi de ( 6 0 m g/ k g x 2 da ys) a n d fl u dara bi ne ( 2 5 
m g/ m 2 x 5 da ys) pri or t o a d o pti ve tra nsfer of T c ells. Patie nts wit h m yel o m a, N H L, a n d C L L ha v e 
bee n tr eate d wit h i nf usi o ns of e x- vi v o c o-sti m ulate d a n d e x pa n de d a ut ol o g o us T cells after 
l y m p h o de pleti n g c he m ot hera p y, a n d o bser ve d i m pr o ve d e n graft me nt6 4 -6 7. I n t his pr ot oc ol tra nsfer 
C A R T- 1 9 cells i nt o s u bjects t hat are gi ve n l y m p h o de pleti n g c he m ot hera p y .  T his a p pr oac h has 
bee n ta ke n wit h pre vi o us reci pie nts of C A R T 1 9 cells (secti o n 1. 4 bel o w).  Rece nt data i n dicates 
t hat t he i ncrease d a ntit u m or effic ac y of a d o pti ve tra nsfer f oll o wi n g h ost c o n diti o ni n g is m ore t ha n 
si m pl y “ ma ki n g r o o m” b eca use t he q ua ntitati ve rec o ver y of a d o pti vel y tra nsferre d T cells i n mice 
re veals t h at i n vi v o pr oliferati o n f oll o wi n g a d o pti ve tra nsfer is i de ntical i n mice wit h or wit h o ut 
pre vi o us irra diati o n. 
1. 3. Pr e cli ni c al D at a 
E xte nsi ve literat ure s u p p orts t he use of e n gi neere d T cells f or t u m or i m m u n ot hera p y i n r o de nt 
t u m or m o dels, re vie we d6 8 -7 2. Ot hers ha ve use d electr o p orati o n or retr o viral vect ors t o create 
C A R T- 1 9 T cells, a n d ha ve s h o w n i n vi v o safet y a n d effi cac y of a d o pti vel y tra nsferre d T cells i n 
i m m u n o deficie nt m o use m o dels7 3 -7 7.   T he i nc or p orati o n of si g nali n g m o d ules s uc h as C D 2 8 a n d 
4 - 1 B B i n 2n d ge nerati o n C A Rs i ncreases p ote nc y of t he e n gi neere d T cells i n pre- cli nical st u dies7 8 -
8 4. T he pre-cli nical data s u p p orti n g C A R T- 1 9 has bee n p u blis he d5 1, 8 5. 
1. 4. Pr e vi o u s Cli ni c al D at a wit h C A R T- 1 9 c ell s 
 
 
 
 
  
 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 1 4  of 1 0 8 
V ersi o n V 1 2. 0 4 -1 4 -2 0 1 7   
 
C O N F I D E N TIA L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 1 5  of 1 0 8 
V ersi o n V 1 2. 0 4 -1 4 -2 0 1 7   
 
C O N F I D E N TIA L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 1 6  of 1 0 8 
V ersi o n V 1 2. 0 4 -1 4 -2 0 1 7   
 
C O N F I D E N TIA L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
C R S has bee n t he m ost si g nifica nt S A E see n i n a d ult a n d pe diatri c patie nts treate d wit h C A R T- 1 9 
has bee n o n tar get C R S.  C R S is descri be d i n details bel o w (secti o n 1. 5. 2) b ut t y picall y be gi ns u p 
t o 2 wee ks after C A R T- 1 9 i nf usi o n. T he C R S t y picall y starts wit h s e veral da ys of fe v ers.  I n all 
cases, e v al uati o n f or i nfecti o ns are d o ne.  Fe v ers te n d t o be s pi ki n g a n d ca n be ass ociate d wit h 
ri g ors, a n ore xia, na usea, diarr hea, dia p h oresis, ca pillar y lea k, h y p o xia a n d h y p ote nsi o n.  I n se veral 
cases I C U l e vel c are, v e ntilat or s u p p ort a n d press ors ha ve b ee n nee de d.  O bser vati o ns ha ve n ot e d 
e x peri me ntall y v er y hi g h le vels of I L 6 d uri n g t he C R S.  I n a d diti o n, t he reacti o n t y picall y a p pears 
t o be ass ociate d wit h M A S.  T his ca n be ma nifest b y e vi de nce of he m ol ysis, c yt o pe nias, el e vate d 
ferriti n, altere d me ntal st at us, a n d ot her c o m plicati o ns. 
 
C R S/ M A S was ma na ge d i n 1 patie nt i nitiall y wit h c ortic oster oi ds.  S u bse q ue ntl y, as m or e data 
beca me a v aila ble, it h as bee n s uccessf ull y ma na ge d wit h s u p p orti ve care a n d w he n n ee de d, 
t ociliz u ma b t hera p y.  T ociliz u ma b is a n a nti-I L 6 rece pt or a nti b o d y a n d has bee n a d mi nistere d at a 
d ose of 4 t o 8 m g/ k g. T his ma y be prefera ble t o s yste mic i m m u n os u p pressi o n wit h c ortic ost er oi ds. 
I n ma n y cases, C R S  has bee n se vere b ut re versi ble.  H o we ver t here ha v e bee n se veral cas es of 
refract or y C R S t hat res ulte d i n deat h.  It is h y p ot h esiz e d t his ma y be relate d t o t u m or b ur de n, s o 
t hat treati n g p atie nts wit h less t u m or b ur de n m a y res ult i n less s e vere c yt o ki ne rel ease s y n dr o me. 
H o we ver, a d diti o nal c o ntri b ut or y p atie nt a n d C A R T- 1 9 relate d fact ors ca n n ot be r ule d o ut.   
Si nce C R S mec ha nisticall y is a re q uire d part of t he a ntit u m or mec ha nis m of i n viv o C A R T- 1 9 cell 
e x pa nsi o n a n d t u m or killi n g, t ociliz u ma b was a d mi nistere d f or C R S wit h w orse ni n g res pirat or y 
distress, i ncl u di n g p ul m o nar y i nfiltrates, i ncreasi n g o x y ge n re q uire me nt i ncl u di n g hi g h-fl o w 
o x y ge n a n d/ or n ee d f or mec ha nic al ve ntilati o n or he m o d y na mic i nsta bilit y d es pite i ntra ve n o us 
fl ui ds a n d m o derate vas o press or s u p p ort or ra pi d cli nical deteri orati o n. Ster oi ds f oll o wi n g C A R T-
1 9 i nf usi o n were a v oi d e d a n d gi ve n o nl y u n der life t hreate ni n g sit uati o ns d ue t o t he k n o w n  
l y m p h ol ytic effects.  
1. 5. D o s e R ati o n al e a n d Ri s k/ B e n efit s 
We ha ve c h ose n t o use s plit d osi n g via a n i ntra ve n o us r o ute of a d mi nistrati o n f or t his pr ot oc ol. 
T he d ose t hat was i nitiall y sele cte d f or a d mi nistrati o n wa s a si n gle d ose of 1- 5 x 1 08 C A R T- 1 9 cells.  
As part of pr ot oc ol versi o n 5  date d J u ne 1 9, 2 0 1 4, t he d ose was re d uce d t o a si n gle d ose of 1- 5 x 
1 0 7 C A R T- 1 9 cells.  I n t he pr ot oc ol a me n d me nt date d N o ve m ber 2 1, 2 0 1 4, t he d ose re mai ne d 1-
5 x 1 0 7 C A R T- 1 9 cells, b ut was re vise d t o be a d mi nistere d via s plit d osi n g: 1 0 % o n Da y 1, 3 0 % 
o n Da y 2, 6 0 % o n Da y 3.   I n t he pr ot oc ol a me n d me nt date d Ma y 5, 2 0 1 5, t he d ose was c ha n ge d 
t o 1- 5 x 1 08 C A R T- 1 9 cells a d mi nistere d via s plit d osi n g: 1 0 % o n Da y 1 ( 1- 5 x 1 07), 3 0 % o n Da y 
2  ( 3 x 1 07- 1. 5 x 1 08), 6 0 % o n Da y 3 ( 6 x 1 07- 3 x 1 08).  T he c urre nt d ose is t he sa me d ose a n d s plit 
fracti o n a d mi nistrati o n sc he d ule t hat t he first si x a d ult s u bjects were tr eate d wit h o n t he first 
C A R T 1 9 pr ot oc ol, U P C C 0 
 All si x of t h ose s u bjects ac hie ve d c o m plete res p o nses a n d 
recei v e d eit her t he 1 0 % fracti o n o nl y or all t hree d ose fracti o ns. 
1. 5. 1. D o s e R ati o n al e 
A ni mal st u dies s u p p ort a t hres h ol d d ose of C A R T- 1 9 cells a n d t heref ore t he i nitial cli nical d ose 
selecti o n was wit hi n t he ra n ge of 1 x 1 0 7 t o 1 x 1 09 C A R T- 1 9 tra ns d uce d cells. F or safet y reas o ns, 
i nitial p hase I d osi n g was di vi de d a m o n g t hree s plit i nf usi o ns ( 1 0 %, 3 0 % a n d 6 0 % of t he t otal 
d ose). Ma n y p atie nts faile d t o recei ve m or e t ha n t he i nitial d ose d ue t o t he o nset of fe vers, yet 
effic ac y res p o nses were o bser ve d. P has e II a d ult p atie nt d osi n g has utilize d eit her a si n gle i nf usi o n 
or s plit d osi n g a d mi nistrati o n of 1- 5 x 1 0 7 or 1- 5 x 1 08 C A R T- 1 9 tra ns d uce d cells t o st u d y d ose 
o p ti mizati o n wit h g o o d cli nical t olera nce. N o si g nifica nt i nf usi o nal t o xicities ha ve bee n o bser ve d.   

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 1 7  of 1 0 8 
V ersi o n V 1 2. 0 4 -1 4 -2 0 1 7   
 
C O N F I D E N TIA L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
I n m ulti ple a d ult patie nts wit h C L L ( U P C C 
 a n d U P C C 
2) a n d i n t he si x a d ult A L L 
patie nt treate d as of D ece m ber 2 0 1 4 ( U P C C 
),  as well as ma n y pe diatric A L L p atie nts 
( C H P 9 5 9), cli nical res p o nses at d os es ra n gi n g fr o m 1. 4 x 1 07 t o 1. 1 x 1 09 C A R T- 1 9 cells h a ve bee n 
o bser ve d e ve n after a si n gle i nf usi o n.  I n a n  i nitial pil ot trial, t he me dia n C A R T 1 9 cell d ose i nf use d 
was 1. 6 x 1 0 8 cells. N o o b vi o us d ose:res p o nse relati o ns hi p ca n be i de ntifie d.  U nli ke sta n dar d dr u gs 
t hat are m eta b oliz e d, C A R T cells are a ble t o pr oliferate e xte nsi vel y i n t he patie nts. T h us, t he 
a d mi nistere d d ose ma y u n deresti mate t he n u m ber of C A R T- 1 9 T cells  i n viv o f oll o wi n g 
e n graft me nt a n d e x pa nsi o n a n d will var y fr o m patie nt t o patie nt.    
 
 
T he first 6 A L L p atie nts treate d o n t his pr ot oc ol recei ve d a si n gle d ose of 1 - 5 x 1 08 C A R T- 1 9 T-
cells. T he s ec o n d 6 A L L patie nts treate d o n t his pr ot oc ol recei ve d a si n gle re d uce d d ose of 1 - 5 x 
1 0 7 C A R T- 1 9 T-cells.  T his c ha n ge was i m ple me nte d i n res p o nse t o t hree patie nt deat hs at t he 1-
5 x 1 0 8 d ose le vel, w hic h were felt t o be p ossi bl y relate d t o refract or y c yt o ki ne release s y n dr o me , 
a n e x pecte d t o xicit y of C A R T- 1 9 T-cells. We h y p ot hesize d  t hat t his re d uce d cell d ose w o ul d elicit 
t he sa me cli nical res p o ns es see n at t he hi g her d ose le vel a n d i n pil ot trials of C A R T- 1 9, b ut res ult 
i n less ra pi d a n d se v ere c yt o ki ne releas e s y n dr o m e t hat c o ul d be b etter c o ntr olle d.  T w o s u bjects 
treate d at t he re d u ce d d ose die d fr o m a n i ntracra nial blee d a n d se psis, res pecti vel y.   W hile t he 
relati o ns hi p of t hese deat hs t o t he i nf use d d ose of C A R T- 1 9 cells is u ncertai n, a relati o ns hi p ca n n ot 
be e x cl u de d, pr o m pti n g a n a d diti o nal m o dificati o n of t he d osi n g sc h e me.  I n or der t o li mit d ose 
relate d t o xicit y, t he d osi n g re gi me n was m o difie d i n a pr ot oc ol a m e n d me nt date d N o ve m ber 2 1, 
2 0 1 4, t o be a d mi nistere d at a re d uce d d ose of 1- 5 x 1 0 7 C A R T- 1 9 cells via s plit d osi n g: 1 0 % o n 
Da y 1, 3 0 % o n D a y 2, 6 0 % o n Da y 3.   As t his d osi n g re gi me n has pr o ve n t o be safe, t h e d ose was 
re-es calate d t o 1- 5 x 1 08 [ as of t he pr ot oc ol a me n d me nt date d 5/ 0 5/ 2 0 1 5] a d mi nistere d vi a s plit 
d osi n g :  1 0 % o n Da y 1 ( 1- 5 x 1 0 7), 3 0 % o n Da y 2 ( 3 x 1 07- 1. 5 x 1 08), 6 0 % o n Da y 3 ( 6 x 1 07- 3 x 1 08). 
1. 5. 2. Ri s k s/ B e n efit s 
Safet y i nf or mati o n o utli ne d i n t he ris k secti o n is lar gel y re pres e ntati ve of t he m uri ne C A R T- 1 9 
e x perie nce.  Base d o n o ur li mite d e x perie nce t h us far wit h h u ma nize d C A R T- 1 9, n o u ne x pecte d 
e ve nts ha ve bee n o bser ve d.  Peri o dic safet y re vie w will be perf or me d a n d t he ris k la n g ua ge will 
be u p date d acc or di n gl y.  
 
P ote ntial Ris ks.  Partici pati o n i n t his st u d y will e x p ose t he p atie nt t o ge neticall y e n gi neere d 
a ut ol o g o us T cells. T he ris k of a d mi nisteri n g u n m o difie d cells al o ne is l o w base d o n e xte nsi ve 
past cli nical e x perie nce. O ne u n k n o w n ris k is t hat T cell pr oliferati o n c o ul d be u nc o ntr olle d, 
h o we ver it has n ot bee n o bser ve d i n pre-cli nical m o dels. I n t his cas e, c ortic oster oi ds, a nti-c yt o ki ne 
t hera p y, a n d c h e m ot hera p y w o ul d be gi ve n t o era dicate t he C A R cells; t his has w or k e d i n pre vi o us 
cases 4 7.  It is p ossi ble t he cells ma y b e i m m u n o ge nic, a n d t hat t h e patie nts will ha ve a n i m m u ne 
res p o nse directe d a gai nst t he sc F v; t his has n ot ha d cli nical c o nse q ue n ces i n pre vi o us trials. If a n 
i m m u ne res p o nse t o t he cells occ urs, it is p ossi ble t hat t he cells will be reject e d. T hree of 3 patie nts 
de vel o pe d H u m a n A nti- M uri ne A nti b o d y ( H A M A) a n d l oss of T cell e n graft me nt i n t he La mers 
st u d y, b ut t his has ge n erall y n ot bee n a n iss ue i n patie nts wit h B cell mali g na n cies. Tra nsie nt or 
per ma ne nt h ost B cell de pleti o n is als o a p ote ntial ris k wit h C A R T- 1 9 cells, si nce n or mal B cells 
e x press C D 1 9.  T his is e x pecte d t o res ol ve w he n t he C A R T- 1 9 cells are cleare d.  Persiste nt B cell 
a plasia le a ds t o h y p o ga m ma gl o b uli ne mia a n d ma y i n crease t he ris k of i nfecti o n. T his ca n be 
ma na ge d 
wit h I VI G re pleti o n. I n pre vi o us trials, res p o n di n g 
C L L patie nts 
w h o are 
h y p o ga m ma gl o b uli ne mic ha ve recei ve d I VI G. N o si g nifica nt u n us ual i nf ecti o n patter ns ha ve bee n 
i de ntifie d. 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 1 8  of 1 0 8 
V ersi o n V 1 2. 0 4 -1 4 -2 0 1 7   
 
C O N F I D E N TIA L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
Tra nsf or mati o n . T here is a ris k t hat p e o ple w h o recei ve ge n e tra nsfer ma y de vel o p n e w t u m ors 
deri ve d fr o m t heir ge n eticall y m o difie d cells. T his ris k is pri maril y ass ociate d wit h vir al ge n e 
tra nsfer v ect ors t hat i nte grate i nt o t he cell ular D N A w here t he y ma y d ysre g ulate ge nes c o ntr olli n g 
pr oliferati o n. Tra nsf or m ati o n has n ot bee n o bser ve d f oll o wi n g a d o pti ve T cell tra nsfer i n h u n dre ds 
of ca ncer a n d HI V pati e nts recei vi n g ga m maretr o viral m o difie d T cells treate d o n m ulti ple 
pr ot oc ols at ma n y aca d e mic ce nters 8 6, a n d i n t he 2 1 HI V patie nts treate d wit h le nti viral m o difie d 
T cells treate d at Pe n n 8 7. 
    
Ge neral Safet y . At t he U ni versit y of Pe n ns yl va nia > 2 0 p atie nts wit h HI V i nfecti o n ha ve bee n 
treate d wit h a ut ol o g o us T cells m o difie d wit h le nti viral vect or. I n t he first pr ot oc ol, eac h s u bject 
recei v e d a si n gle i. v. i nf usi o n of 1 x 1 01 0 le nti viral m o difie d T cells; i n t he sec o n d pr ot oc ol, eac h 
s u bject recei ve d u p t o 6 d oses of 0. 5- 1 x 1 0 1 0 cells. T he le nti viral e n gi neere d T cells were well 
t olerate d i n all patie nts, wit h f oll o w u p of u p t o 5 years. D os es of u p t o 5 x 1 01 0 a ut ol o g o us ex viv o  
n o n - ge ne m o difie d a n d e x pa n de d T cells ha ve bee n a d mi nistere d i n fi ve pr ot oc ols t o 1 2 8 p atie nts 
wit h he mat ol o gic mali g n a ncies a n d HI V, a n d ha v e f o u n d t his t o be well t olerate d 6 4, 8 8- 9 1.  M ore 
t ha n 2 0 patie nts wit h C L L a n d A L L ha ve bee n treate d wit h C A R T 1 9 cells. A gai n, i n all cases t he 
i nf usi o ns were w ell t olerate d. F oll o w- u p h as bee n 3 years i n 2 cases. 
 
Ris k of t u m or l ysis s y n dr o me ( T L S) rel ate d t o c yt ore d ucti ve c he m ot hera p y or C A R T cells.  T he 
ris k of T L S is d e pe n d e nt o n t he dise ase a n d b ur de n of dise ase. Se v eral of t he patie nts tr eate d wit h 
C A R T- 1 9 ha ve de vel o p e d dela ye d T L S pres u m a bl y d ue t o T cell pr oliferati o n a n d t u m or cell 
killi n g at t h at ti me. T h eref ore, all patie nts will be cl osel y m o nit ore d b ot h bef ore a n d after 
c he m ot hera p y a n d C A R T- 1 9 i nf usi o ns i ncl u di n g bl o o d tests f or p ot assi u m a n d uric aci d.  All 
patie nts will recei ve all o p uri n ol pr o p h ylacticall y f or 3 0 da ys after i nf usi o n a n d a p pr o priate cli nical 
t hera p y will be a d mi nistere d s h o ul d a n y si g nifica nt t u m or l ysis occ ur. 
 
I nf usi o n reacti o ns. I m me diatel y f oll o wi n g T cell i nf usi o ns c o ul d occ ur a n d ma y i n cl u de tr a nsie nt 
fe ver, c hills, a n d/ or n a usea. Patie nts 
m ust be pre- m e dicate d 
wit h aceta mi n o p he n a n d 
di p he n h y dra mi ne h y dr oc hl ori de pri or t o t he i nf usi o n of C A R T- 1 9 . A re vie w of i nf usi o n-relate d 
a d verse e ve nts of 3 8 1 T cell pr o d ucts a d mi nistere d t o 1 8 0 reci pie nts, e nr olle d o n 1 8 st u dies, o ver 
a 1 0 year peri o d w as c o n d ucte d b y Cr uz et al. 9 2a n d f o u n d n o gra de 3- 4 i nf usi o n reacti o ns d uri n g 
i nitial m o nit ori n g or 2 4- h o ur f oll o w- u p. Gra d e 1- 2 a d verse e ve nts were o bser ve d i n 2 1 patie nts 
d uri n g or s h ortl y after i nf usi o n a n d i ncl u de d n a usea, v o miti n g, fe ver, a n d/ or c hills. A mil d i nf usi o n 
reacti o n w as rec or de d i n o ne of m ore t ha n 2 0 C L L patie nts wit h C A R T- 1 9 i nf usi o n. 
 
I ntr acra nial H e m orr h a ge. As of Fe br uar y 2 0 1 7, t here ha ve bee n t hree e ve nts of i ntracra nial 
he m orr ha ge o n C A R T- 1 9 trials u n der  
.  O ne e ve nt occ urre d o n U P C C 
 (a d ult 
A L L) i n t he setti n g of t hr o m b oc yt o pe nia (relate d t o pri or l y m p h o de pleti n g c he m ot hera p y a n d 
u n derl yi n g le u ke mia), was deter mi ne d t o be p ossi bl y relate d t o t he C A R T- 1 9 T-cell i nf usi o n, 
occ urre d wit h c o nc urre nt Gra de 4 C R S, a n d res ulte d i n deat h. A n ot her e ve nt occ urre d o n t he C N S 3 
c o h ort o n C H P 9 5 9 ( pe diatric 
A L L) i n t he setti n g of acti ve circ ulati n g le u ke mia, C R S, 
se psis/ bactere mia, a n d ac ute re nal fail ure re q uiri n g dial ysis. T he s u bject die d, a n d i ntracra nial 
he m orr ha ge (s us pecte d cli nicall y, u nc o nfir me d ra di ol o gicall y) was felt t o be t he i m me diate ca use 
of deat h i n t his criticall y ill patie nt.   A t hir d e ve nt occ urre d o n  
 ( pe diatric A L L st u d y) i n 
Fe br uar y 2 0 1 7.  A 3 - year- ol d s u bject wit h refract or y A L L a n d C N S 2 disease e x perie nce d se vere 
C R S c o m plicate d b y 
DI C a n d 
m ulti- or ga n fail ure.   W hile o n e xtrac or p oreal 
me m bra ne 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 1 9  of 1 0 8 
V ersi o n V 1 2. 0 4 -1 4 -2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
o x y ge nati o n, t he s u bject e x perie nce a n i ntracra nial he m orr ha ge,  wit h ass ociate d cere bral e de ma as 
a ter mi nal e ve nt.  
 
C yt o ki ne Releas e S y n dr o me ( C R S) / Macr o p ha ge Acti vati o n S y n dr o me ( M A S).   
 
O ver vie w a n d Cli nical Ma nifestati o ns : Patie nts treate d wit h C A R T- 1 9 ma y e x perie nce a c yt o ki ne 
releas e s y n dr o me (C R S ), w hic h has c orrelate d wit h disease res p o ns e.  Cli nical ma nifestati o ns ha ve 
i ncl u de d hi g h fe vers, fati g ue, a n ore xia, na usea, v o miti n g, diarr hea, 
m yal gias, art hral gias, 
hea dac he, ras h, h y p ote nsi o n ( occasi o nall y re q uiri n g press or s u p p ort) tac h y p n ea, h y p o xia 
( occasi o n all y re q uiri n g v e ntilat or s u p p ort), deliri u m a n d c o nf usi o n (i n se veral patie nts), e vi de nce 
of disse mi nate d i ntra v as c ular c oa g ulati o n as well as 
M A S.  I n s o me cases C R S, T L S a n d 
h y p o te nsi o n h a ve le d t o ac ute ki d n e y i nj ur y a n d se veral patie nts h a ve re q uire d at least tr a nsie nt 
dial ysis. T he C R S has bee n effecti vel y a br o gate d wit h a nti-c yt o ki ne dir ecte d t hera p y,  i ncl u di n g 
t ociliz u ma b, i n m ost patie nts. As of J u ne 2 0 1 4, t hree patie nts ha v e die d of c o m plicati o ns relate d 
t o refract or y C R S a n d i nterc urre nt i nfecti o ns.  I n a d diti o n, it is u nclear if treati n g t he C R S wit h 
a nti-c yt o ki n e directe d t hera p y a d versel y i m pacts t he a nti-t u m or res p o nse. 
 
Feat ur es c o nsiste nt wit h M A S or H L H ha v e b ee n o bser ve d i n patie nts tr eate d wit h C A R T 1 9 , 
c oi nci de nt wit h cli nical ma nifestati o ns of t he C R S.  M A S a p pears t o b e a reacti o n t o i m m u ne 
acti vati o n t hat occ urs fr o m t he C R S, a n d t heref ore s h o ul d be c o nsi dere d a ma nifestati o n of C R S.  
 
Macr o p ha ge acti vati o n s y n dr o me is si milar t o He m o p ha g o c yti c l y m p h o histi oc yt osis ( H L H); it is 
a reacti o n t o i m m u ne sti m ulati o n b y i nf ecti o n, a ut oi m m u ne diseases or ot her preci pita nts, b ut is 
disti n g uis he d fr o m fa milial or ge neticall y me di ate d H L H.  T h ere are n o defi niti ve dia g n ostic 
criteria f or M A S, b ut it is t y picall y dia g n ose d b y meeti n g H L H criteria. 
 
S o me b ut n ot all feat ur es of M A S are t y picall y o bser ve d.  T he cli nical s y n dr o me of M A S is 
c haracteriz e d b y hi g h gra de n o n-re mitti n g fe v er, c yt o pe nias affecti n g at l east t w o of t hree li nea ges, 
a n d he pat os ple n o me gal y.  It is ass ociate d wit h bi oc he mical a b n or malities, s uc h as hi g h circ ulati n g 
le vels of ser u m ferriti n, s ol u ble i nterle u ki n- 2 rece pt or (s C D 2 5), a n d tri gl yc eri des, t o get her wit h a 
decrease of circ ulati n g N K acti vit y.  Ot her fi n di n gs i ncl u de varia ble le v els of tra nsa mi n ases u p t o 
si g ns of ac ut e li ver fail ure a n d c oa g ul o p at h y wit h fi n di n gs c o nsiste nt wit h DI C. A p at h ol o gi c 
feat ur e of M A S is t he prese nce of he m o p h a g oc ytic C D 1 6 3 + macr o p ha ges ( H P C) i n b o ne marr o w 
or l y m p h- n o d e as pirat es. 
 
Dia g n osis is base d o n t h e f ulfill me nt of criteria esta blis he d i n 2 0 0 4 9 3 f or H L H ass ociate d wit h 
a ut os o mal recessi ve dis or ders (fa milial H L H, f H L H).  
 
A dia g n osis of n o n-fa milial H L H/ M A S is ma de b y ha vi n g 5/ 8 criteria: 
 Fe ver 
 S ple n o me gal y 
 C yt o pe nia s ( affecti n g 2 or m ore li nea ges i n t he peri p heral bl o o d; he m o gl o bi n < 9 
g/ d L, platelets < 1 0 0, 0 0 0/ L, A bs ol ute ne utr o p hil c o u nt < 1 0 0 0/ L)  
 Fasti n g tri gl yceri des > 2 6 5 m g/ d L, Fi bri n o ge n   < 1. 5 g/ L 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 2 0  of 1 0 8 
V ersi o n V 1 2. 0 4 -1 4 -2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
 He m o p ha g oc yt osis i n b o ne marr o w or s plee n or l y m p h n o des  
 L o w or a bse nt N K-cell acti vit y 
 Ferriti n > 5 0 0 g/ L 
 S ol u ble C D 2 5 R > 2 4 0 0 U/ L 
S u p p orti ve cli nical criteria i ncl u de ne ur ol o gic s y m pt o ms a n d cere br os pi nal ﬂui d pl e oc yt osis, 
c o nj u gate d h y per bilir u bi ne mia, a n d tra nsa mi nitis, h y p oal b u mi ne mia a n d h y p o natr e mia. T y picall y 
hi g h fe v ers, c yt o pe nias, a n d w he n perf or me d he m o p ha g o c yt osis i n t he b o ne marr o w is o bser ve d 
(t h o u g h marr o w s peci me ns at t he ti me of t he reacti o n are n ot ofte n ta ke n). S ol u ble C D 2 5 R a n d 
N K cell acti vit y are n ot st a n dar d tests, t h o u g h sa m ples are t a ke n f or retr os pecti ve C D 2 5 R a nal ysis.  
T heref ore, patie nts ma y n ot meet strict defi niti o n of H L H/ M A S, b ut gi ve n t he c o nstellati o n of 
fi n di n gs, a n d t he c o nsiste nt dra matic el e vati o n i n Ferriti n, t his is i n dee d t he reacti o n ass ociate d 
wit h t he C R S.   
 
At t his ti me it is still u n k n o w n w het h er C R S/ M A S is be neficial or har mf ul t o t he a nti-t u m or 
res p o nse.  Researc h m o nit ori n g data s h o we d t hat I L 6 l e vels were e xtra or di naril y hi g h d uri n g t h e 
C R S, pr o m pti n g t o t he use of a n a nti-I L 6 rece pt or a nti b o d y t ociliz u ma b t o treat t he C R S/ M A S. 
T he maj orit y of patie nts treate d wit h t ociliz u ma b f or C R S a n d M A S ha d ra pi d ( wit hi n h o urs) 
res ol uti o n of dra matic fe v ers, a n d c o nti n u o us i m pr o ve me nt i n h y p ote nsi o n a n d h y p o xia o ver h o urs 
t o se veral d a ys, a n d s h o we d i m pr o ve me nt i n bi o c he mical e vi de nce of C R S a n d M A S wit hi n 4 8 
h o urs.  A d ult patie nts were tr eate d wit h t ociliz u ma b 4 m g/ k g or 8 m g/ k g.  It is u nclear if earl y 
treat me nt will ne gat e t he a ntit u m or res p o nse.  Treat me nt a n d ti mi n g of treat me nt of t his t o xicit y 
will be at t he discreti o n of t he p atie nt’s p h ysicia n a n d t he st u d y i n v esti gat or, a n d occ ur i n t h e 
setti n g of he m o d y n a mic i nsta bilit y.  
 
Pe diatric A L L p atie nts tr eate d wit h C A R T- 1 9 o n C H P 9 5 9 5 ha ve e x perie n ce d a si milar C R S a n d 
M A S. C H P 9 5 9- 1 0 0 e x perie nce d a s e vere C R S a n d ha d hi g h fe vers, h y p ot e nsi o n, ac ute vas c ular 
lea k s y n dr o me a n d ac ute res pirat or y distress. T he patie nt was treat e d wit h eta nerce pt a n d 
t ociliz u ma b, as descri be d i n Gr u p p et al., N E J M, 2 0 1 3 , a n d all ass ociate d a d verse e ve nts res ol ve d. 
C H P 9 5 9- 1 0 4 a n d C H P 9 5 9- 1 0 5 recei v e d t he 1 0 % d ose o nl y a n d e x perie n ce d C R S. C H P 9 5 9- 1 0 3 
recei v e d t he 1 0 % a n d 3 0 % d oses, res pecti vel y, a n d e x perie nce d a mil d C R S after t he 1 0 % d ose, 
wit h n o C R S e x perie nce d after t he 3 0 % d ose. N o ne of t hese p atie nts e x perie nce d were se v ere 
e n o u g h C R S (i.e. t here were n o i nsta nces of m ore t ha n tra nsie nt o x y ge n re q uire me nts, or 
h y p ote nsi o n r e q uiri n g press or s u p p ort) re q uiri n g treat me nt wit h ster oi ds or c yt o ki ne bl o c ka de. 
 
F at al S A Es wit h C A Rs:  T w o st u dies ha ve re p orte d fatal S A Es f oll o wi n g C A R i nf usi o n i n patie nts 
wit h mali g na nc y.  Bre ntje ns et al desi g ne d a retr o virall y-tra ns d u ce d C A R a gai nst t he C D 1 9 
m olec ule f or p atie nts wit h B cell l y m p h o ma. T he C D 1 9  C A R was t he sec o n d ge n erati o n desi g n 
c o ntai ni n g C D 2 8 a n d C D 3ζ si g nali n g d o mai ns. A t otal of 7 s u bjects ha ve bee n treate d o n t his 
pr ot oc ol, 6 wit h o ut S A E. H o we ver, s u bject f o ur i n t his st u d y was a 6 9 year ol d ma n wit h refract or y 
C L L a n d w h o h a d a si g nifica nt past me dical hist or y of m y ocar dial i nfarcti o n, c or o nar y arter y 
disease, h y p erte nsi o n, a n d c hr o nic re nal fail ure. T his was t he 4 t h patie nt i n t he st u d y a n d t he first 
o ne o n t he c o h ort u n der g oi n g l y m p h o de pleti o n. T his s u bject recei ve d pre- T cell c o n diti o ni n g wit h 
1. 5 g/ m 2 of c ycl o p h os p ha mi de f oll o we d 2 da ys lat er b y i nf usi o n wit h ge neticall y m o difie d C D 1 9 
C A R T cells at 1. 2- 3 x 1 0 7 cells/ k g. T we nt y h o urs f oll o wi n g T cell i nf usi o n, t he patie nt d e vel o pe d 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 2 1  of 1 0 8 
V ersi o n V 1 2. 0 4 -1 4 -2 0 1 7   
 
C O N F I D E N TIA L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
persiste nt fe ver (tra nsie nt fe ver w as o bser ve d i n t he first 3 s u bjects o n t he st u d y t o o) a n d 
h y p ote nsi o n t hat was ra pi dl y f oll o we d b y res pirat or y distress des pite ne gati ve c hest x-ra y, 
h y p o x e mic res pirat or y fail ure, a n d ac ute re n al fail ure. T he fa mil y deci de d t o re m o ve f urt her life 
s ustai ni n g t hera pies a n d t he p atie nt e x pire d 4 4 h p ost- T cell i nf usi o n. T he p ost- m orte m pat h ol o g y 
re p ort faile d t o s u p p ort a dia g n osis of t u m or l ysis s y n dr o me as t he pri mar y s o urce of re nal fail ure. 
A nal ysis of ser u m c yt o ki nes re veale d ele vate d le vels of I L- 2, I L- 7, I L- 1 5, a n d I L- 1 2 f ol l o wi n g 
c ycl o p h os p ha mi de t hera p y w hi c h ma y h a ve b ee n sec o n dar y t o a pri or s u bac ute i nfecti o n 
e x acer bate d 
b y t he i m m u ne s u p pressi o n 
ass ociate d 
wit h 
c ycl o p h os p ha mi de- me diate d 
l y m p h o de pleti o n.  T he a ut h ors c o ncl u de d t hat c o nc o mita nt se psis was t he m ost li kel y ca us e of 
deat h a n d attri b ute d t he eti ol o g y of t he deat h as “ p ossi bl y relate d ” t o C A R T cell i nf usi o n 9 4.  
 
T he sec o n d case of a fat al S A E relate d t o C A R T cells was re p ort e d b y t h e N CI gr o u p ( M or ga n et 
al. 2 0 1 0). T his st u d y atte m pte d t o treat ca ncer patie nts wit h o vere x pressi n g E R B B 2 t u m ors wit h 
a n a nti-E R B B 2 C A R  of 3r d ge nerati o n (c o ntai ni n g C D 2 8, 4 1 B B a n d C D 3ζ si g nali n g d o mai ns). 
T he first s u bject i n t he st u d y was a 3 9- year- ol d fe male wit h c ol o n ca ncer metastatic t o l u n gs a n d 
li ver. T he patie nt recei ve d l y m p h o de pleti n g re gi me n ( 6 0 m g/ k g c ycl o p h os p ha mi de dail y f or 2 d a ys 
f oll o we d b y fl u dara bi ne 2 5 m g/ m2 f or t he ne xt 5 da ys) f oll o we d t he ne xt da y b y retr o virall y-
tra ns d uce d 1 01 0 E R B B 2 C A R T cell (tra ns d ucti o n efficie nc y 7 9 %). At 1 5 mi n p ost-i nf usi o n, t he 
patie nt be ga n t o d e vel o p d ys p n ea a n d h y p o xia wit h p ul m o nar y i nfiltrat es o n c hest x-ra y. T h e 
patie nt pr o gresse d i nt o h y p o x e mic res pirat or y fail ure re q uiri n g mec ha nical ve ntilat or y s u p p ort, 
vas o press or- d e pe n d e nt h y p ote nsi o n, a n d car di o p ul m o nar y arrest. T he patie nt 
was i nitiall y 
res uscitate d a n d starte d o n hi g h d ose ster oi ds, b ut des pite a g gressi ve s u p p orti ve care, t he p atie nt 
e x pire d 5 da ys aft er i nf usi o n. Ser u m c yt o ki ne meas ure me nts de m o nstrate d a dra matic rise i n pr o-
i nfla m mat or y c yt o ki n es (I F N-γ, T N F- α, I L- 6, G M- C S F) wit hi n 4 h o urs of i nf usi o n c o nsiste nt wit h 
a c yt o ki ne st or m i nitiati n g m ulti-s yst e m or ga n fail ure. Dr. M or ga n p ost ulates t hat u p o n first 
p ul m o nar y cir c ulati o n passa ge 9 5, t he C A R E R B B 2 T cells b o u n d t o nati ve l o w l e vel e x pressi o n 
p ul m o nar y e pit helial cell E R B B 2 pr otei ns 9 6, lea di n g t o C A R acti vati o n a n d p ul m o nar y 
micr o vasc ular i nj ur y.  
 
Ot her fatal S A Es h a ve b ee n re p ort e d.  T w o e ve nts occ urre d i n A pril 2 0 1 4 at t he Me m ori al Sl oa n 
Ketteri n g Ca ncer Ce nter usi n g C D 1 9 s pecific C A R re direct e d T cells. Fi ve fat al e ve nts ha ve 
occ urre d at t he U ni versit y of Pe n ns yl va nia usi n g C A R T- 1 9 T -cells (a C D 1 9-s pecific C A R usi n g 
a le nti viral vect or) i n pati e nts wit h ac ut e l y m p h o bl astic le u ke mia. T hree of t he first si x a d ult A L L 
s u bjects i nf use d o n U P C C 
 die d as a res ult of refract or y C yt o ki ne Rel ease S y n dr o me ( C R S) 
i n t he setti n g of i nterc urre nt i nfecti o ns. T hereafter, t he si n gle d os e a d mi nistere d i n U P C C 
 
was re d uce d t o 1- 5 x 1 0 7 C A R T 1 9 cells. I n t he ne xt si x a d ult A L L s u bjects treate d at t he de-
escalate d d os e, t w o die d fr o m a n i ntracra nial blee d a n d se psis, res pecti vel y.  
 
Gra di n g of C R S:  T he C T C gra di n g s yste m was ori gi nall y d e vel o pe d t o ca pt ure a c yt o ki ne 
s y n dr o me occ urri n g d uri n g i nf usi o nal t hera p y; t heref ore, it is i na de q uate t o ca pt ur e t he d ela ye d 
C R S t hat occ urs after C A R T- 1 9 i nf usi o ns.  U ni v ersit y of Pe n ns yl va nia h as pr o p ose d t o m o dif y 
t he C T C gra di n g s pecifi call y t o ca pt ure t o xi cit y f or pr ot oc ols usi n g C A R T- 1 9 cells. M A S/ H L H 
o bser ve d si g ns a n d s y m pt o ms are a ma nifestati o n of C R S a n d will t heref ore n ot be gra de d 
se parat el y ( See T a ble 8 - 1 i n Secti o n 8. 2). 
 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 2 2  of 1 0 8 
V ersi o n V 1 2. 0 4 -1 4 -2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
Graft vers us h ost disease ( G V H D): T h e c ha n ce of G V H D occ urri n g is l o w, b ut it is a p ote ntial ris k 
wit h C A R T- 1 9 t hera p y.  A pri or U Pe n n / C H O P st u d y of acti vate d D LI (ex viv o acti vate d cells 
c ollecte d fr o m t he d o n or a n d gr o w n i n t he sa me fas hi o n as C A R T- 1 9 b ut wit h o ut C A R 
i ntr o d ucti o n) di d n ot s h o w hi g h rates of G V H D ( 2/ 1 8 patie nts wit h gra de 3 G V H D a n d n o ne wit h 
Gra de 4) 9 7.  
 
Patie nts wit h acti ve, ac ut e or c hr o nic G V H D at scree ni n g are e x cl u de d fr o m e nr olli n g i n t his st u d y.  
H o we ver, d ue t o t he p ossi bilit y of s o me de gree of resi d ual d o n or e n graft me nt, w hic h will i ncl u de 
T cells of d o n or ori gi n, p atie nts t hat recei ve d a pre vi o us H S C T at t he H os pital of t he U ni versit y 
of Pe n ns yl va ni a will be assesse d f or d o n or c hi meris m at scree ni n g a n d will be m o nit ore d cl osel y 
t hr o u g h o ut t he st u d y f or si g ns of G V H D.  T o d at e, n o patie nt t hat ha d a pri or all o ge neic H S C T 
de vel o pe d G V H D after a ut ol o g o us C A R T- 1 9 i nf usi o n, e ve n w he n “a ut ol o g o us” cell i ncl u de d cells 
of d o n or ori gi n. 
 
P ote ntial be nefits.   
O utc o me re mai ns p o or f or a d ult patie nts wit h rela pse d or refract or y (r/r), B cell ac ute 
l y m p h o blastic le u ke mia ( B cell A L L). Treat me nt o pti o ns i ncl u de f urt her treat me nt wit h sal va ge 
c he m ot hera p y, all o ge n ei c he mat o p oietic ste m cell tra ns pla ntati o n ( H S C T) or s u p p orti ve care. F or 
t his p o p ulati o n, 5 yea r o verall s ur vi val ( O S) aft er rela ps e is esti mate d at 7 % 4 6.  F or t he s mall 
mi n orit y of patie nts wit h rela pse d A L L w h o ha v e a d o n or i de ntifie d a n d g o o n t o tra ns pla nt, O S is 
esti mate d at 2 3 % a n d t h ose patie nts w h o recei ve c he m ot hera p y o nl y is 4 %.   
 
Base d o n i ncl usi o n criteria, patie nts will be i nc ura ble wit h sta n dar d a vaila ble t h era pies. 
F urt her m ore,  m ost patie nts will n ot be eli gi ble f or all o ge n eic tra ns pla nt.  F or A L L p atie nts, t here 
is little be nefit fr o m all o ge neic S C T wit h rela pse d a n d acti ve disease a n d ma n y ce nt ers d o n ot offer 
patie nts i n t his sit uati o n tra ns pla ntati o n beca use of f utilit y. T h eref ore, a n y b e nefit t hat ma y be s ee n 
wit h C A R T- 1 9 cells will ha ve a maj or i m pact f or patie nts.  
 
F or patie nts w h o rela ps e after all o ge neic tr a ns pla nt, treat me nt o pti o ns are e ve n m ore li mite d a n d 
o utc o mes dis mal. C o n v e nti o nal c he m ot hera p y is n ot c urati ve a n d oft e n hi g hl y t o xic a n d 
i neffecti ve. 2 n d all o ge n eic tra ns pla nt is ass oci ate d wit h e xte nsi ve m or bi dit y, m ortalit y, hi g h 
rela pse rate, a n d is i neffecti ve f or t he m aj orit y of patie nts. D o n or l y m p h oc yt e i nf usi o ns res ult i n 
res p o nse rates bet w ee n 0- 1 3 % a n d t here are ver y fe w l o n g-ter m s ur vi v ors. 
 
O n g oi n g cli nical trials wit h C A R T- 1 9, T cells e x pressi n g a sec o n d ge n erati o n C A R wit h a n a nti-
C D 1 9 sc F v a n d 4- 1 B B a n d T C R si g n ali n g d o mai ns, i n patie nts wit h B-cell A L L a n d C L L ( b ot h 
C D 1 9 e x pressi n g B cell mali g na n cies) des cri be d a b o ve s h o w t hat C A R T- 1 9 t hera p y has p ote nt 
a nti-t u m or acti vit y i n pe diatric a n d a d ult A L L p atie nts 4 7, 4 8 ( descri be d i n det ail i n Secti o n 1. 4). Of 
t he ni ne e val ua bl e pe diatric B cell A L L p atie nts, 7 C R, 1 P R a n d 1 N R ha ve bee n re p ort e d f or a n 
o verall res p o ns e rat e of 8/ 9 ( 8 9 %).  T h e o ne a d ult A L L p atie nt treate d re mai ns i n C R after 2 m o nt hs 
of f oll o w u p a n d has g o ne o n t o ha v e a n all o ge n eic S C T; of n ote, h e was c o nsi dere d pre vi o usl y 
i neli gi ble f or all o ge neic S C T bef ore C A R T 1 9 cell i nf usi o n beca use of his refract or y dise ase.  
 
T heref ore, t he ris k: be nefit rati o f or a n o vel t hera p y wit h t he p ot e ntial t o i n d uce re missi o n i n A L L 
is q uite fa v ora ble. 
 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 2 3  of 1 0 8 
V ersi o n V 1 2. 0 4 -1 4 -2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
2.  S T U D Y O B J E C TI V E S A N D E N D P OI N T S 
 
O bjecti ves  
E n d p oi nts  
Pri m ar y  
E val uate t he c o m plet e re missi o n rate at 
da y 2 8 after C A R T -1 9 t hera p y.  
 O verall C o m plete Re missi o n Rate ( O R R) at Da y 
2 8 w hi c h i ncl u des C R a n d C R wit h i nc o m plete 
bl o o d c o u nt rec o ver y ( C Ri) (see secti o n 6. 1 5 ) 
Sec o n d ar y  
E val uate best o verall res p o nse rates  
 
 
 
 
 Perce nta ge of patie nts wit h a best o verall diseas e 
res p o nse of C R or C Ri, w here t he best o verall 
disease res p o ns e is de fi n e d as t he best diseas e 
res p o nse rec or de d fr o m t he start of t he tr eat me nt 
u ntil deat h, last f oll o w u p, rela pse or st art of ne w 
a ntica ncer t hera p y, w hic he ver c o m es first.  
 Perce nta ge of patie nts a c hie vi n g C R/ C Ri bef ore 
or at M o nt h 6   
E val uate o verall s u r vi val ( O S), d urati o n 
of re missi o n ( D O R) , rela pse free 
s ur vi val ( R F S), a n d e ve nt free s ur vi v al 
( E F S) 
 O verall s ur vi val ( O S), d urati o n or re missi o n 
( D O R), rel a pse free s ur vi val ( R F S), a n d e ve nt 
free s ur vi val ( E F S).  
Descri be ca use of deat h ( C O D) w he n 
a p pr opriate  
 Ca use of deat h ( C O D) w he n a p pr o pri ate.  
Descri be res p o nse i n ter ms of mi ni mal 
resi d ual disease ( M R D) ne gati ve a n d 
p ositi ve testi n g usi n g:  
- 
fl o w c yt o m etr y (sta n d ar d) 
- 
q ua ntitati ve m olec ular 
tec h n ol o gi es ( dee p se q ue nci n g) 
(e x pl orat or y)  
 Perce nta ge of pa tie nts w h o ac hie ve a C R 
ass ociate d wit h mi ni mal resi d ual disease ( M R D) 
ne gati ve b o ne marr o w as deter mi ne d b y hi g h 
se nsiti vit y fl o w c yt o metr y. 
 Perce nta ge of patie nts w h o ac hie ve a C R 
ass ociate d wit h mi ni mal resi d ual disease ( M R D) 
ne gati ve b o ne marr o w as det er mi ne d b y 
q ua ntitati ve m olec ular tec h n ol o gies ( dee p 
se q ue nci n g). T h ese a n al yses will be perf or me d 
o n n ucleic aci d is olate d fr o m pre - a n d p ost - 
treat me nt. 
E val uate ma n ufact uri n g feasi bilit y of 
C A R T -1 9  
 Perce nta ge of ma n ufact uri n g pr o d u cts t hat d o n ot 
meet release criteria f or vect or tra ns d u cti o n 
efficie n c y, T cell pr o d uct p urit y, via bilit y, 
sterilit y or d ue t o t u m or c o nta mi nati o n. 
Assess safet y a n d t olera bilit y of 
C A R T -1 9  
 Fre q u e nc y a n d se verit y of a d verse e ve nts, 
i ncl u di n g, b ut n ot li mite d t o, c yt o ki ne releas e 
s y n dr o me ( C R S) a n d macr o p ha ge acti vati o n 
s y n dr o me ( M A S). 
C haracterize t he i n viv o cell ular 
p har mac o ki netic ( P K) pr ofile (le vels, 
persiste nce, tr affi c ki n g) of C A R T -1 9 
cells i n tar get tiss ues ( bl o o d, b o ne 
 D urati o n of C A R T -1 9 i n viv o s ur vi val as 
deter mi ne d b y Q -P C R perf or me d at a mi ni m u m 
of wee kl y f or t he first m o nt h, m o nt hl y u ntil 
M o nt h 6 a n d e ver y t hr ee m o nt hs u ntil M o nt h 1 2 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 2 4  of 1 0 8 
V ersi o n V 1 2. 0 4 -1 4 -2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
O bjecti ves  
E n d p oi nts  
marr o w, cere bral s pi nal fl ui d a n d ot her 
tiss ues if a vaila ble)  
or u ntil a n y 2 se q u e ntial ne gati ve tests 
d oc u me nti n g l oss of C A R T -1 9 pr o vi de d t hat a 
s pecific bl o o d or tiss ue s a m ple is a vaila ble at t hat 
ti me p oi nt.  
Descri be t h e i nci de nce of 
i m m u n o ge nicit y t o C A R T-1 9  Assess 
c orrel ati o n f or i m m u n o ge nicit y wit h 
l oss of detecta ble C A R T-1 9 (l oss of 
e n graft me nt)  
 H ost i m m u nit y a gai nst a nti -C D 1 9 as deter mi ne d 
b y m ulti para metric fl o w c yt o metr y.   
F or patie nts treate d f or rela pse after 
all o ge n eic S C T, descri b e t he ris ks of 
G V H D  
 I n ci de nce of G V H D   
E val uate bi oacti vit y of C A R T -1 9 cells  
 S yste mic s ol u ble i m m u ne a n d i nfla m mat or y 
fact ors pre- a n d p ost -C A R T -1 9 i nf usi o n as 
deter mi ne d b y L u mi ne x -base d a nal ys es.  
 C D 1 9 a nti ge n a n d peri p h eral B cell le vels i n 
marr o w a n d ot h er. bi o psie d tiss ues pre - a n d p ost -
C A R T -1 9 i nf usi o n as d eter mi ne d b y m ulti -
para metri c fl o w c yt o metr y.  
Patie nt Re p orte d O utc o m es  
 Patie nt’s p h ysical, s o cial/fa mil y, e m oti o nal a n d 
f u ncti o nal well-bei n g at baseli ne a n d m o nt hs 3 
a n d 6 as meas ure d b y F A C T -Le u ( Versi o n 4) a n d 
E O R T C -Q L Q C 3 0 q uesti o n naires.  
F oll o w s u bjects i nf use d wit h less t ha n 
pr ot oc ol -s pecifi e d tar get d ose 
 E x pl orat or y a nal ys es t o i nf or m o n d ose -res p o nse 
acti vit y 
Assess safet y a n d effi cac y of re -i nf usi o n 
of C A R T -1 9 cells i n pre vi o usl y treat e d 
patie nts  
 
 Fre q u e nc y a n d se verit y of a d verse e ve nts a n d 
o t her safet y d ata 
 E x pa nsi o n a n d persiste nce of C A R T -1 9 cells, i n 
c o m paris o n t o t heir ori gi nal i nf usi o n  
 O verall res p o nse, ti me t o res p o nse, d urati o n of 
res p o nse a n d ti me t o alter nati ve t hera p y, i n 
c o m paris o n t o t heir ori gi nal i nf usi o n  
3.  S T U D Y D E SI G N 
3. 1. G e n er al D e si g n 
T he st u d y will c o nsist of f o ur se q ue ntial p hases: 1) a scree ni n g p has e, 2) a m a n ufact uri n g a n d pre-
treat me nt p has e, c o nsisti n g of a p h eresis (if a p plica ble) a n d c h e m ot hera p y, 3) a treat me nt p has e, 
co nsisti n g of a C A R T- 1 9 tra nsf use d cell i nf usi o n, a n d 4) f oll o w u p e val uati o ns. T he e val uati o ns 
a n d i nf usi o n sc he d ule are i ncl u de d i n T a ble 6 - 1.  T he ge neral pr ot oc ol sc he ma is dis pla ye d i n 
Fi g ure 3- 1 . 
 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 2 5  of 1 0 8 
V ersi o n V 1 2. 0 4 -1 4 -2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
Fi g ure 3- 1 St u d y Sc he m atic 
 
 
After si g ni n g i nf or me d c o nse nt,  patie nts will u n d er g o scree ni n g t ests a n d pr oce d ures t o d eter mi ne 
eli gi bilit y. 
O n ce p atie nt eli gi bilit y is c o nfir m e d,  patie nts 
will be sta ge d f or a p h eresis 
(le u ka p herese d) t o o btai n peri p heral bl o o d 
m o n o n uclear cells ( P B M C) f or 
C A R T- 1 9 
ma n ufact uri n g. A P B M C sa m ple fr o m t he a p heresis pr o d uct will be use d f or a test e x pa nsi o n t o 
assess t he s uita bilit y of t he patie nt’s T cells f or C A R T- 1 9 ma n ufact uri n g.  T he test e x pa nsi o n 
res ults will be us e d f or sec o n dar y o bjecti ve a nal ysis, b ut will n ot be a criteri o n f or pr ocee di n g wit h 
C A R T- 1 9 ma n ufact uri n g. C D 3 + T cells will be p urifie d fr o m t he P B M C, tr a ns d uce d wit h t he a nti-
C D 1 9 T C Rζ/ 4- 1 B B le nti viral vect or, e x pa n de d i n vitr o a n d t he n fr oze n f or f ut ure a d mi nistrati o n. 
D ue t o t he hi g hl y pr o gressi ve nat ure of B-cell A L L, cr y o preser ve d hist orical a p h eresis pr o d ucts 
c ollecte d fr o m t he patie nt pri or t o st u d y e ntr y are usa ble f or C A R T- 1 9 ma n ufact uri n g if c ollecte d 
at a n a p pr o priat el y certifie d a p heresis ce nter a n d t he pr o d uct meets a de q uate m o n o n uclear cell 
yi el ds.  If t he arc hi v e d sa m ple passes t he t est e x pa nsi o n, t he patie nt w o ul d n ot ha ve t o re peat t he 
baseli ne a p heresis o n t his st u d y.  If a hist orical a p heresis pr o d uct is n ot a vaila ble, a n a p heresis 
pr oce d ure will be sc he d ule d f or cell pr oc ure me nt after st u d y e ntr y. 
 
U nless c o ntrai n dicate d a n d me dicall y n ot a d visa bl e base d o n pre vi o us c he m ot hera p y, patie nts w ill 
be gi v e n c o n diti o ni n g c he m ot hera p y pri or t o C A R T- 1 9 cell i nf usi o n 
wit h t he i nte nt of 
l y m p h o de pleti o n.  A d diti o nall y, if t he p atie nts W B C ≤ 1, 0 0 0 / u L, c o n diti o ni n g/l y m p h o d e pleti n g 
c he m ot hera p y is N O T re q uire d. T h e c he m ot hera p y will be pla n ne d s o t hat t he last d ose is 
c o m plete d 1 - 4 d a ys B E F O R E t he pla n ne d i nf usi o n of C A R T- 1 9 cells.  T h e c he m ot hera p y start 
date will var y bas e d o n t he d urati o n of t he selecte d c he m ot hera p y re gi me n.  If t he dela ye d peri o d 
fr o m c h e m ot hera p y t o C A R T- 1 9 i nf usi o n is 4 or m ore wee ks, t h e patie nt will nee d t o be re-treate d 
wit h l y m p h o de pleti n g c h e m ot hera p y pri or t o C A R T- 1 9 i nf usi o n. Please refer t o Secti o n 6. 6  f or 
selecti o n g ui d a nce of  t he preferre d c o n diti o ni n g c h e m ot hera p y re gi me ns. 
 
We will e nr oll 3 0 e val ua ble patie nts f or t he pri mar y efficac y e n d p oi nt a nal ysis.  Pri mar y efficac y 
e val ua ble p atie nts are t h ose w h o ha ve recei ve d C A R T- 1 9 cells at eit her 1- 5 x 1 0 8 C A R T- 1 9 cells 
or 1 - 5 x 1 07 C A R T- 1 9 cells, gi ve n as eit her a si n gl e i nf usi o n or gi ve n vi a s plit d osi n g o ver 3 d a ys.  
  
F or t he p ur p oses of t he st u d y, pri mar y efficac y n o n-e val ua ble patie nts will be re place d wit h 
pri mar y efficac y e v al ua ble patie nts. Please refer t o Ta bles 3- 1 a n d 3- 2 f or c o m plete details.  B ot h 
pri mar y effic ac y e val ua ble a n d n o n -e v al ua ble p atie nts will be f oll o we d i n t he s a me m a n ner 
 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 2 7  of 1 0 8 
V ersi o n V 1 2. 0 4 -1 4 -2 0 1 7   
 
C O N F I D E N TIA L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
3. 2. Pri m ar y Effi c a c y N o n- E v al u a bl e P ati e nt s 
T he o nl y differe nce bet w ee n t he pri mar y effi cac y e val ua ble a n d n o n-e val ua ble patie nts is t hat o nl y 
t he pri mar y effic ac y e v al ua ble patie nts will be use d f or pri mar y effi cac y e n d p oi nt a nal ysis. B ot h 
pri mar y effic ac y e val ua ble a n d n o n-e v al ua ble p atie nts will be us e d i n s ec o n dar y efficac y, safet y, 
ma n ufact uri n g feasi bilit y, c orrelati ve a n d e x pl orat or y a n al ys es. T he statistical a nal ysis sets are 
detaile d i n Secti o n 7. 3. 
 
I n Pe n n’s U P C C 
 a d ult C A R T- 1 9 trial, 1. 4 x 1 07– 1 5. 5 x 1 0 8 C A R T- 1 9 cells ha ve bee n 
a d mi nistere d.  C o m plete res p o nses h a ve b ee n ac hi e ve d at b ot h t he hi g hest a n d l o west d ose le vels. 
T h o u g h n u m b ers are s m all o ver t his wi de ra n ge of cell d oses, t here is n o e vi de nce f or eit her a 
d ose:res p o nse or d ose:t o xicit y relati o ns hi p. T heref ore, t h ere is scie ntific a n d cli nical j ustificati o n 
f or gi vi n g s u bjects t he ma n ufact ure d cell d ose, e v e n if bel o w t he pr ot o c ol-s pecifie d d ose ra n ge.  
3. 3. R etr e at m e nt C o h ort 
3. 3. 1. O v er vi e w 
Base d o n a v aila ble cli nic al trial data as of Fe br uar y 1, 2 0 1 4, s ustai ne d persiste nce of C A R T- 1 9 
cells are directl y c orrelate d wit h o n g oi n g res p o nse.  T h us, se veral s u bjects w h o ha ve l ost detecta ble 
C A R T- 1 9 cells ha ve s u bs e q ue ntl y rela ps e d. Rela ps e d s u bjects ha v e bee n retreate d wit h a d diti o nal 
C A R T- 1 9 cell i nf usi o ns a n d, i n s o me cas es, t he i nitial res p o nses were reesta blis he d. Gi ve n t he 
cli nical e vi de nce t hat will be descri be d i n de pt h b el o w, we w o ul d li ke t o all o w f or t he retr eat me nt 
of s u bjects w h o ha d a n i nitial res p o nse t o t h eir 1 st i nf usi o n, l ost detecta bl e C A R T- 1 9 cells a n d ha v e 
s u bse q ue ntl y rela pse d.   
 
 
     
 
 
  
 
 
  
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
   

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 2 8  of 1 0 8 
V ersi o n V 1 2. 0 4 -1 4 -2 0 1 7   
 
C O N F I D E N TIA L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
 
 
 
 
 
 
  
 
Ta ke n t o get her, t here ha ve bee n n o s e vere or u n e x pecte d t o xicities o bser ve d i n a n y s u bject u p o n 
retreat me nt wit h C A R T- 1 9 cells ra n gi n g fr o m 2- 1 2 m o nt hs after t he i nitial i nf usi o n(s) retr eate d 
wit h C A R T- 1 9 cells as of J u ne 1, 2 0 1 5. Gi ve n t he c urre ntl y a vaila bl e safet y data, t here is n o 
s u g gesti o n t hat retreat me nt of t hese tar gete d s u bjects will p ose ris ks t o t he s u bject greater t ha n t hat 
of t heir ori gi nal i nf usi o n. A d diti o nall y, 3 of t h e 7 s u bjects retr eate d h a v e e x perie nce d cli nical 
be nefit wit h fe w alter nati ve treat me nt o pti o ns a v aila ble. T heref ore, retreat me nt wit h a d diti o nal 
C A R T- 1 9 d oses carries p ote ntial be nefit wit h n o o bser va ble i ncrease d ris k ass ociate d wit h t he 
c urre nt d ata.  
 
 
  
   
3. 3. 2. R etr e at m e nt O bj e cti v e s 
T his c o h ort of s u bjects will be a nal yze d se p arat el y i n or der e v al uate t he f oll o wi n g e x pl orat or y 
o bjecti ves: 
 Assess t he fre q u e nc y a n d se verit y of a d v erse e ve nts a n d ot her safet y data i n cl u di n g 
de vel o p me nt of c yt o ki ne releas e s y n dr o me 
 E val uate t he e x pa nsi o n a n d persiste nce of C A R T- 1 9 cells, i n c o m paris o n t o t heir ori gi n al 
i nf usi o n 
 E val uate o verall res p o ns e, ti me t o res p o nse, d urati o n of res p o nse a n d ti me t o alter nati ve 
t hera p y, i n c o m paris o n t o t heir ori gi n al i nf usi o n. 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 2 9  of 1 0 8 
V ersi o n V 1 2. 0 4 -1 4 -2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
3. 3. 3. R etr e at m e nt D o s e 
U p t o o ne retreat me nt d ose (s plit a d mi nistrati o n) will be all o we d per eli gi ble s u bject.   S u bjects 
ma y recei ve eit her m uri n e or h u ma nize d C A R T- 1 9 as part of t his retreat me nt c o h ort.  Prefere nce 
will be f or h u ma nize d C A R T- 1 9 i n retreate d s u bjects, if it is cli nicall y, l o gisticall y, a n d fi na n ciall y 
feasi ble. If n ot det er mi ne d t o be feasi ble a n d/ or a s u bject has a d diti o nal cr y o pres er ve d m uri ne 
C A R T- 1 9 d oses a v aila bl e, t he y ma y recei v e retreat me nt wit h m uri ne C A R T- 1 9.   T he tar get d ose 
f or retreat me nt is 1- 5 x 1 08 C A R T- 1 9 cells a d mi nistere d via s plit d osi n g: 1 0 % o n Da y 1, 3 0 % o n 
Da y 2, 6 0 % o n D a y 3 .   T he mi ni m u m acce pta ble d ose f or retreat me nt is 1 x 1 0 7 C A R T- 1 9 T-cells. 
All s u bjects w h o recei v e C A R T- 1 9 T -cells as part of t his retreat me nt c o h ort will be c o nsi dere d 
e val ua ble.   
 
All prere q uisites f or eli gi bilit y t o recei ve C A R T- 1 9 o utli ne d i n Secti o n 5. 2 m ust be met pri or t o 
retreat me nt.  T he st u d y dr u g will be pre pare d a n d a d mi nistere d p er t he g ui deli nes s et f ort h i n 
Secti o n 5.  All re q uire d st u d y pr oce d ures, pre- me dicati o ns, pr o p h yl a xis, m o nit ori n g, a n d f oll o w-
u p  g ui d eli nes fr o m t he i nitial i nf usi o n o utli ne d i n Secti o n 6 will a p pl y f or t his retreat me nt c o h ort.  
A Retreat me nt C o h ort Visit E val uati o n Sc he d ule has als o bee n d e vel o pe d ( T a ble 6- 2).  
 
A d diti o nal i nf or mati o n relate d t o retreat me nt eli gi bilit y a n d pr oce d ures, is o utli ne d i n Secti o n 6. 1 3 
bel o w.  
 
4.  P A TI E N T S E L E C TI O N A N D WI T H D R A W A L 
N o e x ce pti o ns t o eli gi bilit y will be gra nt e d f or t his st u d y. 
4. 1. I n cl u si o n Crit eri a 
1.  Si g ne d i nf or me d c o nse nt f or m m ust be o btai ne d pri or t o a n y st u d y pr oce d ure 
2.  Rela pse d or refract or y B-cell A L L    
a. 1 st or greater B M r ela pse O R 
b.  A n y marr o w rela pse after all o ge neic H S C T a n d > 1 0 0 da ys fr o m 
tra ns pla nt  O R  
c. F or patie nts wit h refract or y dise ase:  
i. < 6 0 years ol d t hat h a ve n ot ac hie ve d a C R after > 2  or m ore 
c he m ot hera p y re gi me ns  
ii. > 6 0 years ol d t hat h a ve n ot ac hie ve d  a C R after 1 pri or c he m ot hera p y 
re gi me n 
d.  Patie nts wit h P h + A L L are eli gi ble if t he y ha v e faile d t yr osi ne ki nas e i n hi bit or 
t hera p y 
3.  D oc u me ntati o n of C D 1 9 t u m or e x pressi o n i n b o ne marr o w or p eri p heral bl o o d b y 
fl o w c yt o m etr y wit hi n 3 m o nt hs of scree ni n g. 
4.  A de q uate or ga n f u ncti o n defi ne d as:  
a. Creati ni ne < 1. 6  m g/ dl  
b.  A L T/ A S T < 3 x u p per li mit of n or mal ra n ge 
c. Direct bilir u bi n < 2. 0 m g/ dl  

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 3 0  of 1 0 8 
V ersi o n V 1 2. 0 4 -1 4 -2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
d.  M ust ha ve a mi ni m u m le vel of p ul m o nar y res er ve defi ne d as ≤ Gra de 1 
d ys p nea, p ulse o x y ge n > 9 2 % o n r o o m air, a n d D L C O > 4 0 % (c orrecte d f or 
a ne mia if cli nicall y a p pr o priate)  
e. Left Ve ntricl e Ejecti o n Fracti o n ( L V E F) ≥ 4 0 % c o nfir me d b y E C H O/ M U G A 
5.  B o ne marr o w wit h ≥ 5 % l y m p h o blasts  
6.  Lif e e x pecta nc y > 1 2 wee ks R E TI R E D WI T H P R O T O C O L V E R SI O N 6  
7.  Male or fe m ale a ge ≥ 1 8 years 
8.  A E C O G Perf or m a nce St at us t hat is eit her 0 or 1 
9.  N o c o ntrai n dicati o ns f or le u ka p heresis 
4. 2. E x cl u si o n Crit eri a 
1.  Is olat e d e xtra me d ullar y disease rel a pse 
2.  Patie nts wit h c o nc o mita nt ge n etic s y n dr o me: patie nts wit h D o w n s y n dr o me, 
Fa nc o ni a ne mia, K ost ma n n s y n dr o me, S h wac h ma n s y n dr o me or a n y ot her k n o w n 
b o ne marr o w fail ure s y n dr o me R E TI R E D WI T H P R O T O C O L V E R SI O N 9  
3.  Acti ve he patitis B or acti ve he patitis C  
4.  Class III/I V car di o vas c ular disa bilit y acc or di n g t o t he Ne w Y or k Heart 
Ass ociati o n Classificati o n (see A p pe n di x 1) 
5.  HI V i nfecti o n 
6.  Acti ve ac ut e or c hr o nic graft- vers us - h ost disease ( G V H D) or re q uir e me nt of 
i m m u n os u p pressa nt me dicati o ns f or G V H D wit hi n 4 wee ks of e nr oll me nt. 
7.  C o nc urre nt use of s yst e mic ster oi ds or c hr o nic us e of i m m u n os u p pressa nt 
me dicati o ns.  Rece nt or c urre nt use of i n h ale d ster oi ds is n ot e x cl usi o nar y.  F or 
a d diti o nal details re gar di n g use of ster oi d a n d i m m u n os u p pressa nt me dicati o ns, 
please see Secti o n 5. 6.    
8.  Ac ti ve C N S i n v ol ve me nt b y mali g na n c y. N ote: Patie nts wit h hist or y of C N S 
disease t hat has bee n effecti vel y tr eate d will be eli gi ble pr o vi de d t h at treat me nt 
was > 4 w ee ks bef ore e nr oll me nt 
9.  Pre g n a nt or n ursi n g (lactati n g) w o m e n, fe m ale st u d y partici pa nts of re pr o d ucti ve 
p ote ntial m ust ha ve a ne gati ve ser u m or uri n e pre g na nc y test wit hi n 4 8 h o urs 
bef ore i nf usi o n 
1 0.  Partici pati o n i n a pri or i n vesti gati o nal st u d y wit hi n 4 wee ks pri or t o e nr oll me nt. 
Partici pati o n i n n o n-t hera pe utic researc h st u dies is all o we d.     
1 1.  Patie nts wit h a k n o w n hist or y or pri or dia g n osis of o ptic ne uritis or ot her 
i m m u n ol o gic or i nfla m mat or y dis ease affecti n g t he ce ntr al ner v o us s yste m, a n d 
u nrelate d t o le u ke mia or pre vi o us le u ke mia treat me nt.   
 
Eli gi bilit y criteria f or t h e retreat me nt c o h ort are o utli ne d i n Secti o n 6. 1 3 bel o w.  

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 3 1  of 1 0 8 
V ersi o n V 1 2. 0 4 -1 4 -2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
4. 3. P ati e nt R e cr uit m e nt a n d S cr e e ni n g 
Patie nts will be i de ntifie d t hr o u g h t he cli nical practices of t he i n v esti gat or or s u b-i n v esti gat ors 
a n d t hr o u g h referrals fr o m o utsi de h os pitals a n d p h ysicia ns.  N o dir ect- t o- p atie nt a d vertisi n g will 
be perf or me d. 
 
Fe male p atie nts of re pr o d ucti ve p ote ntial ( w o me n w h o ha ve reac he d me narc he or w o me n w h o 
ha ve n ot bee n p ost- me n o pa usal f or at least 2 4 c o nsec uti ve m o nt hs, i.e., w h o ha ve ha d me nses 
wit hi n t he prece di n g 2 4 m o nt hs, or ha ve n ot u n der g o n e a sterilizati o n pr oce d ure [ h ysterect o m y or 
bilateral o o p h orect o m y]) m ust ha ve ne gati ve ser u m pre g n a nc y test perf or me d at t he ti me of 
scree ni n g a n d a ne gati ve uri ne pre g n a nc y test wit hi n 4 8 h o urs of T cell i nf usi o n.  
 
D ue t o t he hi g h ris k le vel of t his st u d y, w hile e nr olle d, all patie nts m ust a gree n ot t o partici pate i n 
a c o n ce pti o n pr ocess (e. g., acti ve atte m pt t o b ec o me pre g n a nt or t o i m pre g nat e, s per m d o nati o n, 
i n vitr o fertilizati o n). A d diti o nall y, if partici pati n g i n se x ual acti vit y t hat c o ul d lea d t o pre g n a nc y, 
t he st u d y patie nt m ust a gree t o use at least o ne relia ble met h o d of c o ntr ace pti o n d uri n g t heir 
partici pati o n i n t he st u d y. 
 
Acce pt a ble birt h c o ntr ol i ncl u des o ne of t he f oll o wi n g met h o ds: 
 
C o n d o ms ( male or fe mal e) wit h or wit h o ut a s per mici dal a ge nt 
 
Dia p hra g m or cer vical ca p wit h s per mici de 
 
I ntr a uteri ne d e vice (I U D) 
 
H or m o nal- bas e d c o ntrace pti o n 
 
Patie nts w h o are n ot of re pr o d ucti ve p ote ntial ( w o me n w h o ha ve bee n p ost me n o pa usal f or a t 
least 2 4 c o ns ec uti ve m o nt hs or ha v e u n der g o ne h ysterect o m y, sal pi n gect o m y, a n d/ or bilateral 
o o p h orect o m y or 
me n 
w h o ha ve d oc u me nte d az o os per mia) d o n ot re q uire t he use of 
c o ntrace pti o n.  Acce pta ble d oc u me ntati o n of sterilizati o n, az o os per mia, a n d me n o pa us e is 
s pecifie d bel o w: 
 
Writte n d oc u me ntati o n b y cli nicia n or cli nicia n’s staff t hr o u g h o ne of t he f oll o wi n g: 
 
P h ysicia n re p ort/letter 
 
O perati ve re p ort or ot h er s o urce d oc u m e ntati o n i n t he patie nt rec or d (a l a b orat or y 
re p ort of az o os per mia is re q uire d t o d oc u m e nt s uc cessf ul vasect o m y) 
 
Disc har ge s u m mar y of st eriliz ati o n pr oce d ure or h ysterect o m y, a n d/ or 
sal pi n gect o m y, o o p h orect o m y 
 
La b orat or y re p ort of az o os per mia 
 F ollicle sti m ulati n g h or m o ne meas ure me nt ele vate d i nt o t he me n o pa usal ra n ge 
4. 4. E arl y Wit h dr a w al of P ati e nt s 
4. 4. 1. 
W h e n a n d H o w t o Wit h dr a w P ati e nt s 
Patie nts w h o d o n ot c o m plete t he st u d y pr ot oc ol will be c o nsi dere d t o ha ve pre mat urel y 
disc o nti n ue d t he st u d y. T he reas o ns f or pre m at ure disc o nti n uati o n (f or e x a m ple, v ol u ntar y 
wit h dra wal, t o xicit y, deat h) m ust be rec or de d o n t h e case re p ort f or m. Fi n al st u d y e val uati o ns will 
be c o m plete d at t he ti me of disc o nti n uati o n.  

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 3 2  of 1 0 8 
V ersi o n V 1 2. 0 4 -1 4 -2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
P ote ntial reas o ns f or pre mat ure disc o nti n uati o n i ncl u de: 
1.  T he patie nt is l ost t o f oll o w- u p. 
2.  T he j u d g me nt of t he pri n ci pal i n vesti gat or t hat t he patie nt is t o o ill t o c o nti n ue if 
t his occ urs pri or t o a n y of t he C A R T- 1 9 T-cell i nf usi o ns. 
3.  Pre g n a nc y:  Wit h dra w patie nt if pre g na nc y o cc urs pri or t o a n y of t he C A R T- 1 9 T-
cell i nf usi o ns  
4.  V ol u ntar y wit h dra w al; a patie nt ma y re m o ve hi ms elf/ herself fr o m t he st u d y at a n y 
ti me wit h o ut prej u dice. A patie nt ma y wit h dra w fr o m t he st u d y at a n y ti me t he y 
wis h t o wit h dra w c o nse nt. 
5.  Si g nifica nt a n d ra pi d pr o gressi o n of mali g n a nc y, re q uiri n g alter nati ve me di cal, 
ra diati o n or s ur gic al i nter ve nti o n i ncl u di n g, b ut n ot li mite d t o, t he de vel o p me nt of 
C N S metastasis if t his occ urs pri or t o a n y of t he C A R T- 1 9 T-cell i nf usi o ns. 
6.  A seri o us a d verse e v e nt t hat re q uires t he p atie nt’s bei n g wit h dr a w n fr o m t he trial if 
t he S A E occ urs pri or t o a n y of t he C A R T- 1 9 T-cell i nf usi o ns. 
7.  Tec h nical diffic ulties are e nc o u ntere d i n t he T cell ge n etic m o dificati o n a n d 
e x pa nsi o n pr oce d ure t hat precl u des t he ge nerati o n of cli nical cell d oses t hat meet 
all Q ualit y C o ntr ol rele as e criteri a as s pecifie d b y F D A. 
8.  Ter mi nati o n of t he st u d y b y t he Pri nci pal I n vesti gat or, t he S p o ns or, t he st u d y 
f u n der, t he I R B, or t he F D A. 
 
O nce a s u bj ect has recei ve d a C A R T- 1 9 T -cell i nf usi o n, s u bjects s h o ul d c o nti n ue t o be f oll o we d 
u ntil t he s u bject wit h dra ws c o nse nt, dies or are l ost t o f oll o w u p. S u bjects are e nc o ura ge d t o e nr oll 
i nt o a 1 5- year l o n g-t er m f oll o w- u p pr ot oc ol t o e v al uate s pecific l o n g-ter m a d verse e ve nts relate d 
t o t he st u d y pr o d uct.  
4. 4. 2. D at a C oll e cti o n a n d F oll o w- u p  
F oll o w- u p data c ollecti o n after ge n e m o difie d cell t hera p y cli nical trials is s pecifie d b y t he F D A.  
As l o n g as p atie nts ha v e dete cta ble cells tr a ns d uce d wit h t h e le nti viral vect or, t he y s h o ul d b e 
f oll o we d f or t o xicit y, i m m u ne reacti o ns, a n d a n y l o n g-ter m a d verse e v e nts.   
 
As part of t his st u d y, s u bjects will c o nti n ue t o be f oll o we d f or 1) e n graft me nt as l o n g as patie nts 
are at ris k ( u ntil e vi de nce of l oss of detecta ble tra ns d uce d T cells), 2) D F S u ntil t h ere is diseas e 
pr o gressi o n or t he y be gi n a ne w ca ncer t hera p y, a n d 3) s ur vi val u ntil t he ti me of deat h; u ntil t he 
patie nt wit h dra ws c o nse nt f or cli nical d ata c ollecti o n or t he e n d of t he st u d y ( Last Patie nt/ Last 
Visit).  
 
I n t he e ve nt t h at a s u bject ca n n ot ret ur n t o t he st u d y site f or f oll o w- u p visits beca use of s u bject 
prefere nce or ge o gra p hic al c o ncer ns, t he s u bject’s pri mar y care p h ysi cia n a n d/ or l ocal o nc ol o gist 
will be as ke d t o pr o vi d e i nf or mati o n fr o m t he s u bj ect’s me dical rec or d t o t h e st u d y t ea m at pr ot oc ol 
defi ne d ti me p oi nts (i ncl u di n g t he res ults of a n y r o uti ne care e x a mi nati o ns a n d/ or la b orat or y 
assess me nts), a n d assist i n t he c ollecti o n of pr ot oc ol re q uire d bl o o d sa m ples (if a p plica ble) w hic h 
will be se nt t o t he U ni v ersit y of Pe n ns yl v a nia f or pr ot oc ol re q uir e d a nal ysis.  T he s u bject a n d l ocal 
pr o vi der will als o be c o ntacte d via tele p h o ne b y a me m ber of t he st u d y t ea m t o assess a n y p ote ntial 
t o xicit y. 
 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 3 3  of 1 0 8 
V ersi o n V 1 2. 0 4 -1 4 -2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
E ver y eff ort will be ma de t o c o nta ct patie nts w h o a p pear t o be l ost t o f oll o w- u p i n or der t o at l east 
o btai n s ur vi val data. I n t he e ve nt a patie nt fails t o c o m plete t he f oll o w- u p re q uire me nts, 
d oc u me ntati o n of all atte m pts t o c o ntact t he p atie nt i ncl u des at least 3 tele p h o ne c o ntacts ( o n 
differe nt d a ys a n d at differe nt ti mes of t he da y), a n d a certifi e d letter.  
 
After s u bjects c o m plete or pre mat urel y disc o nti n ue partici pati o n i n t h e Pri mar y F oll o w- u p P hase 
of t he st u d y, s u bjects will als o be as ke d t o partici pate i n a se parate 1 5- year l o n g-ter m f oll o w- u p 
desti nati o n pr ot oc ol.  
 
5.  S T U D Y D R U G 
5. 1. D e s cri pti o n 
C A R T- 1 9 cells are a ut ol o g o us T cells t hat ha ve bee n e n gi neere d t o e x press a n e xtracell ular si n gl e 
c hai n a nti b o d y (sc F v) wit h s pecificit y f or C D 1 9 li n ke d t o a n i ntracell ular si g n ali n g m olec ule 
c o nsisti n g of a ta n d e m si g nali n g d o mai ns c o m pris e d of t he T C R  si g nali n g m o d ule li n ke d t o t he 
4 - 1 B B c osti m ulat or y d o mai n. T he C A R T- 1 9 cells are cr y o preser ve d i n i nf usi ble cr y o me dia a n d 
will be a d mi nistere d o n Da ys 1 , 2 a n d 3. Eac h ba g/s yri n ge will c o ntai n a n ali q u ot ( v ol u me 
de pe n de nt u p o n d ose) of cr y o me dia c o nt ai ni n g t he f oll o wi n g i nf usi ble gra de rea ge nts ( % v/ v): 
3 1. 2 5 % plas mal yte- A, 3 1. 2 5 % de xtr ose ( 5 %), 0. 4 5 % Na Cl, u p t o 7. 5 % D M S O, 1 % de xtra n 4 0, 
5 % h u ma n ser u m al b u mi n. 
 
E x pecte d t o xicities ass ociate d wit h i nf usi o n of C A R T- 1 9 cells i ncl u de tra nsie nt fe ver, c hills 
na usea, a n d ri g ors.   I n or der t o mi ni mize t hese e ve nts, patie nts will recei ve pre me di cati o n as 
i nstr ucte d bel o w i n Secti o n 5. 4.  T o xicities t hat c o ul d p ote ntiall y o cc ur b ut are u n prece de nt e d are 
pri maril y relate d t o t he ge ne tra nsfer a n d are descri be d i n Secti o n 8. 5 .2 .    T hese i ncl u de ge n erati o n 
of a re plicati o n c o m p ete nt le nti vir us ( R C L), i nserti o nal o nc o ge nesis, a n d u n c o ntr olle d 
pr oliferati o n of t he C A R T- 1 9 cells. 
5. 2. P ati e nt Eli gi bilit y t o R e c ei v e C A R T- 1 9 Tr a n s d u c e d T C ell s 
 
D a y 1 C A R T - 1 9 I nf usi o n: 
1.   All patie nts m ust u n der g o a res pirat or y vir us p a nel ( R V P) wit hi n 1 0 da ys pri or t o 
t he first pla n ne d C A R T- 1 9 i nf usi o n. If t h e patie nt is p ositi ve f or i nfl ue nza, 
Ta mifl u ® or e q ui vale nt s h o ul d be a d mi nistere d per pac ka ge i nsert.   T h e patie nt 
m ust c o m plete treat me nt pri or  t o recei vi n g C A R T- 1 9.  T he test d oes n ot nee d t o be 
re peat e d pri or t o t he first C A R T- 1 9 i nf usi o n; h o we ver,  if i nfl ue nza si g n a n d 
s y m pt o ms are prese nt, t h e C A R T- 1 9 i nf usi o ns s h o ul d be dela ye d u ntil patie nt is 
as y m pt o matic.   If t he patie nt is p ositi ve f or a n ot her vir us o n t he R V P, t he C A R T-
1 9 i nf usi o n will be dela ye d f or at least 7 da ys t o b e s ure cli nical s y m pt o ms of a 
viral i nfecti o n d o n ot de v el o p.  If cli nical s y m pt o ms de vel o p, t he i nf usi o n will be 
dela ye d u ntil res ol uti o n of t hese s y m pt o ms.  
 
2.   Patie nt s h o ul d n ot e x perie nce a si g nifica nt c ha n ge i n p erf or m a nce or cli nical stat us 
c o m pare d t o i nitial eli gi bilit y criteria t hat w o ul d, i n t he o pi ni o n of t he treati n g 
p h ysicia n, i ncrease t he ris k of e x peri me ntal cell i nf usi o n. 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 3 4  of 1 0 8 
V ersi o n V 1 2. 0 4 -1 4 -2 0 1 7   
 
C O N F I D E N TIA L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
3.  Patie nts e x perie nci n g la b orat or y a b n or malities after e nr oll me nt, t hat i n t he o pi ni o n of t he 
treati n g i n v esti gat or or PI ma y i m pact s u bject safet y or t he s u bjects’ a bilit y t o recei ve 
C A R T- 1 9 T-cells, ma y h a ve t heir i nf usi o n dela ye d u ntil b ot h t he treati n g i n vesti gat or a n d 
PI deter mi ne it is cli nicall y a p pr o priate t o pr o cee d wit h t he C A R T- 1 9 i nf usi o n.  
 
4 .  Patie nts e x perie nci n g t o xicities fr o m t heir prece di n g c yt ore d ucti ve c he m ot hera p y ca n 
ha ve t heir i nf usi o n sc h e d ule dela ye d u ntil t hese t o xicities ha ve res ol ve d. N ote:  If patie nts 
C A R T- 1 9 i nf usi o n is dela ye d > 4 wee ks fr o m c yt ore d ucti ve c h e m ot hera p y, t he 
c yt or e d ucti ve c he m ot hera p y s h o ul d b e re p eate d. T he s pecific t o xicities warra nti n g del a y 
of T cell i nf usi o ns i ncl u de: 
a.   P ul m o nar y: Re q uir e me nt f or s u p ple me ntal o x y ge n t o k ee p sat ur ati o n greater t ha n 
9 2 % or pres e nce of ra di o gra p hic a b n or malities o n c hest x-ra y t h at are pr o gressi ve 
b.   Car diac: Ne w car diac arr h yt h mia n ot c o ntr olle d wit h me dical ma na ge m e nt 
c.   H y p ote nsi o n re q uiri n g press or s u p p ort 
d.   Acti ve I nfecti o n(s) as e vi de nt b y p ositi ve bl o o d c ult ures f or b acteri a, f u n g us, or vir us 
wit hi n 4 8 h o urs of C A R T- 1 9 cell i nf usi o n 
 
D a y 2 C A R T- 1 9 I nf usi o n: 
1.  Patie nt s h o ul d n ot e x perie nce a si g nifi ca nt c ha n ge i n perf or ma nce or cli nical stat us 
c o m pare d t o t heir pre vi o us st u d y visit t hat w o ul d, i n t he o pi ni o n of t he treati n g 
p h ysicia n, i ncrease t he ris k of e x peri me ntal cell i nf usi o n. 
 
2.  Patie nts e x perie nci n g n e w  la b orat or y a b n or malities, t hat i n t he o pi ni o n of t he treati n g 
i n vesti gat or or PI m a y i m pact s u bject safet y or t he s u bjects’ a bilit y t o r ecei v e C A R T- 1 9 
T-cells, ma y ha v e t heir i nf usi o n dela ye d u ntil b ot h t he treati n g i n vesti gat or a n d PI 
deter mi ne it is cli nicall y a p pr o priate t o pr o cee d wit h t he C A R T- 1 9 i nf usi o n. 
 
D a y 3 C A R T- 1 9 I nf usi o n: 
1.  Patie nt s h o ul d n ot e x perie nce a si g nifi ca nt c ha n ge i n perf or ma nce or cli nical stat us 
c o m pare d t o t heir pre vi o us st u d y visit t hat w o ul d, i n t he o pi ni o n of t he treati n g 
p h ysicia n, i ncrease t he ris k of e x peri me ntal cell i nf usi o n. 
 
2.  Patie nts e x perie nci n g n e w la b orat or y a b n or malities, t hat i n t he o pi ni o n of t he treati n g 
i n vesti gat or or PI m a y i m pact s u bject safet y or t he s u bjects’ a bilit y t o r ecei v e C A R T- 1 9 
T-cells, ma y ha v e t heir i nf usi o n dela ye d u ntil b ot h t he treati n g i n vesti gat or a n d PI 
deter mi ne it is cli nicall y a p pr o priate t o pr o cee d wit h t he C A R T- 1 9 i nf usi o n.  
5. 3. Tr e at m e nt R e gi m e n 
C A R T- 1 9 tra ns d uce d T cells will be a d mi nistere d at a d ose of 1 t o 5 x 1 0 8 C A R T- 1 9 tra ns d uce d 
cells gi ve n via s plit d osi n g o n Da ys 1 , 2 a n d 3. T he first C A R T- 1 9 i nf usi o n will be s c he d ule d t o 
occ ur a p pr o xi matel y 1 t o 4 da ys f oll o wi n g l y m p h o de pleti n g c he m ot hera p y b ut ma y b e d ela ye d as 
o utli ne d a b o ve ( Secti o n 5. 2).  
5. 4. Pr e p ar ati o n a n d A d mi ni str ati o n of St u d y Dr u g 
Cell ma n ufact uri n g is d o ne acc or di n g t o 
 at t he U ni versit y of Pe n ns yl v a nia 
Cli nical Cell a n d Vacci ne Pr o d ucti o n Facilit y ( C V P F). T he C A R T- 1 9 T cells are pre pare d i n t he 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 3 5  of 1 0 8 
V ersi o n V 1 2. 0 4 -1 4 -2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
C V P F a n d are n ot release d fr o m t he C V P F u ntil F D A a p pr o ve d rel ease crit eria f or t he i nf use d cells 
(e. g., cell d ose, cell p urit y, sterilit y, a vera ge c o p y n u m ber of vect ors/cell, etc.) are met. U p o n 
releas e, t he cells are a d mi nistere d at be dsi de. 
 
Cell T ha wi n g  
T he cells will be tra ns p orte d t o t he patie nt’s be dsi de o n t he da y of t he i nf usi o n. T he cells will be 
t ha we d b y tr ai ne d pers o n nel usi n g a water bat h mai ntai ne d at 3 6C t o 3 8 C.  T he ba g will be 
ge ntl y massa ge d u ntil t he cells ha ve j ust t ha we d.  T here s h o ul d be n o fr oze n cl u m ps re mai ni n g at 
t he ti me it is c o n necte d t o t he i. v site. If t he C A R T- 1 9 cell pr o d uct a p p ears t o be da ma ge d or 
lea ki n g, or ot her wise a p p ears t o be c o m pr o mise d, it s h o ul d n ot be i nf use d, a n d s h o ul d be ret ur ne d 
t o t he C V P F. 
 
Pre me dicati o n 
Si de effects f oll o wi n g T cell i nf usi o ns i ncl u de tra nsie nt fe v er, c hills, a n d/ or na usea 1 1 5. It is 
rec o m me n de d t h at t he patie nt be pre- me dicate d wit h 6 5 0 m g aceta mi n o p he n a n d 2 5- 5 0 m g 
di p he n h y dra mi ne h y dr oc hl ori de pri or t o eac h i nf usi o n of C A R T- 1 9 cells. T hese me dicati o ns ma y 
be re peate d e ver y si x h o urs as nee de d. A c o urse of n o n-ster oi dal a nti-i nfl a m mat or y me di cati o n 
ma y b e pres cri be d if t h e patie nt c o nti n ues t o ha ve fe v er n ot relie ve d b y aceta mi n o p he n. Patie nts 
s h o ul d n ot recei ve s yste mic c ortic oster oi ds s u c h as h y dr oc ortis o ne, pre d nis o ne, pre d nis ol o ne 
( S ol u- Me dr ol) or de x a met has o ne ( Deca dr o n) at a n y ti me, e x ce pt i n t he case of a life-t hr eate ni n g 
e mer ge n c y, si nce t his ma y ha v e a n a d verse effect o n C A R T- 1 9 cell e x pa nsi o n a n d f u ncti o n.   
 
Fe brile reacti o n 
I n t h e e v e nt of fe brile reacti o n, a n e val uati o n f or i nfecti o n s h o ul d be i nitiate d, a n d patie nts 
ma na ge d a p pr o priatel y wit h a nti bi otics, fl ui ds a n d ot her s u p p orti ve care as me dicall y i n dicate d 
a n d deter mi ne d b y t he tr eati n g p h ysicia n. I n t h e e v e nt t hat t he patie nt de vel o ps se psis or s yste mic 
bactere mia f oll o wi n g C A R T cell i nf usi o n, a p pr o priate c ult ures a n d me dical ma na ge m e nt s h o ul d 
be i nitiate d.   If a c o nta mi nate d C A R T- 1 9 T cell pr o d uct is s us pecte d, t he pr o d uct ca n be reteste d 
f or sterilit y usi n g arc hi ve d sa m ples t hat are st ore d i n t he C V P F.  C o nsi derati o n of a C R S s h o ul d 
be gi v e n.   
 
A d diti o nal Safet y Pr oce d ures pri or t o A d mi nistrati o n 
T he o n-site p har m ac y m ust c o nfir m t h at a d ose of t ociliz u ma b  is o n site a n d a v aila ble f or 
a d mi nistrati o n i n or der t o ma na ge s us pecte d t o xicities pri or t o i nf usi o n. 
 
E mer ge nc y me dical e q ui p me nt (i.e., e mer ge nc y tr olle y) m ust be a vaila bl e d uri n g t he i nf usi o n i n 
case t he patie nt has a n aller gic res p o nse, or se v ere h y p ote nsi ve crisis, or a n y ot her reacti o n t o t he 
i nf usi o n. Vital si g ns (te m perat ur e, p ulse, a n d bl o o d press ure) will be ta ke n bef ore i nf usi o n.  
 
Pac ka gi n g a n d La b eli n g 
C A R T- 1 9 tra ns d uce d T cells will be a d mi nistere d at a d ose of 1 t o 5 x 1 0 8 C A R T- 1 9 tra ns d uce d 
cells gi v e n via s plit d osi n g o n D a ys 1, 2 a n d 3. Eac h ba g/s yri n ge will c o ntai n a n ali q u ot ( v ol u me 
de pe n de nt u p o n d ose) of cr y o m e dia c o ntai ni n g t he f oll o wi n g i nf usi ble gra de rea ge nts ( % v/ v): 
3 1. 2 5 % plas mal yte- A, 3 1. 2 5 % de xtr ose ( 5 %), 0. 4 5 % Na Cl, u p t o 7. 5 % D M S O, 1 % de xtra n 4 0, 
5 % h u ma n ser u m al b u mi n. 
 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 3 6  of 1 0 8 
V ersi o n V 1 2. 0 4 -1 4 -2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
Eac h i nf usi o n ba g/s yri n ge will ha ve affi x e d t o it a la bel c o ntai ni n g i nf or m ati o n re gar di n g t h e d ose, 
t he met h o d of ma ni p ulati o n, a n d t he vect or.  I n a d diti o n, t he la bel will ha ve at least t w o u ni q ue 
i de ntifiers. Pri or t o eac h i nf usi o n, t w o i n di vi d uals will i n de pe n de ntl y v erif y all u ni q ue i de ntifier 
i nf or mati o n i n t he prese nce of t he patie nt a n d t o c o nfir m t hat t he i nf or mati o n is c orrectl y matc h e d 
t o t he patie nt. 
5. 5. I nf u si o n of C A R T- 1 9  Pr o d u ct 
Trai ne d st u d y staff will a d mi nister t he C A R T- 1 9 pr o d uct via i. v. i nf usi o n b y gra vit y or s yri n ge 
usi n g preca uti o ns f or i m m u n os u p presse d patie nts.  T he tra ns d uce d T cells will be i nf use d at a fl o w 
rate of a p pr o xi matel y 1 0 t o 2 0 m L per mi n ute. A le u k ore d ucti o n filter m ust n ot be use d f or t he 
i nf usi o n of t he T cell pr o d uct. T he d urati o n of t h e i nf usi o n will be base d o n t he t otal v ol u me t o 
be i nf use d a n d t he rec o m me n de d i nf usi o n rate.  Vital si g ns (te m perat ur e, p ulse, bl o o d press ure, 
a n d o x y ge n sat ur ati o n b y p ulse o xi metr y) will be meas ure d wit hi n 1 0 mi n utes pri or t o t he i nf usi o n , 
wit hi n 1 0 mi n utes after t he i nf usi o n, e ver y 1 5 mi n utes f or t he first h o ur a n d t he n e ver y h o ur f or 
t he ne xt 2 h o urs u ntil t hese si g ns are satisfact or y a n d sta ble. If t he s u bject’s vital si g ns are n ot 
satisfact or y a n d sta ble t hree h o urs p ost- C A R T- 1 9 i nf usi o n, vital si g ns will c o nti n ue t o be 
m o nit ore d at a mi ni m u m of e ver y h o ur or as cli nicall y i n dicat e d u ntil sta ble. T he s u bject will be 
disc har ge d after t he p h ysicia n ma na gi n g t heir care o n t he da y of eac h i nf usi o n has deter mi ne d t hat 
t he y are i n satisf act or y c o n diti o n. 
5. 6. C o n c o mit a nt T h er a p y 
All prescri pti o n a n d n o n prescri pti o n me dicati o n, vita mi ns, her bal a n d n utriti o nal s u p ple me nts, 
ta ke n b y t he p atie nt d uri n g t he 3 0 da ys pri or t o scree ni n g will be rec or de d. At e ver y visit f oll o wi n g 
t he C A R T- 1 9 i nf usi o ns a n d u ntil t he p atie nt h as c o m plete d or h as bee n disc o nti n ue d fr o m 
partici pati o n i n t he st u d y, c o nc o mita nt me dicati o ns will be rec or de d i n t he me dical rec or d a n d o n 
t he a p pr o priate C R F. A n y a d diti o ns, deleti o ns, or c ha n ges of t h ese 
me dicati o ns will be 
d oc u me nte d. T he f oll o wi n g g ui deli nes m ust be a d here d t o d uri n g t he st u d y: 
 G M - C S F s h o ul d be a v oi de d d ue t o p ote ntial t o w orse n C R S s y m pt o ms.  G- C S F 
w o ul d be t he preferre d m yel oi d gr o wt h fact or o v er G M- C S F, if me dicall y i n dicate d. 
T he effects of G- C S F are u n k n o w n a n d ca n b e use d at t he p h ysici a n’s discreti o n. 
 Ster oi ds or ot her i m m u n os u p pressa nt dr u gs s h o ul d N O T be use d wit hi n 1 0 da ys 
pri or t o t he a p heresis pr oce d ure.   
 Ster oi ds or ot her i m m u n os u p pressa nt dr u gs s h o ul d N O T be use d wit hi n 2 4 h o urs 
pri or t o t he C A R T- 1 9 i nf usi o n (refer t o Secti o n 5 . 4) or f oll o wi n g C A R T- 1 9 i nf usi o n 
u nless u n der life t hreate ni n g cir c u msta nces or at t he p h ysici a n’s discreti o n t o 
ma na ge C R S. 
 Patie nts wit h se vere si g ns a n d s y m pt o ms attri b uta ble t o c yt o ki ne release s y n dr o me 
(i.e. C R S) s h o ul d be ma na ge d wit h a d mi nistrati o n of t ociliz u ma b or ot her a nti-
c yt o ki ne dir ecte d t h era pi es ( Refer t o Secti o n 8. 5. 2 f or a d mi nistrati o n details). 
  
6.  S T U D Y P R O C E D U R E S 
 
 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 3 7  of 1 0 8 
V ersi o n V 1 2. 0 4 -1 4 -2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
O ver vie w: 
T he sc he d ule of e val u ati o ns a n d st u d y pr oce d ures are des cri be d i n t he Visit E val uati o n 
Sc he d ules i n T a ble s 6 - 1 ( M ai n Tre at me nt P h ase) a n d 6- 2 ( Retre at me nt C o h ort). Als o, refer 
t o Secti o n 6  f or f urt her details of t he sc he d ule of eac h assess me nt, a nal ysis a n d 
pr ocessi n g/ ha n dli n g of sa m ples. 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
3 9  of 1 0 8 
V ersi o n V 1 2. 0 4 -1 4 -2 0 1 7   
 
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
 
S cr e e ni n g 
a n d 
E nr oll m e nt  
C h e m o -
T h er a p y  
Pr e -I nf u si o n 
I nf u si o n # 1 
I nf u si o n # 2 
I nf u si o n # 3 
F oll o w -U p  
F oll o w -U p  
F oll o w -U p  
F oll o w -U p  
F oll o w -U p  
F oll o w -U p  
M o nt hl y 
F oll o w -U p 2  
Q u art erl y 
F oll o w -U p 2  
S e c o n d ar y 
F oll o w -u p 2 6 
Vi sit N u m b er  
1  
2  
3  
4  
2 0 1  
2 0 2  
5  
6  
7  
8  
9  
1 0  
5 0 1 -5 0 5  
5 0 6 -5 0 7  
6 0 1 +  
 
-1 2 W 
t o        
-1 W  
~ -1 W  
~ -1 D  
D 1  
D 2  
( +) 1 d 
D 3  
( +) 1 d 
D 4  
( +) 1 d 
D 7  
( +/-) 
1 d  
D 1 1  
( +/-) 
1 d  
D 1 4  
( +/-) 1 d 
D 2 1  
( +/-) 3 d 
D 2 8  
( +/-) 3 d 
M 2 M 3 
M 4 M 5 
M 6      
( +/-) 7 d 
M 9 M 1 2  
( +/-) 1 4 d  
E v er y 
6 M o nt h s  
H e m at ol o g y  
( 5 ml l a v e n d er t o p, E D T A) 
x  
 
x  
x  
X  
x  
x  
x  
x  
x  
x  
x  
x  
x  
 
C h e mi str y ( 3 ml S S T)  
x 1 7  
 
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
 
C o a g ul ati o n  [ P T, P T T, 
I N R, fi bri n o g e n, D-di m er] 
( 4. 5 ml bl u e t o p citr at e) 
x  
 
x  
x 2 4  
x 2 4  
x 2 4  
x 1 3  
x  
X 1 3  
x  
x  
x  
x 2 4  
x 2 4  
 
S er u m Pr e g n a n c y T e st 1 1   
( 1 ml S S T)  
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Uri n e Pr e g n a n c y T e st 1 1  
 
 
x  
 
 
 
 
 
 
 
 
 
 
x  
 
T C ell S u b s et s: 
C D 3/ C D 4/ C D 8  
( 4 ml l a v e n d er t o p, E D T A) 
 
 
 
x  
 
 
 
 
 
 
 
x  
x  
 
 
A ut oi m m u n e S cr e e n ( A N A, 
E S R) ( 4 ml S S T; 3 ml 
l a v e n d er t o p E D T A) 
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HI V T e st ( 1 ml S S T)  
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
V ir al S er ol o g y (C M V, E B V, 
H e p atiti s B a n d C) ( 5 ml 
r e d t o p, s er u m) 
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
S er u m I m m u n o gl o b uli n 
l e v el s ( 1 ml S S T) 
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
H L H/ M A S (tri gl y c eri d e s, 
h a pt o gl o bi n)( 4 m L S S T; 
2. 5 m L l a v e n d er t o p, 
E D T A)  
 
 
x  
x 8  
x 8  
x 8  
x 8  
x 8  
x 8  
x 8  
x 8  
x 8  
x 8  
x 8  
 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
4 3  of 1 0 8 
V ersi o n V 1 2. 0 4 -1 4 -2 0 1 7   
 
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
 
S cr e e ni n g 
a n d 
E nr oll m e nt  
C h e m o -
T h er a p y  
Pr e -I nf u si o n 
I nf u si o n # 1 
I nf u si o n # 2 
I nf u si o n # 3 
F oll o w -U p  
F oll o w -U p  
F oll o w -U p  
F oll o w -U p  
F oll o w -U p  
F oll o w -U p  
M o nt hl y 
F oll o w -U p 2  
Q u art erl y 
F oll o w -U p 2  
S e c o n d ar y 
F oll o w -u p 2 6 
Vi sit N u m b er  
1  
2  
3  
4  
2 0 1  
2 0 2  
5  
6  
7  
8  
9  
1 0  
5 0 1 -5 0 5  
5 0 6 -5 0 7  
6 0 1 +  
 
-1 2 W 
t o        
-1 W  
~ -1 W  
~ -1 D  
D 1  
D 2  
( +) 1 d 
D 3  
( +) 1 d 
D 4  
( +) 1 d 
D 7  
( +/-) 
1 d  
D 1 1  
( +/-) 
1 d  
D 1 4  
( +/-) 1 d 
D 2 1  
( +/-) 3 d 
D 2 8  
( +/-) 3 d 
M 2 M 3 
M 4 M 5 
M 6      
( +/-) 7 d 
M 9 M 1 2  
( +/-) 1 4 d  
E v er y 
6 M o nt h s  
Q u alit y of Lif e ( Q o L) 
q u e s ti o n n air e s ( F A C T-L e u 
a n d E O R T C -Q L Q C 3 0)  
x  
 
 
 
 
 
 
 
 
 
 
 
x 9  
 
 
 
T otal cli ni c al bl o o d dr a w ( m L)  
2 7. 5  
0  
1 2. 5  
1 6  
1 6  
1 6  
1 2. 5  
1 2. 5  
1 2. 5  
1 2. 5  
1 2. 5  
1 6. 5  
1 2  
1 2  
 
T otal r e s ear c h bl o o d dr a w ( m L)  
5 5  
0  
3 0  
3 5  
3 5  
3 5  
3 0  
3 0  
3 0  
3 0  
3 0  
1 3 0  
3 0  
3 0  
 
T otal bl o o d dr a w ( m L)  
8 2. 5  
0  
4 2. 5  
5 1  
5 1  
5 1  
4 2. 5  
4 2. 5  
4 2. 5  
4 2. 5  
4 2. 5  
1 4 6. 5  
4 2  
4 2  
 
T otal bl o o d dr a w ( T b s p.; 
a p pr o xi m atel y)  
5. 5  
0  
3  
3. 5  
3. 5  
3. 5  
3  
3  
3  
3  
3  
1 0  
3  
3  
 
1 T u m or res p o nse assess me nts will b e perf or me d at Da y 2 8, M o nt hs 3, 6, 9 a n d 1 2 after C A R T- 1 9 cell i nf usi o ns ( Refer t o Secti o n 6. 1 4 f or f urt her details 
a n d fre q ue nc y) 
2  Tra nslati o nal a n d C orrelati ve St u dies La b orat or y ( T C S L) has re q ueste d la b sa m ples f or res earc h be se nt t o T C S L as s o o n as c ollecte d. If re q uire d t o kee p 
researc h la bs after h o urs, please kee p re d t o ps u pri g ht, la ve n der t u bes s h o ul d be r o o m te m perat ure o n r otati n g platf or ms. I n t he e ve nt t hat s o met hi n g 
u ne x pecte d occ urs, a d diti o nal researc h sa m ple c ollecti o n ma y be d o ne as necessar y. Bl o o d c ollecti o ns are n ot t o e xcee d 3 ta bles p o o ns of bl o o d t wice i n 
o ne wee k ti me wi n d o w. Marr o w/ L N c ollecti o ns w o ul d n ot e xcee d m ore t ha n o ne pr oce d ure per m o nt h. T his w o ul d be at t he PI ’s discreti o n. 
3  M o nt hs 3, 6 a n d 1 2 o nl y 
4  L y m p h o de pleti n g c he m ot hera p y pri or t o C A R T- 1 9 cell i nf usi o n is N O T re q uire d if W B C ≤ 1, 0 0 0 / u L 
5 C D 3 + li nea ge-s pecific c hi meris m preferre d. C hi meris m will be perf or me d o nl y i n patie nts wit h pri or all o ge neic tra ns pla nt at t he H os pital of t he U ni versit y 
of P e n ns yl va nia. 
6  A p heresis will be perf or me d i n or der t o o btai n a tar get of 5 x 1 0 9 P B M Cs f or C A R T- 1 9 ma n ufact uri n g (as re q uire d).   A p heresis ca n occ ur a n yti me after 
i nf or me d c o nse nt is o btai ne d, u p t o 4 wee ks pri or t o C A R T- 1 9 i nf usi o n.   Cr y o preser ve d hist orical a p heresis pr o d ucts c ollecte d fr o m t he patie nt pri or t o 
st u d y e ntr y are usa ble f or C A R T- 1 9 ma n ufact uri n g if c ollecte d at a n a p pr o priatel y certifie d a p heresis ce nter a n d t he pr o d uct meets a de q uate m o n o n uclear 
cell yiel ds.    
7  M o nt h 1 2 o nl y.  

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
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C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
8  As cli nicall y i n dicate d if H L H/ M A S or C R S is s us pecte d 
9  M o nt hs 3 a n d 6 
1 0  M o nt hs 3, 6, 9 a n d 1 2 
1 1  Pre g na nc y test ( q ua ntitati ve) f or fe males o nl y 
1 2  Vital si g ns will be ta ke n wit hi n 1 0 mi n utes pri or, wit hi n 1 0 mi n utes after eac h i nf usi o n, e ver y 1 5 mi n utes f or t he first o ne h o ur a n d t he n e ver y h o ur f or t he 
ne xt t w o h o urs u ntil t hese si g ns are satisfact or y a n d sta ble. 
1 3  D- di mer re q uire d o n Da ys 4 a n d 1 1.  A d diti o nal testi n g t o be perf or me d if H L H/ M A S or C R S is s us pecte d. 
1 4  B o ne marr o w bi o ps y/as pirate t o be perf or me d wit hi n 4 8 h o urs pri or t o t he first C A R T- 1 9 T-cell i nf usi o n. T he res ults of t his baseli ne b o ne marr o w are n ot 
re q uire d pri or t o i nf usi o n.  
1 5  D L C O > 4 0 %; P ulse O x y ge n > 9 2 % o n r o o m air 
1 6  C T/ M RI will o nl y be perf or me d o n Da y 2 8 a n d M o nt h 3 visits if baseli ne c hest x-ra y i n dic ates me diasti nal disease 
1 7  Direct bilir u bi n will b e perf or me d at scree ni n g o nl y 
1 8  Al l p atie nts m ust u n der g o a res pirat or y vir us pa nel ( R V P) t o test f or i nfl ue nza wit hi n 1 0 da ys pri or t o t he first pla n ne d C A R T- 1 9 i nf usi o n.  If t he patie nt is 
p ositi ve f or i nfl ue nza, oselta mi vir p h os p hate ( T a mifl u ®) or e q ui vale nt s h o ul d be a d mi nist ere d (see T a mifl u ® p ac ka ge i nsert f or d osi n g i nf or mati o n). T he 
patie nt m ust c o m plete t his c o urse of pre ve ntati ve treat me nt pri or t o recei vi n g t he first C A R T- 1 9 i nf usi o n. If t he patie nt is p ositi ve f or i nfl ue nza a n d is als o 
e x perie nci n g fl u-li ke s y m pt o ms, all cli nical s y m pt o ms m ust als o be res ol ve d pri or t o t he C A R T- 1 9 i nf usi o n.  If a patie nt is p ositi ve f or a n ot her vir us o n 
t he R V P, C A R T- 1 9 i nf usi o ns will b e dela ye d f or at least 7 da ys t o be s ure cli nical s y m pt o ms of a viral i nfecti o n d o n ot d e vel o p.  If cli nical s y m pt o ms 
de vel o p, t he i nf usi o ns will be dela ye d u ntil res ol uti o n of t hese s y m pt o ms. 
1 9  Researc h bl o o d ( 5 cc re d t o p) t o be ta ke n pri or t o eac h i nf usi o n a n d bet wee n 2 0- 1 2 0 mi n ut es p ost-i nf usi o n. 
2 0  Researc h bl o o d ( 2 5 cc la ve n der t o p) t o be ta ke n bet wee n 2 0- 1 2 0  mi n utes p ost-i nf usi o n. 
2 1  E C H O/ M U G A m ust be perf or me d wit hi n 8 wee ks pri or t o t he first C A R T- 1 9 i nf usi o n. 
2 2  L y m p h n o de bi o ps y is o pti o nal a n d perf or me d if accessi ble a n d/ or as cli nicall y i n dicate d  
2 3  If t he res ults of a hist orical b o ne marr o w bi o ps y ( o btai ne d at t he ti me of t he patie nt’s last rela pse) are a vaila ble at t he ti me of e nr oll me nt, t his d oes n ot 
nee d t o be re p eate d f or e nr oll me nt.  If s u bj ects recei ve treat me nt f or t heir A L L after st u d y eli gi bilit y is c o nfir me d, a re p eat b o ne marr o w s h o ul d be 
perf or me d pri or t o l y m p h o de pleti n g c he m ot hera p y (if a d mi nistere d) a n d wit hi n 4 wee ks pri or t o t he first C A R T- 1 9 i nf usi o n. If l y m p h o de pleti n g 
c he m ot hera p y is n ot a d mi nistere d, t he pre-i nf usi o n b o ne marr o w (t o be perf or me d wit hi n 4 8 h o urs pri or t o t he first C A R T- 1 9 i nf usi o n) is s ufficie nt.  
2 4  P erf or me d if cli nicall y i n dicat e d. 
2 5  Pr o p h ylactic gra m ne gati ve a nti bi otics m ust be i nitiate d be gi n ni n g o n Da y 1.   T he c h oice of a nti bi otic will be left t o t he p h ysicia n-i n vesti gat or’s discreti o n 
a n d will be a d mi nistere d per i nstit uti o nal g ui deli nes. 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
4 5  of 1 0 8 
V ersi o n V 1 2. 0 4 -1 4 -2 0 1 7   
 
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
2 6  F or s u bj ects w h o c o m plete or pre mat urel y disc o nti n ue fr o m t he Pri mar y F oll o w- u p P hase of t he st u d y w hile i n re missi o n, f oll o w- u p atte m pts will be ma d e 
t o assess t he s u bj ect’s rela pse a n d s ur vi val stat us e ver y 6 m o nt hs p ost C A R T- 1 9 i nf usi o n u ntil t he e n d of t he st u d y ( Last P atie nt/ Last Visit). O nce s u bj ects 
rela pse t he y will be f oll o we d f or s ur vi val u ntil t he e n d of t he st u d y ( Last P atie nt/ Last Visit) o nl y. 
2 7 Researc h bl o o d dra w ( ~ 2 5cc) will be c ollecte d at scree ni n g/e nr oll me nt a n d a gai n at t he ti me of a p heresis.  
 
 
 
 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
4 7  of 1 0 8 
V ersi o n V 1 2. 0 4 -1 4 -2 0 1 7   
 
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
 
S cr e e ni n g 
a n d 
E nr oll m e nt  
C h e m o -
T h er a p y  
Pr e -I nf u si o n 
I nf u si o n # 1 
I nf u si o n # 2 
I nf u si o n # 3 
F oll o w -U p  
F oll o w -U p  
F oll o w -U p  
F oll o w -U p  
F oll o w -U p  
F oll o w -U p  
M o nt hl y 
F oll o w -U p 2  
Q u art erl y 
F oll o w -U p 2  
S e c o n d ar y 
F oll o w -u p 2 6 
Vi sit N u m b er  
1 0 1  
1 0 2  
1 0 3  
1 0 4  
1 0 5  
1 0 6  
1 0 7  
1 0 8  
1 0 9  
1 1 0  
1 1 1  
1 1 2  
5 5 1 -5 5 5  
5 5 6 -
5 5 7  
6 0 2 +  
 
-1 2 W 
t o        
-1 W  
~ -1 W  
~ -1 D  
D 1  
D 2  
( +) 1 d 
D 3  
( +) 1 d 
D 4  
( +) 1 d 
D 7  
( +/-) 1 d 
D 1 1  
( +/-) 1 d 
D 1 4  
( +/-) 1 d 
D 2 1  
( +/-) 3 d 
D 2 8  
( +/-) 3 d 
M 2 M 3 M 4 
M 5 M 6      
( +/-) 7 d 
M 9 
M 1 2  
( +/-) 
1 4 d  
E v er y 
6 M o nt h
s  
C o a g ul ati o n  [ P T, P T T, 
I N R, fi bri n o g e n, D-di m er] 
( 4. 5 ml bl u e t o p citr at e) 
x  
 
x  
x 2 4  
x 2 4  
X 2 4  
x 1 3  
x  
X 1 3  
x  
x  
x  
x 2 4  
x 2 4  
 
S er u m Pr e g n a n c y T e st 1 1   
( 1 ml S S T) 
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Uri n e Pr e g n a n c y T e st 1 1  
 
 
x  
 
 
 
 
 
 
 
 
 
 
x  
 
T C ell S u b s et s: 
C D 3/ C D 4/ C D 8  
( 4 ml l a v e n d er t o p, E D T A) 
 
 
 
X  
 
 
 
 
 
 
 
x  
x  
 
 
A ut oi m m u n e S cr e e n ( A N A, 
E S R) ( 4 ml S S T; 3 ml 
l a v e n d er t o p E D T A) 
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HI V T e st ( 1 ml S S T)  
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vir al S er ol o g y ( C M V, E B V, 
H e p atiti s B a n d C) ( 5 ml 
r e d t o p, ser u m)  
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
S er u m I m m u n o gl o b uli n 
l e v el s ( 1 ml S S T) 
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
H L H/ M A S (tri gl y c eri d e s, 
h a pt o gl o bi n)( 4 m L S S T; 
2. 5 m L l a v e n d er t o p, 
E D T A)  
 
 
x  
x 8  
x 8  
x 8  
x 8  
x 8  
x 8  
x 8  
x 8  
x 8  
x 8  
x 8  
 
F erriti n, L D H a n d C R P f or 
C yt o ki n e R el e a s e 
S y n dr o m e  
 
 
x  
x 8  
x 8  
x 8  
x 8  
x 8  
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x 8  
 

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5 2  of 1 0 8 
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C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
1 1  Pre g na nc y test ( q ua ntitati ve) f or fe males o nl y 
1 2  Vital si g ns will be ta ke n wit hi n 1 0 mi n utes pri or, wit hi n 1 0 mi n utes after eac h i nf usi o n, e ver y 1 5 mi n utes f or t he first o ne h o ur a n d t he n e ver y h o ur f or t he 
ne xt t w o h o urs u ntil t hese si g ns are satisfact or y a n d sta ble. 
1 3  D- di mer re q uire d o n Da ys 4 a n d 1 1.  A d diti o nal testi n g t o be perf or me d if H L H/ M A S or C R S is s us pecte d. 
1 4  B o ne marr o w bi o ps y/as pirate t o be perf or me d wit hi n 4 8 h o urs pri or t o t he first C A R T- 1 9 T-cell i nf usi o n. T he res ults of t his baseli ne b o ne marr o w are n ot 
re q uire d pri or t o i nf usi o n.  
1 5  D L C O > 4 0 %; P ulse O x y ge n > 9 2 % o n r o o m air 
1 6  C T/ M RI will o nl y be perf or me d o n Da y 2 8 a n d M o nt h 3 visits if baseli ne c hest x-ra y i n dic ates me diasti nal disease 
1 7  Direct bilir u bi n will b e perf or me d at scree ni n g o nl y 
1 8  All patie nts m ust u n der g o a res pirat or y vir us pa nel ( R V P) t o test f or i nfl ue nza wit hi n 1 0 da ys pri or t o t he first pla n ne d C A R T- 1 9 i nf usi o n.  If t he patie nt is 
p ositi ve f or i nfl ue nza, oselta mi vir p h os p hate ( T a mifl u ®) or e q ui vale nt s h o ul d be a d mi nist ere d (see T a mifl u ® p ac ka ge i nsert f or d osi n g i nf or mati o n). T he 
patie nt m ust c o m plete t his c o urse of pre ve ntati ve treat me nt pri or t o recei vi n g t he first C A R T- 1 9 i nf usi o n. If t he patie nt is p ositi ve f or i nfl ue nza a n d is als o 
e x perie nci n g fl u-li ke s y m pt o ms, all cli nical s y m pt o ms m ust als o be res ol ve d pri or t o t he C A R T- 1 9 i nf usi o n.  If a patie nt is p ositi ve f or a n ot her vir us o n 
t he R V P, C A R T- 1 9 i nf usi o ns will b e dela ye d f or at least 7 da ys t o be s ure cli nical s y m pt o ms of a viral i nfecti o n d o n ot d e vel o p.  If cli nic al s y m pt o ms 
de vel o p, t he i nf usi o ns will be dela ye d u ntil res ol uti o n of t hese s y m pt o ms. 
1 9  Researc h bl o o d ( 5 cc re d t o p) t o be ta ke n pri or t o eac h i nf usi o n a n d bet wee n 2 0- 1 2 0 mi n ut es p ost-i nf usi o n. 
2 0  Researc h bl o o d ( 2 5 cc la ve n der t o p) t o be ta ke n bet wee n 2 0- 1 2 0 mi n utes p ost-i nf usi o n. 
2 1  E C H O/ M U G A m ust b e perf or me d wit hi n 8 wee ks pri or t o t he first C A R T- 1 9 i nf usi o n. 
2 2  L y m p h n o de bi o ps y is o pti o nal a n d perf or me d if accessi ble a n d/ or as cli nicall y i n dicate d  
2 3  If t he res ults of a hist orical b o ne marr o w bi o ps y ( o btai ne d at t he ti me of t he patie nt’s last rela pse) are a vaila ble at t he ti me of e nr oll me nt, t his d oes n ot 
nee d t o be re p eate d f or e nr oll me nt.  If s u bj ects recei ve treat me nt f or t heir A L L after st u d y eli gi bilit y is c o nfir me d, a re p eat b o ne marr o w s h o ul d be 
perf or me d pri or t o l y m p h o de pleti n g c he m ot hera p y (if a d mi nistere d) a n d wit hi n 4 we e ks pri or t o t he first C A R T- 1 9 i nf usi o n. If l y m p h o de pleti n g 
c he m ot hera p y is n ot a d mi nistere d, t he pre-i nf usi o n b o ne marr o w (t o be perf or me d wit hi n 4 8 h o urs pri or t o t he first C A R T- 1 9 i nf usi o n) is s ufficie nt.  
2 4  P erf or me d if cli nicall y i n dicat e d. 
2 5  Pr o p h ylactic gra m ne gati ve a nti bi otics m ust be i nitiate d be gi n ni n g o n Da y 1.  T he c h oice of a nti bi otic will be left t o t he p h ysicia n-i n vesti gat or’s discreti o n 
a n d will be a d mi nistere d per i nstit uti o nal g ui deli nes. 
2 6  F or s u bj ects w h o c o m plete or pre mat urel y disc o nti n ue fr o m t he Pri mar y F oll o w- u p P hase of t he st u d y w hile i n re missi o n, f oll o w- u p atte m pts will be ma d e 
t o assess t he s u bj ect’s rela pse a n d s ur vi val stat us e ver y 6 m o nt hs p ost C A R T- 1 9 i nf usi o n u ntil t he e n d of t he st u d y ( Last P atie nt/ Last Visit). O nce s u bj ects 
rela pse t he y will be f oll o we d f or s ur vi val u ntil t he e n d of t he st u d y ( Last P atie nt/ Last Visit) o nl y. 
2 7 Researc h bl o o d dra w ( ~ 2 5cc) will be c ollecte d at t he ti me of a p heresis (if perf or me d).  

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 5 3  of 1 0 8 
V ersi o n V 1 2. 0 4 -1 4 -2 0 1 7   
C O N FI D E N TI A L  
T his d oc u me nt is c o nfi de nti al a n d t he pr o pe rt y of t he U ni ve rsit y of Pe n ns yl v a ni a.  N o p art of it m a y be tr a ns mitte d, 
re pr o d uce d, p u blis he d, or use d b y ot he r pers o ns wit h o ut pri or w ritte n a ut h oriz ati o n fr o m t he st u d y s p o ns or.  
6. 1. S cr e e ni n g a n d E nr oll m e nt A s s e s s m e nt s 
I nf or me d c o ns e nt m ust be o btai ne d bef ore t he patie nt ca n u n der g o a n y researc h relate d 
pr oce d ures.  
 
Scree ni n g/e nr oll me nt assess me nts are d escri be d i n t his secti o n a n d i n t he Visit E val uati o n 
Sc he d ule (T a ble 6 - 1). 
 Verific ati o n of i ncl usi o n a n d e x cl usi o n criteria 
 De m o gra p h y i ncl u di n g d ate of birt h, se x, race, a n d et h nicit y  
 D oc u me ntati o n of me dical hist or y i ncl u di n g pri or a n d c urre nt me dical c o n diti o ns, a n d 
c hil d beari n g stat us  
 D oc u me ntati o n of hist orical a n d c o n c o mita nt me dicati o ns a n d si g nifica nt n o n- dr u g 
t hera pies 
 Re vie w of pri or a nti ne o plastic me dicati o ns- i ncl u di n g bli nat u m o ma b 
 P h ysical e x a m a n d meas ure me nt of vital si g ns ( hei g ht, wei g ht, B S A, bl o o d press ure, 
b o d y te m perat ur e, heart rate a n d o x y ge n s at urati o n via p ulse o xi metr y 
 E C O G perf or ma nce stat us 
 Scree ni n g E C H O/ M U G A m ust be perf or m e d wit hi n 8  wee ks pri or t o t he first C A R T-
1 9 i nf usi o n.  
 Bl o o d will be ta ke n f or He mat ol o g y, C oa g ul ati o n, a n d Bi oc he mistr y a nal ysis. Viral 
ser ol o gi es ( HI V, C M V, E B V, He patitis B/ C). If t he H C V a nti b o d y is p ositi ve, a 
scree ni n g H C V R N A b y a n y R T- P C R or b D N A assa y m ust be p erf or m e d. Eli gi bilit y 
will be deter mi ne d bas e d o n t he scree ni n g v al ue. T he test is n ot re q uire d if 
d oc u me ntati o n of a ne gati ve res ult of a H C V R N A test perf or me d wit hi n 6 0 da ys pri or 
t o scree ni n g is pr o vi de d. 
 Ser u m pre g na n c y test f or fe males of c hil d beari n g p ote ntial 
 A ut oi m m u ne scree ni n g: a nti n uclear a nti b o d y ( A N A) a n d Er yt hr o c yte se di me ntati o n 
rate ( E S R) 
 D o n or c hi meris m assess me nt f or t h ose patie nts t h at ha ve ha d pre vi o us all o ge n eic 
H S C T  at t he H os pital of t he U ni versit y of Pe n ns yl va nia 
 Ser u m i m m u n o gl o b uli n le vels 
 B C R- A B L ( P h + A L L p atie nts o nl y) 
 B o ne marr o w a n d peri p h eral bl o o d sa m ples will be ta ke n f or res earc h a nal ysis as 
descri be d i n T a ble 6- 1 . 
 B o ne marr o w as pirate a n d l y m p h n o de bi o ps y (if accessi ble) f or dise ase a n d M R D  
assess me nt  as descri be d i n T a ble 6 - 1. If t h e res ults of a hist orical b o ne marr o w bi o ps y 
( o btai ne d at t he ti me of t he patie nt’s last rel a pse) are a v aila ble at t he ti me of 
e nr oll me nt, a b o ne marr o w d oes n ot nee d t o be re p eate d f or e nr oll me nt. 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 5 4  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
 C hest x-ra y f or m e diasti nal disease ass ess me nt. If t he c hest x-ra y re v eals m e diasti nal 
wi de ni n g, t he n a C T or M RI sca n is re q uir e d at b aseli ne. 
 C S F e val uati o n- If C S F e val uati o n i n dicates t hat t he y h a ve C N S i n v ol ve me nt, brai n 
i ma gi n g b y M RI or C T will be perf or me d t o f urt her assess C N S le u ke mic 
i n v ol ve me nt. 
 P ul m o nar y f u ncti o n test ( D L C O)  
 Q ualit y of lif e q uesti o n naires ( F A C T- Le u versi o n 4 a n d E O R T C- Q L Q C 3 0) 
I n t he e ve nt t hat t he ti me bet wee n t he b aseli ne assess me nt a n d t he i nf usi o n of C A R T- 1 9 T cells 
e x cee ds t he 1 2  wee k Scree ni n g/ E nr oll me nt 
Wi n d o w t he f oll o wi n g will be re peate d: P h ysi cal 
E x a mi nati o n, Perf or ma nce Stat us Assess me nt, C o m plete Bl o o d C o u nt wit h differe ntial a n d 
Platelet C o u nt, C he mistr y Pa n el, Pre g na n c y test, a n d HI V a n d He patitis B/ C tests.   A n 
E C H O/ M U G A sca n m ust be perf or m e d wit hi n 8 wee ks pri or t o t he first C A R T- 1 9 i nf usi o n. 
6. 2. A p h er e si s a n d T e st e x p a n si o n  
After t he patie nt has bee n e nr olle d, patie nts will be sc he d ule d f or a p heresis (le u ka p heres e d) t o 
o btai n a tar get of 5 x 1 0 9 P B M Cs f or C A R T- 1 9 m a n ufact uri n g. A P B M C sa m ple fr o m t he a p heresis 
pr o d uct will be use d f or a test e x pa nsi o n t o assess t he s uita bilit y of t he patie nt’s T cells f or C A R T-
1 9 ma n ufact uri n g. T he t est e x pa nsi o n res ults will be use d f or s ec o n dar y o bjecti ve a n al ysis, b ut 
will n ot be a criteri o n f or pr ocee di n g wit h C A R T- 1 9 ma n ufact uri n g. 1 x 1 0 8 cells fr o m t he a p heresis 
pr o d uct will be deli vere d t o T C S L b y t he C V P F.   
 
As n ote d i n T a ble 6- 1 , t he a p heresis ca n occ ur bet wee n 1 2 t o 4 wee ks pri or t o C A R T- 1 9 i nf usi o n. 
A p heresis s h o ul d be s c he d ule d pri or t o a n y pla n ne d c he m ot hera p y a d mi nistrati o n. After 
c o m pleti o n of a p heresis, cells s h o ul d be cr y o preser ve d b y sta n dar d te m perat ure c o ntr olle d 
pr oce d ure a n d t he n s hi p pe d t o t he C V P F. T h e cell pr o d uct is e x pecte d t o be releas e d a p pr o xi matel y 
3 - 4 wee ks after m a n ufact uri n g has c o m me nce d.  
 
Hist oric al A p heresis S a m ple 
Cr y o preser ve d hist orical a p heresis pr o d ucts c ollecte d fr o m t he patie nt pri or t o st u d y e ntr y are 
usa ble f or C A R T- 1 9 ma n ufact uri n g if c ollecte d at a n a p pr o priatel y certifie d a p heresis ce nter a n d 
t he pr o d uct m eets a de q uate m o n o n uclear cell yiel ds.  If t his is t he case, t he p atie nt t heref ore w o ul d 
n ot ha ve t o re p eat t he bas eli ne a p h eresis o n t his st u d y a n d t his hist orical sa m ple will als o be use d 
t o deter mi ne t he feasi bilit y f or t he T-cell test e x pa nsi o n assa y. If a hist orical a p heresis pr o d uct is 
n ot a vaila ble, a n a p heresis pr oce d ure (as d escri b e d a b o ve) will be p erf or me d f or cell pr oc ure m e nt 
after st u d y eli gi bilit y has bee n c o nfir me d. Refer t o secti o n 6. 5 f or d etaile d pr oce d ures re gar di n g 
a p heresis a n d a nal ysis. 
6. 3. A s s e s s m e nt T y p e s 
6. 3. 1. D e m o gr a p hi c s, Eli gi bilit y V erifi c ati o n, M e di c al Hi st or y, Hi st ori c al a n d 
C o n c o mit a nt M e di c ati o n s 
Patie nt de m o gra p hics will be rec or de d o n t he de m o gra p h y s o urce d o c u me nts. T he I n v esti gat or or 
desi g nat e d staff will re vi e w i ncl usi o n/e xcl usi o n criteria t o verif y eli gi bilit y. A detaile d me dical 
hist or y will be ta ke n a n d rec or de d o n t he me dical hist or y C R F as well as c urre nt a n d pri or ( wit hi n 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 5 5  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
3 0 da ys of pre-e ntr y) c o n c o mita nt me dicati o ns.   F or s u bjects e nr olli n g i nt o t he retreat me nt c o h ort, 
de m o gra p hic i nf or mati o n a n d det aile d me dical hist or y will n ot be re-c ollecte d. A n i nter val me dical 
hist or y will be c ollecte d as a p pr o priat e per s u bject stat us. 
6. 3. 2. P h y si c al E x a m 
A c o m plete p h ysic al e x a mi nati o n will be perf or me d b y t he i n vesti gat or acc or di n g t o T a ble 6- 1 .  
Hei g ht will be meas ure d i n ce nti meters a n d rec or de d i n t he s o urce d o c u me nts. Wei g ht will be 
meas ure d i n kil o gra ms a n d rec or de d i n t he Vital Si g ns s o urce d o c u me nts.  
  
 
Si g nifica nt fi n di n gs t hat are pres e nt pri or t o t h e start of st u d y dr u g m ust be i ncl u de d o n t he 
Rele va nt Me dical Hist or y/ C urre nt M e dical C o n diti o n pa ges of t he C R F. Si g nifica nt fi n di n gs 
ma de after t he start of st u d y dr u g w hic h meet t he defi niti o n of a n A d verse E ve nt m ust be rec or de d 
o n t he A d verse E ve nt part i n t he C R F. 
6 . 3. 3. Vit al Si g n s 
Bl o o d press ur e, b o d y t e m perat ure, o x y ge n sat ur ati o n b y p ulse o xi metr y, a n d heart rate will be 
meas ure d as i n dicate d i n t he T a ble 6- 1  a n d will be rec or de d o n s o urce d oc u me nts, a n d tra nscri be d 
i nt o t he a p pr o priate C R F pa ges. Bl o o d press ure a n d p ulse s h o ul d be meas ure d o n patie nts after at 
least 3 mi n utes i n t he sitti n g p ositi o n. Vital si g ns will be ta ke n 1 0 mi n utes pri or t o a n d 1 0 mi n utes 
i m me diatel y after eac h i nf usi o n a n d t he n e ver y 1 5 mi n utes f or at least o ne h o ur a n d t he n e ver y 
h o ur f or t he ne xt t w o h o urs u ntil t hese si g ns are satisfact or y a n d sta ble.  If t he s u bject’s vital si g ns 
are n ot satisfact or y a n d sta ble t hree h o urs p ost- C A R T- 1 9 i nf usi o n, vital si g ns will c o nti n ue t o be 
m o nit ore d at a mi ni m u m of e ver y h o ur or as cli nicall y i n dicate d u ntil sta ble. 
 
If hi g h fe vers ( ≥ 1 0 1. 5o F / 3 8. 6o C) occ ur i n t he da ys t o wee ks f oll o wi n g t h e C A R T- 1 9 i nf usi o ns, 
a d diti o nal assess me nts are re q uire d t o m ore cl osel y m o nit or t h e patie nt u ntil res ol uti o n of t he 
fe ver ( bel o w 1 0 1. 5o F / 3 8. 6o C). Please refer t o Secti o ns 6. 3. 2. 1, 6. 3. 2. 2 a n d 6. 3. 3 f or details. 
6. 3. 4. E C O G P erf or m a n c e st at u s 
At Visits acc or di n g t o T a ble 6- 1 , t he E C O G p erf or ma nce scale i n de x will be use d t o e val uate t he 
perf or ma n ce stat us of t h e patie nts. 
T a ble 6 - 2: E C O G Perf o r m a nce st at us gr a de: 
Gr a de  E C O G  
0  
F ull y acti ve, a bl e t o carr y o n all pre -diseas e perf or ma nce wit h o ut restricti o n  
1  
Restricte d i n p h ysic all y stre n u o us acti vit y b ut a m b ulat or y a n d a ble t o carr y o ut 
w or k of a li g ht or se d e ntar y nat ur e, e. g., li g ht h o use w or k, offi ce w or k  
2  
A m b ulat or y a n d ca p a ble of all self -care b ut u n a ble t o carr y o ut a n y w or k 
acti vities. U p a n d a b o ut m ore t ha n 5 0 %  of wa ki n g h o urs  
3  
Ca pa ble of o nl y li mite d self -care, c o nfi ne d t o be d or c hair m ore t ha n 5 0 % of 
wa ki n g h o urs  
4  
C o m pletel y disa ble d. Ca n n ot carr y o n a n y self -care. T otall y c o nfi ne d t o b e d or 
c hair  

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 5 6  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
Gr a de  E C O G  
5  
Dea d  
6. 3. 5. C ar di a c A s s e s s m e nt: E C H O/ M U G A 
A n E C H O/ M U G A test is re q uire d t o be c o m plete d wit hi n 8  wee ks pri or t o t he first C A R T- 1 9 
i nf usi o n t o c o nfir m pr ot oc ol eli gi bilit y. A n y a b n or malities t hat are cli nicall y si g nifica nt s h o ul d be 
rec or de d o n t he Patie nt’s Me dical Hist or y C R F. P atie nts m ust ha ve a L V E F ≥4 0% t o be i ncl u de d 
i nt o t he st u d y. 
6. 3. 6. L o c al L a b or at or y E v al u ati o n s 
Pre-e ntr y, scree ni n g a n d ot her la b orat or y assess m e nts will be perf or me d acc or di n gl y t o T a ble 6-
1 .  N ote: A d diti o nal assess me nts s h o ul d be perf or me d bet wee n visits as cli nicall y re q uir e d t o 
f oll o w A Es or C A R T- 1 9 e x pecte d e ve nts.  F or all la b orat or y assess me nts t hat occ ur o n Da ys 1, 2 
a n d 3, t hese s h o ul d be perf or me d pri or t o C A R T- 1 9 i nf usi o n u nless i n dicate d ot her wise.  
 
T he I n vesti gat or will e val uate t he cli nical si g nifica nce of eac h a p plica ble  la b orat or y val u e o utsi de 
of t he refere nce ra n ge. T his decisi o n s hall be base d u p o n t he nat ure a n d de gree of t he o bser ve d 
a b n or malit y. Val ues w hi c h are c o nsi dere d cli nicall y si g nifi ca nt a n d/ or st u d y relate d t o C A R T- 1 9 
will be n ote d.  T h e I n v esti gat or ma y c h o ose t o re peat a n y a b n or mal res ult o nce, i n or der t o r ule 
o ut la b orat or y err or. " N C S" will be e ntere d o n t he ori gi nal la b orat or y s heet of all la b orat or y val ues 
w hic h are o utsi de t he refere nce ra n ge, b ut are j u d ge d " n ot cli nicall y si g nifica nt." T h e p h ysici a n 
ma ki n g t hese assess me nts s hall date a n d i nitial eac h f or m. F urt her details o n rec or di n g a b n or mal 
la b orat or y val u es as A Es are des cri be d i n Secti o n 8. 1. 
T a ble 6- 3   L oc al Cli nic al l a b or at or y p ar a meters c ollecti o n pl a n 
Test C ate g o r y  
Test N a me  
He mat ol o g y  
He mat ocrit,  He m o gl o bi n , Platelets, W hite bl o o d cells wit h a 
c o m plete differe ntial, i ncl u di n g l y m p h o blasts 
C he mistr y  
Gl uc ose, B U N, Creati ni ne, S o di u m, P otassi u m, Calci u m, T otal 
Pr otei n, Al b u mi n, T otal Bilir u bi n, Al kali ne p h os p hatase, A L T 
( S G P T), A S T ( S G O T), Ma g n esi u m, P h os p hate, L D H, Uric Aci d; 
Direct bilir u bi n (t o be perf or me d at s cree ni n g o nl y)  
H L H/ M A S a n d 
C R S scree n –  
re peat e d if 
cli nicall y 
i n dicate d 
Ferriti n, C R P, Ha pt o gl o bi n , tri gl yceri des, L D H 
C oa g ulati o n  
Pr ot hr o m bi n ti me ( P T) , I nternati o nal n or malize d rati o ( I N R), Partial 
t hr o m b o plasti n ti me ( P T T), fi bri n o ge n, D-di mer  
A ut oi m m u ne 
Scree n  
A nti n uclear a nti b o d y ( A N A) a n d Er yt hr oc yte s e di me ntati o n rate 
( E S R) 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 5 7  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
Test C ate g o r y  
Test N a me  
Ser ol o g y  
Viral Ser ol o g y ( C M V, E B V), H C V a nti b o d y, H C V R N A -P C R (if 
a p plica ble), H bs A g  
R V P   
Res pirat or y Vir u s Pa nel: I n cl u des I nfl u e nza A, I nfl ue nza B, 
Res pirat or y S y n c yti al Vir us A, Res pirat or y S y nc ytial Vir us B, 
Parai nfl ue nza Vir us T y p e 1, Parai nfl ue nza Vir us T y pe 2, 
Parai nfl ue nza Vir us T y p e 3, A de n o vir us  
T -Cell S u bsets  
C D 4, C D 3, C D 8  
D o n or c hi meris m  
W h ole bl o o d ( mi ni m u m re q uire d) a n d C D 3 + li nea ge -s pecific 
c hi meris m preferre d  
A d diti o nal 
Assess me nts  
S er u m i m m u n o gl o b uli n le vels, Ser u m a n d Uri ne Pre g na nc y Test  
6. 3. 6. 1. 
H e m at ol o g y , C o a g ul ati o n a n d T - c ell S u b s et s 
He mat ol o g y & C oa g ulati o n safet y assess me nts will be perf or me d at scree ni n g, pre-
i nf usi o n ( Da y- 1), pri or t o t he C A R T- 1 9 i nf usi o ns o n Da ys 1, 2 a n d 3, a n d at eac h st u d y 
visit acc or di n g t o T a ble 6- 1 . Assess me nts will i ncl u de W B C (t otal) wit h differe ntial 
c o u nt i ncl u di n g % l y m p h o blasts, he mat ocrit, he m o gl o bi n, p latelets, pr ot hr o m bi n ti me, 
I N R, P T T, Fi bri n o ge n a n d d- di mer. 
 
T-cell s u bsets a nal ysis ( C D 3, C D 4 a n d C D 8) will be perf or m e d pri or t o t he first C A R T-
1 9  i nf usi o n o n Da y 1 a n d a gai n o n Da y 2 8, M o nt h 2, 3, 4, 5 a n d 6.  
 
A d diti o nal assess me nt of D- di mer f or C R S 
As n ote d, si de effects f oll o wi n g C A R T- 1 9 cell i nf usi o ns ca n i n d uce hi g h fe vers a n d 
s h o ul d be e x pecte d. If hi g h fe v ers ( ≥ 1 0 1. 5 o F / 3 8. 6o C) occ ur f oll o wi n g C A R T- 1 9 
i nf usi o n, e ver y atte m pt will be ma de t o m o nit or D- di mer le vels d ail y  at fe ver o nset a n d 
u ntil res ol uti o n of t he fe v er ( bel o w 1 0 1. 5 o F / 3 8. 6 o C).  
6. 3. 6. 2. 
C h e mi str y 
Bi oc he mical safet y assess me nts will be perf or me d at scree ni n g, pre-i nf usi o n ( Da y- 1), 
pri or t o t he C A R T- 1 9 i nf usi o ns o n Da ys 1, 2 a n d 3, a n d at eac h st u d y visit acc or di n g 
t o Ta ble 6- 1. Assess me nts will i ncl u de Gl uc ose, B U N, Creati ni ne, S o di u m, P otassi u m, 
Calci u m, T otal Pr otei n, Al b u mi n, T otal Bilir u bi n, Al kali ne p h os p hatase, A L T ( S G P T), 
A S T ( S G O T), Ma g nesi u m, P h os p hate, L D H, Uric Aci d.   
 
A d diti o nal assess me nt of Ferriti n, L D H  a n d C R P le vels f or C R S  
As n ote d, si de effects f oll o wi n g C A R T- 1 9 cell i nf usi o ns ca n i n d uce hi g h fe vers a n d 
s h o ul d be e x pecte d. If hi g h fe v ers ( ≥ 1 0 1. 5o F / 3 8. 6o C) occ ur foll o wi n g C A R T- 1 9 
i nf usi o n, e ver y atte m pt will be ma de t o m o nit or a d diti o nal Ferriti n, L D H a n d C R P 
le vels d ail y  at fe ver o nset a n d u ntil res ol uti o n of t he fe ver ( bel o w 1 0 1. 5o F / 3 8. 6o C). 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 5 8  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
Ot her c he mistries s h o ul d be m o nit ore d per T a ble 6 - 1 or as cli nicall y i n dicate d if C R S 
is s us pecte d.  
 
A d diti o nal assess me nts of Ha pt o gl o bi n a n d Tri gl yceri des f or H L H/ M A S scree n 
Ha pt o gl o bi n a n d tri gl yceri des will be assesse d at pre-i nf usi o n ( Da y - 1) a n d s h o ul d be 
m o nit ore d per T a ble 6- 1  or as cli nicall y i n dicate d if H L H/ M A S is s us pecte d. 
6. 3. 6. 3. 
Vir al S er ol o g y 
Bl o o d will be ta ke n f or E B V, C M V, He patitis B, a n d He patitis C at baseli ne.  If t he 
H C V a nti b o d y is p ositi ve, a scree ni n g H C V R N A b y a n y R T- P C R or b D N A assa y m ust 
be perf or m e d. Eli gi bilit y will be deter mi ne d base d o n t he scree ni n g val ue. T he test is 
n ot re q uire d if d oc u m e ntati o n of a n e gati ve res ult of a H C V R N A test p erf or me d wit hi n 
6 0 da ys pri or t o scree ni n g is pr o vi de d. 
6. 3. 6. 4. 
S er u m I m m u n o gl o b uli n L e v el s 
Peri p heral bl o o d will be sa m ple d at scree ni n g a n d acc or di n gl y t o T a ble 6- 1 , f or 
a nal ysis of ser u m i m m u n o gl o b uli n.  
6. 3. 6. 5. 
D o n or c hi m eri s m 
D ue t o t he p ossi bilit y of s o me de gree of resi d ual d o n or e n graft me nt, w hic h will i ncl u de 
T cells of d o n or ori gi n, p atie nts t hat recei ve d a pre vi o us all o ge n eic H S C T tra ns pla nt at 
t he H os pital of t he U ni versit y of Pe n ns yl va nia will be assesse d f or d o n or c hi meris m at 
scree ni n g a n d t h e n at Da y 2 8, M o nt h 3, 6, 9 a n d 1 2. T his assess me nt will be us e d t o 
i de ntif y ris k f or p ote ntial G V H D. W h ole bl o o d a n d C D 3 + li nea ge-s p ecific c hi meris m 
is preferre d.   
6. 3. 6. 6. 
Pr e g n a n c y T e sti n g 
W o me n of c hil d- beari n g p ote ntial, defi ne d as all w o me n p h ysi ol o gicall y ca pa ble of 
bec o mi n g pre g na nt, m ust use effecti ve c o ntr ace pti o n (see Secti o n 4. 3 f or details).  F or 
w o me n of c hil d beari n g p ote ntial, a ser u m pre g n a nc y test ( β- H C G) will be perf or me d 
acc or di n g t o T a ble 6- 1  at scree ni n g.  D uri n g tr eat me nt, a n a d diti o nal t est will be 
perf or me d pri or ( wit hi n 4 8 h o urs) t o t he first C A R T- 1 9 i nf usi o n a n d a gai n at t he e n d 
of st u d y visit ( M o nt h 1 2). A d diti o nall y, if me nses is dela ye d f or m ore t h a n 7 da ys, t he 
patie nt s h o ul d be i nstr uct e d t o c o n d uct a uri ne pre g na n c y t o r ule o ut a n y p ossi bilit y of 
pre g na nc y.  Patie nts s h o ul d be i nstr ucte d t o i nf or m site of a n y p ositi ve uri ne pre g na nc y 
res ults n ot c o n d ucte d at t he cli nic. Re peat ser u m pre g na nc y t esti n g will be perf or m e d 
f or c o nfir m ati o n of a p ositi ve uri ne pre g na n c y test. I n case of pre g n a n c y pri or t o 
C A R T - 1 9 T-cell i nf usi o n, patie nts m ust be wit h dra w n fr o m t he st u d y. 
6. 3. 7. 
R e s e ar c h A s s e s s m e nt s t o A s s e s s E n gr aft m e nt, P er si st e n c e a n d      
Bi o a cti vit y 
T he f oll o wi n g assess me nts will be c ollecte d acc or di n g t o T a ble s 6- 1 a n d 6- 2 a n d will be a nal yz e d 
as descri be d b el o w .  
 I m m u n o ge nicit y: H u m a n A nti- M uri ne A nti b o d y ( H A M A) a n d H u ma n A nti-
C A R A nti b o d y ( H A C A) 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 5 9  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
 Ser u m C yt o ki nes 
 D N A Q- P C R C T L 0 1 9 p ersiste nce 
 D N A R C L ( V S V- G Q- P C R)  
 C T L 0 1 9 I m m u ne p h e n ot y pi n g (fl o w c yt o metr y) 
 S pectra-t y pi n g (cl o n ot y pi n g a n d M R D b y dee p se q ue nci n g) 
 
F or m olec ular st u dies ( Q- P C R a n d Q- R T - P C R), i m m u ne p he n ot y pi n g a n d f u ncti o nal assa ys, 
peri p heral bl o o d a n d marr o w sa m ples will be c ollecte d i n La ve n d er t o p ( K 2 E D T A) t u bes. F or 
c yt o ki ne a n al ys es peri p h eral bl o o d a n d marr o w sa m ples will be c ollecte d i n re d t o p ( n o a d diti ve) 
t u bes.    Sa m ples will be deli vere d, pr ocesse d, a n d fr oze n as per S O P t o t he Tra nslati o nal a n d 
C orrelati ve St u dies La b orat or y ( T C S L) ( U ni v ersit y of Pe n ns yl va ni a). Sa m ples will be st ore d i n 
t he T C S L at t he U ni versit y of Pe n ns yl v a nia f or st ora ge a n d b ul k a nal ys es.  D oc u me ntati o n f or 
sa m ple - recei pt, - pr ocessi n g, a n d st ora ge a n d pri mar y d ata fr o m t he researc h a n al ys es will be 
c ollecte d a n d st ore d i n t he T C S L.  
 
Tra nslati o nal a n d C orrelati ve St u dies La b orat or y  
U ni versit y of Pe n ns yl v a nia Perel ma n Sc h o ol of M e dici ne  
Tra nslati o nal Researc h C e nter, 9- 1 8 8 
3 4 0 0 Ci vic Ce nter B o ule var d, B uil di n g 4 2 1 
P hila del p hia, P A 1 9 1 0 4- 5 1 5 7  
 
A d diti o n al assess me nt of Ser u m C yt o ki nes a n d C A R T- 1 9 le vels 
As n ote d, si de effects f oll o wi n g C A R T- 1 9 cell i nf usi o ns ca n i n d u ce hi g h fe vers a n d s h o ul d be 
e x pecte d. If hi g h fe v ers ( ≥ 1 0 1 . 5o F / 3 8. 6o C) o cc ur f oll o wi n g C A R T- 1 9 i nf usi o n u ntil M o nt h 2 
visit, a d diti o nal bl o o d dra ws t o ass ess Ser u m C yt o ki ne a n d C A R T- 1 9 le vels are re q uire d t o be 
m o nit ore d o n t he o nset of fe vers a n d e ver y 3- 4 d a ys u ntil res ol uti o n of t he fe ver ( bel o w 1 0 1. 5o F 
/ 3 8. 6o C).  
 
A n a d diti o nal lar ger bl o o d dra w ( ~ 1 0 0cc) o n Da y 2 8 will be dra w n a n d arc hi ve d f or f ut ure researc h 
p ur p oses. T his bl o o d sa m ple will als o be se nt t o T C S L as i n dicate d a b o ve.  
6. 3. 8. C yt o g e n eti c s/ FI S H 
C yt o ge netics/ FI S H ass ess me nts 
will be perf or me d at eac h ti me p oi nt a b o ne 
marr o w 
as pirate/ bi o ps y is sa m ple d (per T a ble 6- 1 ).  
6. 3. 9. Q u alit y of Lif e ( Q o L)  
Q ualit y of life q u esti o n naires will be a d mi nistere d at scree ni n g a n d a gai n at M o nt hs 3 a n d 6.  If 
t he patie nt disc o nti n ues t he st u d y pri or t o M o nt h 3 ( or after M o nt h 3 b ut bef ore M o nt h 6), all 
atte m pts s h o ul d be ma de t o o btai n a fi nal Q O L q uesti o n naire pri or t o patie nt disc o nti n ui n g t he 
st u d y.  T he F A C T- Le u ( Versi o n 4) 9 8 a n d E O R T C- Q L Q C 3 09 9 q uesti o n naires will be use d t o 
assess t he patie nt’s healt h as well as p h ysic al, s ocial/fa mil y, e m oti o nal a n d f u ncti o nal well- bei n g.  
If site staff is a d mi nisteri n g t o t he patie nt, t he q uesti o ns s h o ul d be descri be d t o elicit patie nt 
e x perie nces, o pi ni o ns a n d o bser vati o ns o n h o w t h eir disease is affecti n g t h e m. 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 6 0  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
6. 4. P ati e nt E nr oll m e nt 
T o e nr oll a patie nt o n t his st u d y, pr o vi de t he d o c u me nts liste d bel o w t o: 
S p o ns or Pr ot oc ol M o nit or a n d S p o ns or Pr oject Ma na ger 
Ce nter f or Cell ular I m m u n ot hera pies ( C CI) 
 
 
D oc u me nts re q uir e d: 
1.  
C o m plete E nr oll me nt F or m (i ncl u di n g patie nt past 
me dical hist or y, la b orat or y, 
ra di ol o gic al re p orts, p h ysical e x a m, c o nc o mita nt me dicati o ns a n d a n y ot her s o urce 
d oc u me ntati o n t o s u p p ort patie nt meets eli gi bilit y criteria a n d has c o m plete d all 
re q uire d scree ni n g assess me nts) 
2.  
C o p y of si g ne d patie nt c o nse nt a n d HI P A A f or m 
 
U p o n i nf or me d c o nse nt c o m pleti o n a n d recei pt of scree ni n g a n d eli gi bilit y d oc u me nt ati o n, t he 
S p o ns or Pr ot oc ol M o nit or will re vie w a n d pr o vi de d oc u me ntati o n t hat t he m o nit ori n g visit f or 
eli gi bilit y has bee n c o m plete d.  T his d oc u me ntati o n m ust be recei ve d pri or t o cell pr o d uct 
ma n ufact uri n g.  
 
Eac h patie nt is i de ntifie d i n t he st u d y b y a S u bject N o. t hat is assi g ne d w he n t he s u bject is first 
e nr olle d f or pre-scree ni n g a n d is retai ne d as t he pri mar y i de ntifier f or t he s u bject t hr o u g h o ut 
his/ her e ntire partici pati o n i n t he trial. T he S u bject N o. c o nsists of t he Ce nter N u m ber ( Ce nter N o.) 
(as assi g ne d b y S p o ns or t o t he i n vesti gati ve site) wit h a se q u e ntial s u bject n u m ber s uffi x e d t o it, 
s o t hat eac h s u bject is n u m bere d u ni q uel y acr oss t he e ntire data base.  After a s u bject has passe d 
all scree ni n g pr oce d ures a n d is rea d y t o be e nr olle d, t he s u bject is e nr olle d usi n g t he sa me S u bject 
N o. pr o vi de d at pre-s cree ni n g. O n ce assi g ne d, t h e S u bje ct N o. m ust n ot be re use d f or a n y ot her 
s u bject a n d t he S u bject N o. f or t hat i n di vi d ual m ust n ot be c ha n ge d, e v e n if t he s u bject is re-
scree n e d. If t he s u bject fails scree ni n g f or a n y reas o n, t he reas o n will be e ntere d i nt o t he Scree ni n g 
Dis p ositi o n pa ge. 
6. 5. A p h er e si s Vi sit Pr o c e d ur e 
F or patie nts t hat d o n ot ha ve a hist orical a p h eresis a vaila ble, a 4 - 6 bl o o d v ol u me a p heresis 
pr oce d ure will be carrie d o ut at t he a p heresis ce nt er d uri n g t he scree ni n g pr oce d ures. P B M C are 
o btai ne d f or C A R T- 1 9 d uri n g t his pr oce d ur e. Fr o m a si n gle le u ka p h eresis, t he i nte nti o n is t o 
har vest at least 5 x 1 0 9 w hite bl o o d cells t o ma n ufact ure C A R T- 1 9 T cells. Baseli ne bl o o d 
le u k oc yt es f or F D A re q uire me nts a n d f or res earc h are als o o bt ai ne d a n d cr y o preser ve d. After t he 
P B M C is se nt f or C A R T- 1 9 ma n ufact uri n g, t h e cell pr o d uct is e x pecte d t o be rea d y f or releas e 
a p pr o xi matel y 4 wee ks later. 
 
As me nti o ne d i n Secti o n 6. 1. 3, f or t h ose patie nts t hat d o ha ve a hist orical a p heresis a vaila ble, t his 
pr o d uct ma y be a bl e t o be use d.  If t his is t he c ase, t he patie nt t heref ore w o ul d n ot ha ve t o re peat 
t he baseli ne a p h eresis o n t his st u d y.  

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 6 1  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
6. 6. C yt or e d u cti v e c h e m ot h er a p y 
Pri or t o C A R T- 1 9 cell i nf usi o n, a n a d diti o nal c he m ot hera p y c ycle is pl a n ne d. A selecti o n is 
pr o vi de d bel o w f or g ui d a nce; h o we v er,  t he re gi me n of c he m ot hera p y will be at t he discreti o n of 
t he i n vesti gat or a n d de p e n de nt o n t he patie nt’s pri or hist or y, diseas e b ur de n a n d ot her patie nt 
s pecific fact ors.  
 
* * N ote, t he l y m p h o de pleti n g c he m ot hera p y pri or t o C A R T- 1 9 cell i nf usi o n is N O T  nee de d if t he 
patie nts W B C ≤ 1, 0 0 0 / u L. A d diti o nall y, if t he d ela ye d peri o d fr o m c h e m ot hera p y t o C A R T- 1 9 
i nf usi o n is 4 or m or e wee ks, t he patie nt will nee d t o be re-tr eate d wit h l y m p h o de pleti n g 
c he m ot hera p y pri or t o C A R T- 1 9 i nf usi o n. 
 
F or B- cell A L L p atie nts, t he c yt or e d ucti o n/c o n diti o ni n g re gi me n a d mi nistere d pri or t o C A R T- 1 9 
will be at t he discreti o n of t he p h ysi cia n. T he s u g geste d re gi me ns are as f oll o ws:  
 
a. Cl ofara bi ne 4 0 m g/ m 2/ d x 5 d 
b.  Hi g h d ose m et h otre x ate 3 g m/ m 2 
c. Ara C 1. 5- 3 g m/ m 2 q 1 2 hr x 6- 1 2 d oses 
d.  Met h otre x ate 1 m g/ m
2 wi t h Ara C 1- 3 g m/ m2 x 4 d oses 
e. C V A D (c yt o x a n, vi ncristi ne, a dria m yci n, deca dr o n) 
f. C ycl o p h os p ha mi de 1. 5 - 3 g m/ m2 o ver 1- 3 da ys 
g.  I C E (if os p h a mi de, car b o plati n, et o p osi de) 
h.  
 Da u n or u bici n
 / Ara C 
i. Fl u dara bi n e ( 3 0 m g/ m2/ d x 4 da ys) a n d C ycl o p h os p ha mi de ( 5 0 0 m g/ m 2/ d x 2 da ys) 
 
T he c h e m ot hera p y will b e pla n ne d s o t hat t he last d ose is c o m plete d 1 - 4 d a ys B E F O R E t h e first 
pla n ne d i nf usi o n of C A R T- 1 9 cells f or A L L.  E ac h re gi me n is of differe nt d urati o n s o t he start 
da y of c he m ot hera p y will var y.  T h e p ur p os e of t he c he m ot hera p y is t o i n d uce l y m p h o pe nia i n 
or der t o facilitate e n graft me nt a n d h o m e ostatic e x pa nsi o n of C A R T- 1 9 cells.  I n a d diti o n, 
c he m ot hera p y ca n p ote ntiate t he a bilit y of T cells t o kill t u m or cells 1 1 6, 1 1 7. T he c he m ot hera p y is 
n ot i n vesti gati o nal a n d ma y be gi v e n b y a p atie nt’s l ocal o n c ol o gist wit hi n t he s pecifie d ti me 
fra me. 
 
All patie nts m ust u n der g o a res pirat or y vir us pa n el ( R V P) t o test f or i nfl ue nza wit hi n 1 0 da ys pri or 
t o t he first pla n ne d C A R T- 1 9 i nf usi o n.  If t he patie nt is p ositi ve f or i nfl ue nza, oselta mi vir 
p h os p hate ( Ta mifl u ®) or e q ui vale nt s h o ul d be a d mi nistere d (see Ta mifl u ® pac ka ge i nsert f or 
d osi n g i nf or mati o n). T he patie nt m ust c o m plete t his c o urse of treat me nt pri or t o recei vi n g t he first 
C A R T- 1 9 i nf usi o n. If t he patie nt is p ositi ve f or i nfl ue nza a n d is als o e x perie nci n g fl u-li ke 
s y m pt o ms, all cli nical s y m pt o ms m ust be res ol ve d pri or t o t he first C A R T- 1 9 i nf usi o n.  If t he 
patie nt is p ositi ve f or a n ot her test o n t h e R V P, t h e C A R T- 1 9 i nf usi o n will be del a ye d f or at least 
7 da ys t o be s ur e cli nical s y m pt o ms of a vir al i nfecti o n d o n ot de v el o p.  If cli nical s y m pt o ms 
de vel o p, t he i nf usi o n will be dela ye d u ntil res ol uti o n of t hese s y m pt o ms.  
6. 7. C A R T - 1 9 I nf u si o n 
T he first C A R T- 1 9 i nf usi o n will be gi n 1 t o 4 da ys after c o m pleti o n of c he m ot hera p y as i n dicate d 
i n Secti o n 6. 6.  O n D a ys 1, 2 a n d 3, pri or t o eac h i nf usi o n, patie nts will ha ve a C B C wit h 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 6 2  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
differe ntial, a n d assess m e nt of C D 3, C D 4 a n d C D 8 c o u nts si nce c he m ot hera p y is gi ve n i n part t o 
i n d uce l y m p h o p e nia. 
 
T he d ose will be a d mi nistere d as a s plit i nf usi o n of 1 t o 5 x 1 0 8 t otal C A R T- 1 9 tra ns d uce d cells: 
1 0 % o n Da y 1, 3 0 % o n Da y 2, 6 0 % o n Da y 3 . Patie nts will be i nf use d a n d pre me dicat e d as 
descri be d i n Secti o n 5. 4. 
 
A bl o o d sa m ple f or det er mi nati o n of a baseli ne C A R T- 1 9 le vel is o btai ne d pri or t o eac h  i nf usi o n 
a nd 2 0 mi n utes t o 2 h o urs p ost eac h i nf usi o n (a n d se nt t o T C S L) per Ta ble 6- 1 . 
 
Patie nts e x perie nci n g t o xicities fr o m t heir prece di n g c yt or e d ucti ve c he m ot hera p y will ha ve t heir 
i nf usi o n dela ye d u ntil t he f oll o wi n g t o xicities ha ve res ol ve d:  
1)  P ul m o nar y: Re q uire me nt f or s u p ple me ntal o x y ge n t o kee p sat urati o n greater t ha n 
9 2 % or pres e nce of ra di o gra p hic a b n or malities o n c hest x-ra y t h at are pr o gressi ve  
2)  Car diac: Ne w car diac arr h yt h mia n ot c o ntr olle d wit h me dical ma na ge me nt.  
3)  H y p ote nsi o n r e q uiri n g press or s u p p ort.  
4)  Acti ve I nfecti o n: P ositi ve bl o o d c ult ures f or b acteria, f u n g us, or vir us wit hi n 4 8 h o urs 
of T cell i nf usi o n. 
 
Pr o p h yla ctic gra m ne gati ve a nti bi otics m ust be i nitiate d be gi n ni n g o n Da y 1.  T he c h oice of 
a nti bi otic will be left t o t he p h ysici a n i n vesti gat or’s discreti o n a n d will be a d mi nistere d per 
i nstit uti o nal g ui deli nes. 
6. 8. D a y 2 8: F oll o w U p 
At t he Da y 2 8 visit, patie n ts will u n der g o t he f oll o wi n g:  ph y sical e x am,  d oc u me ntati o n  of a d verse 
e ve nts a n d bl o o d dra ws f or he mat ol o g y, c he mistr y, e n graft me nt a n d persiste nce of C A R T- 1 9 cells 
a n d researc h la bs.   I n a d diti o n, resta gi n g is d o ne i n or der t o pr o vi de t u m or b ur de n meas ure me nts. 
Resta gi n g testi n g is deter mi ne d b y t he p atie nts’ baseli ne disease assess me nt a n d ma y i n cl u de 
i ma gi n g, M R D assess me nts, C S F assess me nts, b o ne marr o w as pirat e a n d bi o ps y a n d/ or o pti o nal 
l y m p h n o de bi o ps y as necessar y. T u m or res p o ns e assess me nts will be d o ne acc or di n g t o Nati o nal 
C o m pre he nsi ve Ca ncer Net w or k ( N C C N) v 1 2 0 1 3 g ui deli nes ( Secti o ns 6. 1 4  a n d 6. 1 5) 
6. 9. M o nt hl y E v al u ati o n s 2 t o 6 M o n t h s P o st I nf u si o n 
Patie nts will ret ur n t o t he cli nic o n a m o nt hl y b asis d uri n g m o nt hs 3  t o 6 p ost C A R T- 1 9 cell 
i nf usi o n.  At t hese st u d y visits, patie nts will u n der g o t he f oll o wi n g:  c o nc o mita nt me dicati o n, 
p h ysical e x a m, d oc u me ntati o n of a d verse e ve nts a n d bl o o d dra ws f or he mat ol o g y, c h e mistr y, 
e n graft me nt a n d persiste nce of C A R T- 1 9 cells a n d res earc h la bs.  T u m or res p o nse will be 
meas ure d acc or di n gl y t o Secti o ns 6. 1 4  a n d 6. 15  at M o nt hs 3  a n d M o nt h 6.  
6. 1 0.  
Q u art erl y E v al u ati o n s f or u p t o 1 Y e ar P o st I nf u si o n 
Pa tie nts will be e val uate d o n a q uart erl y basis u ntil 1 year p ost i nf usi o n. At t hese st u d y visits, 
patie nts will u n der g o t he f oll o wi n g:  c o nc o mita nt me dicati o n, p h ysic al e x a m, d oc u me ntati o n of 
a d verse e ve nts a n d bl o o d dra ws f or h e mat ol o g y, c h e mistr y, e n graft me nt a n d persiste nce of C A R T-
1 9 cells a n d researc h la bs.  T he D N A R C L ( V S V- G Q- P C R) assa y will be perf or me d at 3, 6 a n d 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 6 3  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
1 2 m o nt hs p ost C A R T- 1 9 cell i nf usi o n t o e x cl u de t he prese nce of detecta ble R C L. T u m or res p o nse 
will be meas ure d acc or di n gl y t o Secti o ns 6. 1 4  a n d 6. 1 5 at M o nt hs 9  a n d 1 2 . 
6. 1 1.  
S e c o n d ar y F oll o w- u p  
F or s u bjects w h o c o m plete or pre m at urel y disc o nti n ue fr o m t he Pri mar y F oll o w- u p P hase of t he 
st u d y w hile i n re missi o n, f oll o w- u p atte m pts will be ma de t o assess t he s u bject’s rela pse a n d 
s ur vi val stat us e ver y 6 m o nt hs p ost C A R T- 1 9 i nf usi o n u ntil t he e n d of t he st u d y ( Last Patie nt/ Last 
Visit). O nce s u bjects rela pse t he y will be f oll o we d f or s ur vi v al u ntil t he e n d of st u d y ( Last 
Patie nt/ Last Visit) o nl y.   Last Patie nt/ Last Visit ( L P L V) is defi ne d as t he last pri mar y f oll o w- u p 
visit of t he last s u bject re mai ni n g i n i n pri mar y f oll o w- u p.   
6. 1 2. 
L o n g -t er m F oll o w- u p Pr ot o c ol 
After s u bjects’ c o m plete or pre mat urel y disc o nti n ue partici pati o n i n t he Pri mar y F oll o w- u p P hase 
of t he st u d y, s u bjects will be as ke d t o partici pate i n a se parate 1 5 year l o n g-ter m f oll o w -u p 
desti nati o n pr ot oc ol.   
6. 1 3. 
R e -tr e at m e nt C o h ort Pr o c e d ur e s 
6. 1 3. 1.  
Eli gi bilit y f or R etr e at m e nt 
U p t o o ne retr eat me nt d ose (s plit a d mi nistrati o n) will be all o we d per eli gi ble s u bject.    
1.  S u bjects pre vi o usl y i nf us e d wit h m uri ne C A R T 1 9 cells as part of t his pr ot o c ol a n d 
w h o ha ve rela pse d wit h C D 1 9 + disease. 
2.  S u bjects ha ve u n der g o n e t he 2 8  da y efficac y e n d p oi nt e val uati o n.  
3.  S u bjects ha ve < 5 % C A R T 1 9 cells i n t he C D 3 + p o p ulati o n b y fl o w c yt o metr y o n 
P B M Cs 
4.  S u bjects ha ve rec o ver e d fr o m a n y t o xicit y attri b ute d t o t he i nitial C A R T- 1 9 i nf usi o n, 
s uc h as C R S. 
I n a d diti o n, s u bjects m ust als o meet t he f oll o wi n g: 
Retre at me nt  I ncl usi o n Criteri a 
1.  Perf or ma nce Stat us 0- 1 
2.  A de q uate or ga n s yste m f u ncti o n i ncl u di n g: 
o  Creati ni ne < 1. 6 m g/ dl 
o  A L T/ A S T < 3 x u p per li mit of n or mal 
o  T otal Bilir u bi n < 2. 0 m g/ dl 
o  M ust ha ve a mi ni m u m le vel of p ul m o nar y res er ve defi ne d as ≤ Gra de 1 
d ys p nea, p ulse o x y ge n > 9 2 % o n r o o m air, a n d D L C O > 4 0 % (c orrecte d f or 
a ne mia if cli nicall y a p pr o priate)  
3.  Left Ve ntric ul ar Eje cti o n Fracti o n ≥ 4 0 % 
4.  N o c o ntrai n dicati o ns f or le u ka p heresis (if re q uir e d f or retr eat me nt)  
5.  Gi ves v ol u ntar y i nf or me d c o nse nt f or retreat me nt 
 
Retre at me nt E xcl usi o n Criteri a 
1.  Pre g n a nt or lact ati n g w o me n.   
2.  Acti ve he patitis B or he p atitis C  

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 6 4  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
3.  C o nc urre nt use of s yst e mic ster oi ds  or c hr o nic us e of i m m u n os u p pressa nt 
me dicati o ns.  Rece nt or c urre nt use of i n h ale d ster oi ds is n ot e x cl usi o nar y.  F or 
a d diti o nal details re gar di n g use of ster oi d or i m m u n os u p pressa nt me dicati o ns, please 
see Secti o n 5. 6. 
4.  HI V i nfecti o n 
5.  Patie nts wit h acti ve C N S i n v ol ve me nt wit h mali g na n c y.  Patie nts wit h pri or C N S 
disease t hat h as bee n effecti vel y treate d will be eli gi ble pr o vi di n g treat me nt was > 4 
wee ks bef ore e nr oll me nt o n t he retreat me nt c o h ort. 
6.  Class III/I V car di o v asc ular disa bilit y acc or di n g t o t he Ne w Y or k Heart Ass ociati o n 
Classificati o n (see A p p e n di x 1). 
7.  Patie nts wit h a k n o w n hist or y or pri or dia g n osis of o ptic ne uritis or ot her 
i m m u n ol o gic or i nfla m mat or y dis ease affecti n g t he ce ntr al ner v o us s yste m, a n d 
u nrelate d t o le u ke mia or pre vi o us le u ke mia treat me nt.   
8.  Acti ve ac ut e or c hr o nic graft- vers us - h ost disease ( G V H D) or re q uir e me nt of 
i m m u n os u p pressa nt me dicati o ns f or G V H D wit hi n 4 wee ks of e nr oll me nt. 
6. 1 3. 2.  
R etr e at m e nt Pr o c e d ur e s 
S u bjects eli gi ble f or retr eat me nt w h o c o nse nt t o partici pate i n t his c o h ort will be e nr olle d o n t he 
retreat me nt c o h ort.  T o e nr oll a s u bject o n t he retreat me nt c o h ort, pleas e pr o vi de t he d o c u me nts 
liste d bel o w t o: 
Pr ot oc ol M o nit or a n d S p o ns or Pr oject Ma na ger 
Ce nter f or Cell ular I m m u n ot hera pies ( C CI) 
 
 
D oc u me nts re q uir e d: 
 C o p y of si g ne d retreat me nt c o nse nt 
 C o m plete d Retreat me nt C o h ort E nr oll me nt F or m- i ncl u di n g d oc u me ntati o n of retreat me nt 
c o nse nt, c urre nt p h ysi cal e x a mi nati o n, la b orat or y a n d ra di ol o gical re p orts, c urre nt/ past me dical 
hist or y a n d c o n c o mita nt me dicati o ns, a n d a n y ot her d oc u me nt ati o n t o s u p p ort t he s u bjects’ 
e nr oll me nt o nt o t he retreat me nt c o h ort a n d has c o m plete d all re q uire d assess me nts. 
 
U p o n i nf or me d c o nse nt c o m pleti o n f or retreat me nt a n d recei pt of retr eat me nt scree ni n g a n d 
eli gi bilit y d o c u me ntati o n, t he S p o ns or Pr ot oc ol M o nit or will re vie w a n d pr o vi de d oc u me nt ati o n 
t hat t he m o nit ori n g visit f or retreat me nt eli gi bilit y has bee n c o m plete d.  T his d oc u me ntati o n m ust 
be recei ve d pri or t o cell pr o d uct ma n ufact uri n g. 
 
T he sa me S u bject N u m b er pre vi o usl y assi g ne d will be use d t o i de ntif y partici pa nts.  E nr oll me nt 
o n t he retreat me nt c o h ort will be trac ke d b y a d di n g “r” t o t he e n d of t his e xisti n g s u bject 
i de ntificati o n n u m ber (i.e. 1 0 0 0- 0 00 0 1 R), h o we v er t he sa me S u bject N u m b er pre vi o usl y assi g n e d 
will be use d i n t he cli nical data base.  
 
All prere q uisites f or eli gi bilit y t o recei ve C A R T- 1 9 o utli ne d i n Secti o n 5. 2 m ust be met pri or t o 
retreat me nt.  T he st u d y dr u g will be pre pare d a n d a d mi nist ere d p er t he g ui deli nes s et f ort h i n 
Secti o n 5.  All re q uire d st u d y pr oce d ures, pre- me di cati o ns, pr o p h yl a xis, a n d  m o nit ori n g g ui deli nes 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 6 5  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
fr o m t he i nitial i nf usi o n o utli ne d i n Secti o n 6 will a p pl y f or t his retreat me nt c o h ort. S u bjects will 
als o be f oll o we d per t he Retreat me nt C o h ort Visit E val uati o n Sc he d ule i n Ta ble 6- 2 .   
6. 1 4.  
Effi c a c y A s s e s s m e nt s  
Efficac y assess me nts will be perf or me d  acc or di n g t o t he G ui deli nes f or efficac y e val uati o n i n 
Ac ute L y m p h o blastic Le u ke mia st u dies.  T his d oc u me nt is base d o n t he sta n dar dize d res p o nse 
criteria d efi ne d b y Nati o nal C o m pre he nsi ve Ca n cer Net w or k ( N C C N G ui deli nes ( N C C N, 2 0 1 3 
v 1) a n d f urt her s u p p orte d b y t h e w or ks h o p re p ort o n ac ute l e u ke mia fr o m A merica n S ociet y of 
He mat ol o g y ( A S H) ( A p p el ba u m et al 2 0 0 7) a n d t he I nter nati o nal W or ki n g Gr o u p (I W G) g ui deli ne 
f or ac ut e m yel oi d le u ke mia ( A M L) ( C hes o n et al 2 0 0 3).   
 
T u m or res p o nse ass ess me nts will be d o ne at baseli ne ( pri or t o C A R T- 1 9 i nf usi o n) a n d  t he n at Da y 
2 8 a n d M o nt hs 3, 6, 9 a n d 1 2 after C A R T- 1 9 cell i nf usi o ns or u ntil t h e patie nt re q uires alter nati ve 
t hera p y f or t heir disease. Assess me nts will be ma de as cli nicall y i n dicate d b y p h ysical e x a m, c hes t 
x-ra y, C S F e v al uati o n, he mat ol o g y bl o o d pa nel, a n d b o ne marr o w bi o ps y a n d as pirate.  
 
Disease ass ess me nt c ollecti o n pla n is detaile d i n T a ble 6- 4 . 
 
T a ble 6- 4:  Dise ase Assess me nt C ollecti o n Pl a n 
Pr o ce d ure  
Scree ni n g/ Pre -i nf usi o n 
P ost I nf usi o n Assess me nts  
B o ne marr o w as pirate a n d 
bi o ps y  
Ma n date d
 
Ma n date d: Da y 2 8, M o nt hs 
3, 6, 9 a n d 1 2  
 
Peri p heral Bl o o d f o r blast, 
ne utr o p hil a n d platelet cell 
c o u nts  
Ma n date d
 
Ma n date d: Da y 2 8, M o nt hs 
3, 6, 9 a n d 1 2  
L y m p h N o d e bi o ps y  
If accessi ble 
O pti o nal if 
accessi ble/ necess ar y at D a y 
2 8, M o nt hs 3, 6, 9 a n d 1 2  
C S F Assess me nt f or C N S 
disease   
Ma n date d  
Perf or me d a s cli nicall y 
i n dicate d b y t he pres e nce of 
ne ur ol o gi c s y m pt o ms  
C N S Brai n I ma gi n g 
( M RI/ C T) 
As  cli nicall y i n dicate d  
As cli nicall y i n dicate d  
C hest x -ra y f or 
me diasti nal disease  
Ma n date d  
As cli nicall y i n dicate d  
C hest C T/ M RI s ca n  f or 
me diasti nal disease  
If t he scree ni n g c h est x -ra y 
s u g gests me diasti nal 
e nlar ge me nt  
Ma n date d o nl y if a b n or m al 
at or bef ore scree ni n g:  D a y 
2 8 a n d M o nt h 3  

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 6 6  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
Pr o ce d ure  
Scree ni n g/ Pre -i nf usi o n 
P ost I nf usi o n Assess me nts  
E val uati o n  f or 
e xtra me d ullar y dise ase  
Ma n date d
 
Ma n date d Da y 2 8, M o nt hs 
3, 6, 9 a n d 1 2   
( See Secti o n 6. 1 4. 1 f or 
a d diti o nal i nf or mati o n) 
M R D assess me nt of b o n e 
marr o w b y fl o w c yt o metr y 
(e ver y p atie nt) 
Ma n date d  
Ma n date d Da y 2 8, M o nt hs 
3, 6, 9 a n d 1 2  
B C R -A B L Q -P C R  of 
bl o o d a n d b o ne marr o w 
as pirate f or patie nts wit h 
P h +  A L L  
Ma n date d  
Ma n date d Da y 2 8, M o nt hs 
3, 6, 9 a n d 1 2  
Tra nsf usi o n dates  
Assess de pe n de n c y  
Rec or d as nee de d d uri n g 
t he c o urse of t h e trial 
6. 1 4. 1.  
E v al u ati o n f or e xtr a m e d ull ar y di s e a s e 
A n e val uati o n will be perf or me d t o assess e vi de nce of e xtra me d ullar y dis ease at t he ti me p oi nts 
i de ntifie d i n Ta ble 6- 4 a b o ve. T he s c o pe of assess me nts perf or me d as p art of t his e val u ati o n is 
base d o n t he res ults of t h e pre-i nf usi o n assess me nt a n d t he p h ysicia n’s cli nical discreti o n.   T his 
ma y i ncl u d e assess me nts of t he li ver, s ple e n, l y m p h n o des, s ki n, g u m i nfiltrati o n, testic ular 
i n v ol ve me nt, a n d ot her sites as a p plica ble.   
6. 1 4. 2.  
B o n e M arr o w A s pir at e/ Bi o p s y a n d P eri p h er al Bl o o d 
B o ne marr o w bi o psies a n d as pirate will be meas ure d f or t u m or e v al uati o ns a n d efficac y a n al ysis 
per Ta ble 6- 5 .   
6. 1 4. 3.  
C er e br o s pi n al Fl ui d ( C S F) A s s e s s m e nt  
C S F will be assesse d at s cree ni n g. S u bse q ue nt C S F ass ess me nts after C A R T - 1 9 i nf usi o n will b e 
perf or me d as cli nicall y i n dicate d (i.e. w he n ne w n e ur ol o gical s y m pt o ms are prese nt). C S F will be 
a nal yze d f or cell c o u nt a n d differe ntial, c yt ol o g y, a n d f or t he prese n ce of C A R T- 1 9 cells.   
6. 1 4. 4.  
M e di a sti n al Di s e a s e A s s e s s m e nt 
A c hest x-ra y 
will be perf or me d at scree ni n g.  If t he c hest x-ra y re veals 
me diasti nal 
wi de ni n g/e nl ar ge me nt, t he n a C T/ M RI sca n is re q uire d at bas eli ne t o c o nfir m t he prese n ce of 
me diasti nal disease a n d s u bse q ue nt visits are re q uire d at Da y 2 8 a n d at M o nt h 3 . If t he scree ni n g 
c hest x-ra y s u g gests n o me diasti nal disease t he n n o f urt her c h est i ma gi n g is re q uire d.  
 
If at a n y ti me p oi nt, me diasti nal disease is prese nt b y C T/ M RI assess me nt, t he n f oll o w- u p C T/ M RI 
is re q uire d t o d oc u me nt t he a bse nce of me diasti n al i n v ol ve me nt w he ne v er t he patie nt meets all 
ot her criteria f or c o m plet e res p o nse. T w o e v al uati o ns at least 2 8 da ys a part are n ee de d t o c o nfir m 
a res p o nse i n me diasti nal dise ase. T he ti mi n g of t he C T/ M RI m ust be wit hi n t he re q uire d ti me 
wi n d o w of t he ot her disease res p o ns e c o m p o ne nts ( T a ble 6- 4 ). 
 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 6 7  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
F or o pti mal e val uati o n of patie nts, t he sa me i ma gi n g met h o d of assess me nt (i.e. C T or M RI) a n d 
tec h ni q ue (i.e. wit h or wit h o ut c o ntrast) s h o ul d be use d t o c haract erize eac h i de ntifie d a n d re p ort e d 
lesi o n at baseli ne a n d d uri n g f oll o w- u p. A c ha n ge i n met h o d ol o g y ca n be defi ne d as eit her a c ha n ge 
i n c o ntrast use (e. g. kee pi n g t he sa me tec h ni q ue, li ke C T, b ut s witc hi n g fr o m i ntra ve n o us c o ntr ast 
use t o n o n-c o ntrast e n ha nce d C T, re gar dless of t he j ustificati o n f or t he c ha n ge) or a c h a n ge i n 
tec h ni q ue (e. g. fr o m C T t o M RI, or vice- v ersa). 
6. 1 4. 5. 
  Mi ni m al R e si d u al Di s e a s e ( M R D)  
All patie nts will ha v e m ulti para meter fl o w c yt o metr y o n b o ne marr o w as pir ate f or M R D st at us at 
eac h ti me p oi nt a b o ne m arr o w as pirate is perf or m e d ( per Ta ble 6- 1) .  
6. 1 4. 6.  
Q u a ntit ati v e B C R- A B L: P h + A L L P ati e nt s 
B o ne m arr o w as pir ates sa m ple d at t he ti me p oi nts f or t u m or assess me nts will a d diti o nall y b e 
a nal yze d f or q ua ntitati ve B C R- A B L l e vels f or P h p ositi ve A L L patie nts o nl y.   
6. 1 4. 7.  
E v al u ati o n of Tr a n sf u si o n D e p e n d e n c y 
I nf or mati o n o n tra nsf usi o n de pe n de nc y will be assesse d at scree ni n g as well as d uri n g t he c o urse 
of t he tri al f or all p atie nts. Tra nsf usi o n of bl o o d pr o d ucts will be rec or de d i n a s e parate m o d ule of 
t he e C R F. T he t y pe of tra nsf usi o n, start a n d e n d date as well as t he n u m ber of u nits will be ca pt ure d 
at eac h visit wit h he mat ol o gic ass ess me nt. 
 
A peri o d of at least o ne wee k wit h o ut a n y tra nsf usi o n has bee n ta ke n as a c o n ve nti o n t o defi ne t he 
stat us of tra nsf usi o n i n de pe n de nce t o assess a C R vs. C Ri res p o nse 1 0 0. A n y sa m ple of peri p heral 
bl o o d w hic h was ta ke n less t ha n se ve n da ys after a tra nsf usi o n will be c o nsi dere d as ta ke n w hil e 
t he patie nt is tra nsf usi o n de pe n de nt. 
6. 1 5.  
A L L R e s p o n s e Crit eri a 
T he res p o nse criteria will be e val uate d acc or di n gl y t o t he G ui deli nes f or efficac y e v al uati o n i n 
Ac ute L y m p h o blastic Le u ke mia st u dies.  T his d oc u me nt pr o vi d es t he w or ki n g d efi niti o ns, 
s pecificati o ns, c o m p o n e nts a n d ti mi n g of o verall disease res p o nse e val uati o n f or a c o nsiste nt a n d 
efficie nt a n al ysis of efficac y assessi n g a nti ne o plastic acti vit y i n A L L.  T he defi niti o ns are 
pri maril y bas e d o n t he sta n dar dize d res p o nse criteria defi ne d b y Nati o nal C o m pre he nsi ve Ca ncer 
Net w or k ( N C C N) G ui deli nes ( N C C N, 2 0 1 3  v.1 ) a n d f urt h er s u p p ort e d b y t he w or ks h o p re p ort 
fr o m A merica n S ociet y of He m at ol o g y ( A S H)1 0 1 a n d t h e I nter nati o nal W or ki n g Gr o u p (I W G) 
g ui deli ne f or ac ute m yel oi d le u ke mia ( A M L) 1 0 2. T he C hes o n I W G g ui deli n e a n d A p pel ba u m A S H 
re p ort were use d i n rece nt dr u g a p pr o vals (e. g. Mar qi b o) i n A L L, pri or t o t he N C C N g ui deli ne 
a vaila bilit y. T he N C C N g ui da n ce is a m or e rece ntl y p u blis he d u p date d U S base d g ui deli ne f or 
A L L. 
 
Efficac y ass ess me nts will be perf or me d base d o n b o ne marr o w a n d bl o o d m or p h ol o gic criteria, 
p h ysical e x a mi nati o n fi n di n gs, al o n g wit h la b orat or y assess me nts of C S F a n d b o ne 
M R D 
assess me nt. T he o verall disease res p o ns e is deter mi ne d at a gi ve n e v al uati o n usi n g t he criteria 
descri be d i n T a ble 6 - 5.  
 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 6 8  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
T a ble 6- 5: O ver all dise ase res p o nse cl assific ati o n at a gi ve n e v al u ati o n ti me 
R e s p o n s e c at e g or y  D efi niti o n  
C o m pl et e r e mi s si o n 
(C R)  
All t h e f oll o wi n g crit e ri a ar e m et: 
B o n e m arr o w  
 
Trili n e a g e H e m at o p oi e si s  ( T L H) a n d < 5 % bl a st s* 
P eri p h er al bl o o d  
 
N e utr o p hil s > 1. 0 x 1 0 9 / L, a n d 
 
Pl at el et s >  1 0 0 x 1 0 9 / L, a n d 
 
Cir c ul ati n g bl a st s < 1 %  
E xtr a m e d ull ar y di s e a s e  
 
N o e vi d e n c e of e xtr a m e d ull ar y di s e a s e ( n o C N S di s e a s e, 
m e d i a sti n al di s e a s e C R, n o ot h er e xtr a m e d ull ar y sit e s of 
i n v ol v e m e nt) 
Tr a n sf u si o n i n d e p e n d e n c y  
 
N o pl at el et a n d/ or n e utr o p hil tr a n sf u si o n s wit hi n 1 w e e k  b ef or e 
p eri p h er al bl o o d s a m pl e f or di s e a s e a s s e s s m e nt  
C o m pl et e r e mi s si o n wit h 
i n c o m pl et e bl o o d c o u nt 
r e c o ver y ( C Ri)  
All crit eri a f or C R a s d efi n e d a b o v e ar e m et, e x c e pt t h at t h e f oll o wi n g e xi st:  
 
N e utr o p hil s ≤ 1. 0 x 1 0 9 / L, or  
 
Pl at el et s ≤ 1 0 0 x 1 0 9 / L, or 
 
Pl at el et a n d/ or n e utr o p hil tr a n sf u si o n s wit hi n w e e k  b ef or e 
p eri p h er al bl o o d s a m pl e f or di s e a s e a s s e s s m e nt  
C o m pl et e r e mi s si o n 
( C R) wit h r e si d u al 
m e di a sti n al di s e a s e   
All crit eri a f or C R or C Ri a s d efi n e d a b o v e  ar e m et, e x c e pt t h at m e di a sti n al 
di s e a s e  (i. e. C R u or P R ) i s pr e s e nt ( S e e N ot e B el o w) : 
N o r e s p o n s e ( Tr e at m e nt 
f ail ur e) 
F ail ur e t o att ai n t h e crit eri a n e e d e d f or a n y r e s p o n s e c at e g ori e s  
R el a p s e d Di s e a s e  
O nl y i n p ati e nt s wit h a C R o r C Ri: 
 
R e a p p e ar a n c e of bl a st s i n t h e bl o o d ( ≥ 1 %), or  
 
R e a p p e ar a n c e of bl a st s i n b o n e m arr o w ( ≥ 5 %), or  
 
( R e-) a p p e ar a n c e of a n y e xtr a m e d ull ar y di s e a s e aft er C R 
U n k n o w n  
 
 
 
I n c a s e t h e r e s p o n s e a s s e s s m e nt w a s n ot d o n e, t h e b a s eli n e a s s e s s m e nt 
w a s n ot d o n e, t h e a s s e s s m e nt w a s i n c o m pl et e or w a s n ot d o n e  wit hi n t h e 
r e s p e cti v e ti m e fr a m e. If t h er e i s e vi d e n c e of r el a p s e, t h e o v er all r e s p o n s e 
will b e a s s e s s e d a s r el a p s e wit h t h e r el a p s e d c o m p o n e nt al o n e.  
 
* Bl a st p er c e nt a g e a s s e s s m e nt i s b a s e d o n a b o n e m arr o w a s pir at e diff er e nti al c o u nt. O c c a si o n all y, 
a p r e ci s e a s pir at e diff er e nti al c o u nt i s pr e cl u d e d b y h e m o dil uti o n or ot h er t e c h ni c al f a ct or s. S u c h 
c a s e s m a y still b e s c or e d a s c o m p ati bl e wit h c o m pl et e r e mi s si o n ( C R) if n o ot h er m or p h ol o gi c or 
a n cill ar y ( e. g fl o w  c yt o m etr y , m ol e c ul ar, c yt o g e n eti c) e vi d e n c e of r e si d u al/r e c urr e nt di s e a s e i s 
i d e ntifi e d b y t h e p at h ol o gi st. 
N ote: T he N C C N g ui d eli ne has defi ne d me diasti nal res p o nse criteria i ncl u di n g C R u a n d P R. 
I n t he case a patie nt ac hie ves C R or C Ri at all ot her n o n- me diasti nal disease sites, a n d has 
resi d ual me diasti nal disease ( C R u or P R), a cate g or y f or of o verall disease res p o nse of C R or 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 6 9  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
C Ri wit h resi d ual me diasti nal disease has bee n i n cl u de d i n t his d oc u me nt, w hic h is n ot part of 
t he N C C N g ui da n ce.  
 
T he N C C N g ui da nce has defi ne d a pr o gressi ve disease ( P D) cat e g or y. I n t his d oc u me nt, P D is 
c o nsi dere d t he sa me as “ N o res p o nse” or “ Treat me nt fail ure”, w hic h is c o nsiste nt wit h t he 
C hes o n et al. ( 2 0 0 3) g ui deli ne 1 0 2. T he differe nce b et wee n P D a n d “ N o res p o nse” i n A L L is n ot 
belie ve d t o be cli nical m ea ni n gf ul. 
6. 1 5. 1.  
C o nfir m ati o n of R e s p o n s e  
F or a nal ysis p ur p oses, a p atie nt will be c o nsi dere d t o ha ve ac hie ve d C R o nl y if t he patie nt satisfies 
all criteria f or C R at t w o c o nsec uti ve assess me nts t hat are at least 4 wee ks a part. T he date of C R 
will t he n be deri ve d as t h e earlier of t he t w o assess me nt dates.  
 
O verall dise ase res p o nse e val uati o n, i n cl u di n g bl o o d, b o ne marr o w, e xtra me d ullar y diseas e ( per 
Secti o n 6. 1 4. 1), C T/ M RI (if nee de d), m ust be perf or me d at Da y 2 8, a n d t he n at M o nt h 2 t o 3 t o 
c o nfir m res p o ns e stat us assesse d at Da y 2 8. T his res p o nse c o nfir mati o n ca n n ot be p erf or me d 
earlier t h a n 4 w ee ks f oll o wi n g t he Da y 2 8 assess me nt. T heref ore, if n ecessar y t h e M o nt h 3 
res p o nse e val uati o n ma y b e perf or me d earlier, b ut m ust be m ore t ha n 2 8 da ys aft er t he last 
c o m p o ne nt of t he D a y 2 8 e val uati o n. C S F will be perf or me d at baseli ne a n d at p ost-i nf usi o n ti me 
p oi nts as cli nicall y a p pr o priate.    
T he sa me pri nci ple a p pli es w he n t h e i nitial diseas e res p o ns e occ urs be y o n d Da y 2 8 (e. g. M o nt h 3, 
M o nt h 6, etc.). A c o nfir m ati o n is re q uire d m ore t ha n 2 8 da ys later t ha n l ast c o m p o ne nt of t he i nitial 
res p o nse e v al uati o n. 
 
If a patie nt s atisfie d C Ri at o ne assess me nt a n d l ater c o nfir me d as a C R i n t he ne xt assess me nt 
m ore t ha n 4 w ee ks a p art, t he patie nt will be c o nsi dere d as h a vi n g c o nfir me d C R. H o we ver, t he 
date of C R will be deri ve d as t he latter (c o nfir me d) assess me nt dates. 
 
7.  S T A TI S TI C A L P L A N 
7. 1. D e si g n O v er vi e w  
T his is a si n gle ce nter, si n gle ar m, o pe n-la bel p hase II st u d y t o deter mi ne t he efficac y a n d s afet y 
of a ut ol o g o us T cells e x pressi n g C D 1 9 c hi meric a nti ge n rece pt ors e x pressi n g ta n de m T C Rζ a n d 
4 - 1 B B ( T C Rζ/ 4- 1 B B) c o-sti m ulat or y d o mai ns (referre d t o as “ C A R T- 1 9” cells) i n a d ult patie nts 
wit h rela pse d or refract or y B-cell ac ute l y m p h o blastic le u ke mia.  
7. 2. S a m pl e Si z e J u stifi c ati o n  
T he st u d y will tar get a t otal of 3 0  pri mar y efficac y e val u a ble rela pse d/r efract or y A L L patie nts 
treate d wit h C A R T- 1 9 cells i n t he st u d y. T he s a m ple siz e was i ncreas e d t o 3 0 f or a me n d me nt 1 1 
w hic h will yiel d m or e e x perie nce, a t otal of 1 5 s u bjects, wit h t he t ar gete d fracti o nate d 1- 5 x 1 0 8 
d ose.  
 
T he pri mar y o bje cti ve i n t his st u d y is t o det er mi ne o verall c o m plete re missi o n rate ( O R R) w hic h 
i ncl u des c o m plete re missi o n ( C R) a n d C R wit h i nc o m plete bl o o d c o u nt rec o ver y ( C Ri) at Da y 2 8. 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 7 0  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
I n a rec e nt st u d y of vi ncristi ne s ulfate li p os o me i njecti o n i n a d ult A L L p atie nts i n sec o n d or great er 
rela pse or w h os e diseas e has pr o gresse d f oll o wi n g t w o or m ore a nti-le u ke mia t hera pies, t he 
o bser ve d O R R was 1 5. 4 % ( 9 5 % CI [ 7. 6, 2 4. 5]) ( Mar qi b o ® U S la bel).   T h e half- wi dt h of t he 9 5 % 
e x act c o nfi de nce i nter val f or O R R will be n o lar ger t ha n 1 9 % f or a c o h ort of siz e 3 0 a n d n o lar ger 
t ha n 2 6 % f or a c o h ort of siz e 1 5.  
7. 3. A n al y si s S et s 
 T he E nr olle d Set c o m prises all patie nts w h o si g n a n i nf or me d c o ns e nt f or m a n d 
are e nr olle d i n t he st u d y, e x cl u di n g scree n fail ure patie nts. 
 T he Effic ac y E v al u a ble Set c o m prises all patie nts w h o recei ve t he C A R T- 1 9 
cells at t he i nte n de d d ose ra n ge a n d c o m plete d t he res p o nse ass ess me nts f or t he 
pri mar y efficac y e n d p oi nt as pla n ne d b y t he pr ot o c ol. Efficac y e v al ua ble p atie nts 
als o i ncl u de t h ose wit h disease pr o gressi o n or deat h pri or t o t he pri mar y efficac y 
e n d p oi nt res p o nse ass ess me nt. T hese are t he pri m ar y efficac y e val u a ble patie nts 
as defi ne d b el o w. T he Efficac y E v al ua ble Set will be use d f or t h e pri mar y 
effic ac y e n d p oi nt a n al ysis.  
 T he F ull A n al ysis Set ( F A S)  c o m prises all patie nts w h o recei ve d t he C A R T- 1 9 
cells. T his set i ncl u des b ot h pri mar y effi cac y e val ua ble a n d n o n-e val ua ble 
patie nts as defi ne d b el o w. T he F ull A nal ysis Set will be use d f or t he sec o n d ar y 
effic ac y, safet y a n d c orrelati ve e n d p oi nts or ot her e x pl orat or y a n al ys es. 
 
Defi niti o ns relev a nt t o t he A n alysis Sets: 
 Scree ni n g f ail ure  - A n y patie nt w h o fails t o meet t he i ncl usi o n/e xcl usi o n criteria 
s pecifie d b y t he pr ot o c ol.   
 M a n uf act uri n g f ail ure  – A n y p atie nt w h o has m a n ufact ure d C A R T- 1 9 cells t hat d o n ot 
meet t he ma n ufact uri n g release criteria.   
 Pri m ar y effic ac y e v al u a ble p atie nt  –  A n y patie nt w h o is i nf use d wit h at least 1 - 5 x 1 07 
C A R T- 1 9 cells a n d c o m plete d t he res p o nse assess me nts f or t he pri mar y efficac y 
e n d p oi nt as pla n ne d b y t he pr ot oc ol. Effi cac y e val ua ble patie nts als o i ncl u de t h ose wit h 
disease pr o gressi o n or deat h pri or t o t he pri mar y efficac y e n d p oi nt res p o ns e assess me nt. 
 Pri m ar y effic ac y n o n-e v al u a ble p atie nt  –  A n y patie nt w h o is i nf use d wit h t he C A R T-
1 9 cells at less t ha n t he pr ot oc ol-s pecifi e d d ose. T hese patie nts are als o c o u nte d as 
ma n ufact uri n g fail ures.  Patie nts w h o are i nf use d a n d dr o p o ut bef ore t he Da y 2 8 
assess me nt d ue t o reas o ns ot her t ha n disease pr o gressi o n or deat h are als o c o nsi dere d 
n o n -e val ua ble.  
7. 4. A n al y si s of Pri m ar y O bj e cti v e  
T he pri mar y e n d p oi nt is t he o verall c o m plete re missi o n rate ( O R R) at Da y 2 8. T he o verall 
c o m plete re missi o n rate is c o m p ute d as t he pr o p orti o n of patie nts wit h C R or C Ri acc or di n g t o t he 
res p o nse criteri o n d escri be d i n Secti o n 6. 1 5.  A nal yses of s u b gr o u ps b y d ose-le vel will als o b e 
c o nsi dere d. 
T he t w o-si de d e x act Cl o p per- Pears o n 9 5 % c o nfi de nce i nter vals f or Da y 2 8 O R R will be 
c o m p ute d. T he st u d y w o ul d i n dicate mea ni n gf ul efficac y if t he l o w er b o u n d of t he 2-si de d 9 5 % 
e x act c o nfi de nce i nter val is greater t ha n 1 5 %, s o t hat t he n ull h y p ot hesis t h at t he O R R is less t ha n 
or e q ual t o 1 5 % ca n be rejecte d. 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 7 1  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
7. 5. A n al y si s of S e c o n d ar y Effi c a c y O bj e cti v e s  
F or t he sec o n dar y efficac y o bj ecti ves f or t his st u d y, t he pr o p orti o n of pati e nts will be c o m p ute d 
wit h a best o verall disease res p o nse of C R or C Ri, w here t he best o verall disease res p o nse is 
defi ne d as t he best diseas e res p o nse rec or de d fr o m t he start of t he treat me nt u ntil deat h, last f oll o w 
u p, rela pse or start of n e w a ntica n cer t hera p y, w hic he ver c o mes first. Pr o p orti o n of patie nts 
ac hie vi n g C R or C Ri bef ore or at M o nt h 6 ( pri or t o recei vi n g ot her a ntica n cer t hera p y if a n y), a n d 
t he pr o p orti o n of patie nts wit h a mi ni mal resi d ual disease ( M R D) ne g ati ve b o ne marr o w as 
deter mi ne d acc or di n g t o Secti o n 6. 1 4  will als o be c o m p ute d. T w o-si de d e x act Cl o p per- Pears o n 
9 5 % c o nfi de n ce i nter vals f or t he pr o p orti o ns will b e pr o vi de d. A s u bset a nal ys is of s pecific d osi n g 
s u b gr o u ps (e. g. t he fracti o nate d 1- 5 x 1 0 8 d o se gr o u p) ma y als o be c o nsi dere d f or s ec o n dar y 
e n d p oi nts. 
 
Sec o n dar y efficac y o bj ecti ves f or t his st u d y als o i ncl u de t he e val uati o n of t he f oll o wi n g ti me t o 
e ve nt e n d p oi nts: o verall s ur vi val ( O S), d urati o n of re missi o n ( D O R), rela pse free s ur vi v al ( R F S), 
a n d e v e nt free s ur vi val ( E F S). D efi niti o ns f or eac h of t h e e n d p oi nts are descri be d bel o w. T h e 
s ur vi val f u ncti o n of t h ose e n d p oi nts usi n g t he Ka pla n- Mei er met h o d will be esti mate d. 9 5 % 
c o nfi de nce i nter val f or t he s ur vi val pr o ba bilit y at a s pecific ti me p oi nt (e. g., 3- m o nt h o v erall 
s ur vi val) will be c o m p ute d base d o n t he l o g-l o g tra nsf or mati o n. M e dia n s ur vi val ti me al o n g wit h 
t he ass ociate d 9 5 % c o nfi de nce i nter vals will be prese nte d if a p pr o priate d. O ver all s ur vi v al ( O S) 
is defi ne d as t he ti me fr o m t he date of C A R T- 1 9 i nf usi o n t o t he date of d eat h d ue t o a n y reas o n. 
I n cas e a p atie nt is ali ve at t he date of last c o ntact o n or bef ore t he dat e of data c ut off, O S is 
ce ns ore d at t he date of last c o ntact. Ca use of deat h will be descri be d w he n a p plica ble. D ur ati o n 
of re missi o n ( D O R) is defi ne d as t he d urati o n fr o m t he date w he n t he res p o nse criteria of C R or 
C Ri is first met t o t he date of rel a pse or d eat h d ue t o A L L. D O R will be ass esse d o nl y i n p atie nts 
wit h t he best o verall res p o nse of C R or C Ri. 
 
I n case a p atie nt d oes n ot rela ps e or die d u e t o A L L pri or t o t he d ate of dat a c ut off, D O R will be 
ce ns ore d at t he date of t he last a de q uate ass ess me nt o n or pri or t o t he earliest ce ns ori n g e v e nt. T he 
ce ns ori n g e v e nt c o ul d be:  
• 
L ost t o f oll o w- u p 
• 
Wit h dre w c o nse nt 
• 
Deat h d ue t o r eas o n ot her t ha n A L L  
• 
Ne w a ntica ncer t hera p y (i ncl u di n g H S C T w he n perf or me d i n C R or C Ri) 
• 
E ve nt after at least t w o missi n g sc he d ule d disease assess me nt 
Alt h o u g h patie nts i n re missi o n mi g ht c h o ose t o recei v e H S C T, data o n rela pse, s ur vi v al, a n d 
res p o nse stat us after H S C T will n ot be use d f or t he calc ulati o n of D O R. T his is beca use H S C T 
pr oce d ure c o ul d affect re missi o n d urati o n i n de pe n de nt of C A R T 1 9 t hera p y; i n a d diti o n it is li kel y 
t o re m o ve a n y re mai ni n g C A R T- 1 9 cells i n t he patie nt t h us o utc o mes after H S C T ca n n ot be s olel y 
attri b ute d t o t he C A R T- 1 9 treat me nt. If a s u bsta ntial n u m ber of patie nts c h o ose t o recei ve H S C T 
w hile i n C R or C Ri, se nsiti vit y a nal ysis will be perf or me d i n w hic h p atie nts w h o recei ve H S C T 
w hile i n C R or C Ri are n ot ce ns ore d at ti me of H S C T; a n a n al ysis wit h H S C T re gar de d as a 
c o m peti n g ris k t o t he e ve nt of i nterest (e. g., rela pse after C A R T- 1 9 tr eat me nt) ma y als o be 
c o nsi dere d. I n a c o m peti n g ris k a n al ysis, t h e c u m ulati ve i nci de nce f u ncti o n ( CI F) w o ul d b e 
c o m p ute d t o esti mate t he pr o ba bilit y of rela pse i n t he prese n ce of t he c o m p eti n g ris k d ue t o H S C T.   

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 7 2  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
A nal ys es w hic h treat d eat h f or reas o ns u nrel ate d t o A L L as a c o m peti n g ris k will als o b e 
c o nsi dere d.  
 
Rel a pse free s ur vi v al ( R F S) is defi ne d as t he d urati o n bet wee n t he d ate w he n t he res p o ns e criteria 
of C R or C Ri is first met t o t he date of rela pse or deat h d ue t o a n y ca use. R F S will be assesse d 
o nl y i n patie nts wit h t he best o verall res p o ns e of C R or C Ri. 
 
I n cas e a patie nt d o es n ot rela ps e or di e d ue t o a n y ca use pri or t o t he dat e of data c ut off, R F S will 
be ce ns ore d at t he date of t he last a de q u ate assess me nt o n or pri or t o t h e earliest ce ns ori n g e v e nt. 
T he ce ns ori n g e ve nt c o ul d be:  
 L ost t o f oll o w - u p 
 Wit h dre w c o nse nt 
 Ne w a ntica ncer t hera p y (i ncl u di n g H S C T w he n perf or me d i n C R or C Ri) 
 E ve nt after at least t w o missi n g sc he d ule d disease assess me nt 
Se nsiti vit y a n al ys es si milar t o t h ose descri be d f or t he a nal ysis D O R will be perf or me d.   
 
E ve nt free s ur vi v al ( E F S) is defi ne d as t he ti me fr o m start of C A R T- 1 9 i nf usi o n t o t he earliest of 
t he f oll o wi n g:  
 Deat h fr o m a n y ca us e 
 Rela pse  
 Treat me nt f ail ure: Defi ne d as n o res p o nse i n t he st u d y a n d dis c o nti n uati o n fr o m t he st u d y 
d ue t o a n y of t he f oll o wi n g reas o ns: 
o  A d verse e ve nt(s) 
o  A b n or mal la b orat or y v al ue(s) 
o  A b n or mal test pr oce d ure res ults 
o  Ne w ca ncer t hera p y (e x cl u di n g H S C T w he n perf or me d i n C R or C Ri) 
 
I n case a patie nt d oes n ot e x perie nce a n e ve nt of i nterest pri or t o t he date of data c ut off, E F S is 
ce ns ore d at t he last a de q uate res p o nse assess me nt date o n or pri or t o t he d ate of data c ut off. 
 
All sec o n dar y effic ac y e n d p oi nts will be assesse d usi n g t he F A S. 
7. 6. A n al y si s of S e c o n d ar y S af et y o bj e cti v e s  
F or all safet y a nal yses, t he F ull A nal ysis Set ( F A S) will be use d. All a d verse e ve nts ( A E) will be 
c ollecte d i n acc or da n ce wit h secti o n 8. 1,  starti n g at t he ti me of C A R T- 1 9 i nf usi o n, i ncl u di n g, b ut 
n ot li mite d t o, c yt o ki ne release s y n dr o me ( C R S) a n d macr o p ha ge acti vati o n s y n dr o me ( M A S) will 
be liste d. I nci de n ce a n d s e verit y of A Es will be s u m marize d a n d ta b ulate d b y s yst e m or ga n class, 
preferre d ter m a n d m a xi m u m t o xicit y gra de ( bas e d o n C T C A E v 4. 0 3 ). E x act c o nfi de nce i nter val 
f or pr o p orti o ns will be c o m p ute d if a p pr o priate. C ha n ges i n la b orat or y v al ues a n d vital si g ns fr o m 
ti me of i nf usi o n will be s u m marize d descri pti vel y f or eac h sc he d ule d a n d u nsc he d ule d ti me p oi nts. 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 7 3  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
La b orat or y val ues o utsi de n or mal li mits will be i de ntifie d i n data listi n g a n d will i ncl u de fla gs f or 
hi g h a n d l o w v al ues.  A p atie nt wit h m ulti ple C T C gra des f or a n A E will be s u m marize d u n der t h e 
ma xi m u m C T C gra de rec or de d f or t he e v e nt. T he fre q u e nc y of C T C gra de 3 a n d 4 A Es will be 
s u m marize d se paratel y. I n a d diti o n, A Es relate d t o st u d y dr u g will be pres e nte d b y pri mar y s yste m 
or ga n class, preferre d ter m, a n d ma xi m u m C T C gra de. Seri o us a d verse e ve nts ( S A Es) will be 
s u m marize d se paratel y. A s u bset a nal ysis of s pecific d osi n g s u b gr o u ps (e. g. t he fracti o nate d 1-
5 x 1 0 8 d ose gr o u p) ma y als o be c o nsi dere d f or safet y e n d p oi nts. 
7. 7. A n al y si s of Ot h er S e c o n d ar y O bj e cti v e s 
Descri pti ve statistics will be calc ulate d f or c orrel ati ve e n d p oi nts a n d patie nt re p orte d o utc o mes. 
F or c o nti n u o us varia bles, mea n, me dia n, sta n d ar d de viati o n, i nter- q uartile ra n ge will be pr o vi d e d. 
F or discrete varia bles, fre q ue nc y a n d pr o p orti o ns will be use d. T he c orrelati o n bet wee n meas ures 
of i m m u n o ge nicit y a n d t he l oss of C A R T- 1 9 e n graft me nt will be e val uate d usi n g Pears o n’s 
c orrel ati o n c oefficie nt or t he n o n para metric e q ui vale nt of S pear ma n ra n k c orrelati o n. 
W he n 
e n d p oi nts of i nterest are o btai ne d fr o m t h e sa me p atie nt at m ulti ple ti me p oi nts (e. g., C A R T- 1 9 i n 
vi v o s ur vi val is meas ure d b y Q- P C R wee kl y f or t h e first m o nt h, m o nt hl y u ntil M o nt h 6 a n d e ver y 
t hree m o nt hs u ntil 
M o nt h 1 2), statistical met h o ds a p pr o priate f or l o n git u di nal data will be 
i m ple me nte d. T o e val uate ma n ufact uri n g feasi bilit y, t he pr o p orti o n of ma n ufact uri n g pr o d ucts t hat 
d o n ot meet releas e criteria f or v ect or tra ns d ucti o n efficie nc y, T cell pr o d uct p urit y, via bilit y, 
sterilit y or d ue t o t u m or c o nta mi nati o n will be c o m p ute d usi n g patie nts i n t he e nr olle d s et. T he 
pr o p orti o n of patie nts t hat meet s uccessf ul test e x pa nsi o n criteria will be c o m p ute d. 9 5 % 
c o nfi de nce i nter val a p pr o priate f or eac h st atistic will be use d. 
7. 8. R etr e at m e nt C o h ort A n al y si s 
Safet y a n d effic ac y e n d p oi nts f or t h ose s u bjects partici pati n g i n t he retreat me nt c o h ort will i ncl u de 
fre q ue n c y a n d se verit y of a d verse e v e nts, o verall res p o nse, ti me t o res p o nse, d urati o n of res p o nse 
a n d ti me t o alter nati ve t hera p y, e x pa nsi o n a n d persiste nce of C A R T- 1 9 cells. Defi niti o n a n d 
statistical met h o ds use d f or t h ose e n d p oi nts will be t he sa me as descri b e d i n Secti o ns 7. 4 a n d 7. 5 
b ut wit h t he start of t h e o bser vati o n ti me as ti me of t he re-i nf usi o n. Data a n al ys es f or t he 
retreat me nt c o h ort will be e x pl orat or y a n d perf or me d se paratel y fr o m t he a nal ys es f or t he i nitial 
i nf use d s u bjects. I n parti c ular, we will use statistical met h o ds a p pr o priate f or paire d d ata (e. g., 
paire d t-test, Mc N e mar t est) t o c o m pare e n d p oi nts fr o m t he sa me s u bject b et wee n t he first a n d re-
i nf usi o n. Res ults fr o m t hese a nal ys es will be use d t o ge n erate h y p ot h eses f or f ut ure st u di es. 
7. 9. M o nit ori n g of S af et y 
O n  J ul y 1 4, 2 0 1 4 a n d N o ve m ber 2 0, 2 0 1 4, t he C A R T- 1 9 researc h tea m met wit h t he F D A t o 
disc uss t he st u d y st o p pi n g/ pa usi n g r ul es.  At t hat ti me, t he y a d vise d us t o treat 3 a d diti o nal s u bjects 
at t he re d u ce d d os e le v el of 1 - 5 x 1 07 C A R T- 1 9 T-cells a n d t o sta g ger t hese i nf usi o ns b y at least 7 
da ys t o e val uate safet y.  O n Ma y 5, 2 0 1 5, after t h e 3 r d s u bject reac he d Da y +1 4 , t he researc h tea m 
met wit h t he F D A t o re vi e w t he o utc o mes/safet y of t hese s u bse q ue nt 3 s u bjects.   T he F D A a gree d 
wit h t he pr o p osal t o d ose escalate t o 1- 5 x 1 0 8 C A R T- 1 9 T-cells a d mi nistere d via s plit d osi n g, a n d 
t o treat 6 a d diti o nal s u bjects sta g gere d at least 7 da ys a p art t o e val u ate safet y.   
 
After t he 6 t h s u bject i nf us e d wit h 1- 5 x 1 08 C A R T- 1 9 T-cells a d mi nistere d via s plit d osi n g reac h e d 
Da y + 1 4, t he C A R T- 1 9 researc h tea m met wit h t he F D A t o re vie w t he safet y of t hese s u bjects a n d 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 7 4  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
cli nical o utc o mes.   As t he safet y of t he C A R T- 1 9 T-cells ha d bee n esta blis he d at t his d ose le vel, 
t he F D A a gree d wit h t he pr o p osal t o c o nti n u e t o e nr oll s u bjects per pr ot oc ol. 
  
8.  S A F E T Y A N D A D V E R S E E V E N T S 
8. 1. D efi niti o n s 
 
A d v er s e E v e nt  
A n a dverse eve nt ( A E) is a n y u nt o war d me dical occ urre nce ass ociate d wit h t he use of a dr u g i n 
h u ma ns, w het her or n ot c o nsi dere d dr u g relat e d.  I nterc urre nt ill nesses or i nj uries s h o ul d be 
re gar de d as a d v erse e ve nts. 
 
S eri o u s A d v er s e E v e nt  
A d verse e ve nts are classifie d as s eri o us or n o n-seri o us.  A seri o us a dverse eve nt is a n y A E t hat 
is:  
 fatal 
 life-t hreat e ni n g 
 re q uires or prol o n gs h os pital 
 lea ds t o a persiste nt or si g nifica nt disa bilit y or i n ca pacit y or s u bsta ntial disr u pti o n of t he 
a bilit y t o c o n d uct n or mal life f u ncti o ns  
 a c o n ge nital a n o m al y or birt h defect  
 a n i m p orta nt me dical e v e nt  
 
N ote t hat h os pitaliz ati o ns t hat meet t he f oll o wi n g criteria s h o ul d n ot be re p orte d as seri o us a d verse 
e ve nts: 
 R o uti ne treat me nt or m o nit ori n g of t he st u die d i n dicati o n, n ot ass oci ate d wit h a n y 
deteri orati o n i n c o n diti o n, s uc h as pre pl a n ne d st u d y visits a n d pre pl a n ne d h os pitalizati o ns 
f or st u d y pr oce d ures or treat me nt a d mi nistrati o n 
 Electi ve or pre - pla n n e d treat me nt f or a pre-e xisti n g c o n diti o n t hat is u nrelate d t o t he 
i n dicati o n u n der st u d y a n d has n ot w orse ne d si nce si g ni n g t he i nf or me d c o nse nt 
 S ocial reas o ns a n d res pit e care i n t he a bse nce of a n y det eri orati o n i n t he p atie nt’s ge n eral 
c o n diti o n. 
N ote t hat treat me nt o n a n e mer ge n c y o ut patie nt basis t hat d oes n ot res ult i n h os pital a d missi o n a n d 
i n v ol ves a n e v e nt n ot f ulfilli n g a n y of t he d efi niti o ns of a S A E gi ve n a b o ve is n ot a seri o us a d v erse 
e ve nt.  
 
I m p ort a nt me dical e ve nts are t h ose t hat ma y n ot be i m me diatel y life t hreate ni n g, b ut are cl earl y 
of maj or cli nical si g nifica nce.  T he y m a y je o par di ze t he patie nt, a n d ma y re q uire i nter ve nti o n t o 
pre ve nt o ne of t he ot her seri o us o utc o mes n ote d a b o ve.  F or e x a m ple, dr u g o ver d ose or a b use, a 
seiz ure t hat di d n ot res ult-i n patie nt h os pitalizati o n, or i nte nsi ve treat me nt of br o nc h os pas m i n a n 
e mer ge n c y de part me nt w o ul d t y picall y be c o nsi dere d seri o us. 
 
All a d vers e e v e nts t hat d o n ot meet a n y of t he criteria f or seri o us s h o ul d be re gar de d as 
n o n-seri o us a dverse eve nts . 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 7 5 of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
U n e x p e ct e d a d v er s e e v e nt s 
A n  a d verse e ve nt i s c o nsi dere d u ne x pecte d if t he e ve nt se verit y a n d/ or fre q ue nc y is n ot 
descri be d i n t he i n vesti gat or br oc h ure or pr ot oc ol (i n t he a bse nce of a n i n vesti gat or br o c h ure).  
Please refer t o t he i n vesti gat or br oc h ure f or a d diti o nal detail relate d t o se v erit y a n d/ or fre q u e nc y 
of a partic ul ar e v e nt.   
 
R el at e d a d v er s e e v e nt s 
A n a d verse e v e nt is c o nsi d ere d rel at e d t o partici pati o n i n t h e res earc h if t h ere is a reas o na ble 
p ossi bilit y t hat a n e ve nt was ca use d b y a n i n vesti gati o nal pr o d uct, i nter ve nti o n, or researc h-
re q uire d pr oce d ures.  F or t he p ur p os es of t his st u d y, "reas o na ble p ossi bilit y" me a ns t h ere is 
e vi de nce t o s u gge st a ca usal relati o ns hi p.  
 
A d v er s e E v e nt R e p orti n g P eri o d  
T he st u d y peri o d d uri n g w hic h a d verse e ve nts m ust be re p orte d is n or m all y d efi ne d as t he p eri o d 
fr o m t he i nitiati o n of a n y st u d y pr oce d ures t o t he e n d of t he st u d y tr eat me nt f oll o w- u p.  F or t his 
st u d y, a d vers e e v e nts are re p orte d starti n g o n Da y 1 (fr o m t he start of t h e first C A R T- 1 9 i nf usi o n) 
u ntil t he s u bject disc o nti n ues pri mar y f oll o w- u p or u ntil t he 1 2 m o nt h st u d y f oll o w- u p  visit. 
Patie nts e x perie nci n g t o xicit y fr o m t heir prece di n g c yt or e d ucti ve c he m ot hera p y will ha ve t h eir 
sc he d ule dela ye d u ntil t hese t o xicities ha ve res ol v e d.  
 
If a s u bject is ta ke n off st u d y wit hi n 3 0 da ys of t he T-cell i nf usi o n, all S A Es e x perie nce d wit hi n 
3 0 da ys after t he T-cell i nf usi o n s h o ul d be re p ort e d t o t he s p o ns or. A n y S A Es e x perie nce d after 
t his 3 0- da y peri o d s h o ul d be re p orte d t o t he s p o ns or if t he i n vesti gat or s us pects a ca usal 
relati o ns hi p t o t he st u d y treat me nt.  
 
Pr e e xi sti n g C o n diti o n/ G e n er al P h y si c al E x a mi n ati o n Fi n di n g s  
A pree xisti n g c o n diti o n is o ne t hat is prese nt at t h e start of t he st u d y.  At scree ni n g, a n y cli nicall y 
si g nifica nt a b n or malit y s h o ul d be rec or de d as a pree xisti n g c o n diti o n o n t he me dical hist or y e C R F.  
D uri n g t he c o urse of t he st u d y, a pree xisti n g c o n diti o n s h o ul d be rec or de d as a n a d verse e v e nt if 
t he fre q u e nc y, i nte nsit y, or t h e c h aracter of t he c o n diti o n w orse ns.  Pree xisti n g c o n diti o ns t hat 
i m pr o ve s h o ul d als o be rec or de d a p pr o pri atel y. 
 
A b n or m al L a b or at or y V al u e s  
A cli nical la b orat or y a b n or malit y s h o ul d be d oc u me nte d as a n a d v erse e ve nt if a n y o ne of t h e 
f oll o wi n g c o n diti o ns is met: 
 
T he la b orat or y a b n or malit y is n ot ot her wise ref ute d by a re peat test t o c o nfir m t he 
a b n or malit y 
 
T he a b n or malit y s u g gests a disease a n d/ or or ga n t o xicit y 
 
T he a b n or malit y is of a d e gree t h at re q uir es acti ve ma na ge me nt; e. g. c ha n ge of d ose, 
disc o nti n uati o n of t he dr u g, m ore fre q ue nt f oll o w- u p assess me nts, f urt her dia g n ostic 
i n vesti gati o n, etc. 
 
La b orat or y a b n or malities t hat meet t he criteria f or A d verse E ve nts s h o ul d be f oll o we d u ntil t he y 
ha ve ret ur n e d t o n or mal or a n a de q uate e x pla nati o n of t he a b n or malit y is f o u n d. W he n a n a b n or mal 
la b orat or y or test res ult c orres p o n ds t o a si g n/s y m pt o m of a n alrea d y re p ort e d a d verse e v e nt, it is 
n ot necessar y t o se paratel y rec or d t he l a b/test res ult as a n a d diti o nal e ve nt. A Gra d e 3 or 4 e v e nt 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 7 6  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
(se vere) as p er C T C A E d oes n ot a ut o maticall y i n dicate a S A E u nless it meets t he d efi niti o n of 
seri o us as defi ne d bel o w a n d/ or as per i n vesti gat or’s discreti o n.  W he ne ver p ossi ble, a dia g n osis, 
rat her t ha n a s y m pt o m s h o ul d be pr o vi de d (i.e. a ne mia i nstea d of l o w he m o gl o bi n).   
8. 2. R e c or di n g of A d v er s e E v e nt s 
Safet y will be assesse d b y m o nit ori n g a n d rec or di n g p ote ntial a d verse effects of t he treat me nt 
usi n g t he C o m m o n T o xicit y Criteria v ersi o n 4. 0 3 at eac h st u d y visit. S u bjects will be m o nit ore d 
b y me di cal hist ories, p h ysical e x a mi nati o ns, a n d bl o o d st u dies t o detect p ote ntial t o xicities fr o m 
t he treat me nt.  If C T C A E gra di n g d oes n ot e xist f or a n a d verse e ve nt, t he se verit y of mil d, 
m o derate, se vere, life-t hr eate ni n g, a n d deat h, c orres p o n di n g t o Gra des 1- 5, will be use d w he ne ver 
p ossi ble. 
 
At eac h c o ntact wit h t he s u bject, t he i n vesti gat or m ust see k i nf or mati o n o n a d verse e ve nts b y n o n-
directi ve q uesti o ni n g a n d, as a p pr o priate, b y e x a mi nati o n. A d verse e ve nts als o ma y be detecte d 
w he n t he y are v ol u nteere d b y t he s u bject d uri n g t h e scree ni n g pr ocess or b et wee n visits, or t hr o u g h 
p h ysical e x a mi nati o n, la b orat or y test, or ot her assess me nts. I nf or mati o n o n all a d verse e ve nts 
s h o ul d be rec or de d i n t he s o urce d o c u me ntati o n. All clearl y relate d si g ns, s y m pt o ms, a n d a b n or mal 
dia g n ostic pr oce d ures res ults s h o ul d be rec or de d i n t he s o urce d oc u me nt, t h o u g h s h o ul d be 
gr o u pe d u n der o ne dia g n osis. T o t he e xte nt p ossi ble, a d verse e ve nts s h o ul d be rec or de d as a 
dia g n osis,  a n d s y m pt o ms use d t o ma ke t he dia g n osis rec or de d wit hi n t he di a g n osis e ve nt.  D o n ot 
list s y m pt o ms if a dia g n osis ca n be assi g ne d.  
 
All a d verse e ve nts occ urri n g d uri n g t he a d verse e ve nt re p orti n g peri o d ( defi ne d i n Secti o n 8. 1 
a b o ve) m ust be rec or de d. 
 
As  far as p ossi ble, eac h a d verse e v e nt s h o ul d be e val uate d t o deter mi ne: 
1.  T he se verit y gra de ( C T C A E v 4. 0 3  Gra d e 1- 5 ) 
2.  Its d ur ati o n ( Start a n d e n d dates) 
3.  Its r elati o ns hi p t o t he st u d y treat me nt [ Reas o na ble p ossi bilit y t hat A E is rel ate d: N o 
( u nrelate d/ n ot s us pecte d) or Yes (a s us pecte d a d verse reacti o n)].  If yes (s us pecte d)- is 
t he e ve nt p ossi bl y, pr o ba bl y or defi nitel y relate d t o t he i n vesti gati o nal treat me nt?  
4.  E x pecte d ness t o st u d y treat me nt- [ U ne x pecte d- if t he e ve nt se v erit y a n d/ or fre q ue nc y 
is n ot descri be d i n t he i n vesti gat or br oc h ure or pr ot oc ol (i n t he a bse nce of a n 
i n vesti gat or br o c h ure)]. 
5.  Acti o n ta ke n wit h res p ect t o st u d y or i n vesti gati o nal treat me nt ( n o ne, d ose a dj uste d, 
te m p oraril y i nterr u pte d, per ma ne ntl y disc o nti n ue d, u n k n o w n, n ot a p plica ble) 
6.  W het her me dicati o n or t hera p y ta ke n ( n o c o n c o mita nt me dicati o n/ n o n- dr u g t hera p y, 
c o nc o mita nt me dicati o n/ n o n- dr u g t hera p y) 
7.  W het her it is seri o us, w here a s eri o us a d v erse e ve nt ( S A E) is defi ne d as i n Secti o n 8 . 1. 
 
All a d vers e e v e nts s h o ul d be treate d a p pr o pri atel y. If a c o nc o mita nt m e dicati o n or n o n- dr u g 
t hera p y is gi ve n, t his acti o n s h o ul d be rec or de d. O nce a n a d v erse e ve nt is detecte d, it s h o ul d be 
f oll o we d u ntil its res ol uti o n or u ntil it is j u d ge d t o be per m a ne nt, a n d assess me nt s h o ul d be ma de 
at eac h visit ( or m ore fre q ue ntl y, if necessar y) of a n y c h a n ges i n se verit y, t he s us pect e d 
relati o ns hi p t o t he st u d y treat me nt, t he i nter ve nti o ns re q uire d t o treat it, a n d t he o utc o me.  
 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 7 7  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
A d verse e v e nts t hat occ ur c o nc urre ntl y wit h t he pr o gressi o n of mali g na n c y b ut t hat are n ot relate d 
t o disease pr o gressi o n (i. e. dee p vei n t hr o m b osis or he m o pt ysis) will be re p orte d as a n a d v erse 
e ve nt as des cri be d a b o v e.  Pr o gressi o n of mali g n a nc y res ulti n g i n deat h s h o ul d be re p orte d as a 
seri o us a d vers e e v e nt.  
 
Seri o us a d verse e ve nts t h at are still o n g oi n g at t h e e n d of t he a d verse e v e nt re p orti n g peri o d m ust 
be f oll o we d t o deter mi ne t he fi nal o utc o me. A n y seri o us a d verse e ve nt t hat o cc urs after t he a d v erse 
e ve nt re p orti n g peri o d a n d is c o nsi dere d t o b e p ossi bl y rel ate d t o t h e st u d y tr eat me nt or st u d y 
partici pati o n s h o ul d be rec or de d a n d re p ort e d. 
 
Gra di n g S yste m of C yt o ki ne Release S y n dr o me ( C R S)   
A pr ot oc ol s pecific gra di n g s yste m ( Ta ble 8- 1) h as bee n de vel o p e d t o ca pt ure c yt o ki ne release 
s y n dr o me ( C R S) i n C A R T-cell pr ot oc ols.  Pleas e refer t o secti o n 1. 5 f or a d diti o nal detail o n C R S 
i n C A R T-cell t hera p y.  
 
F or t he p ur p oses of re p orti n g a n d gra di n g o n cli nical trials usi n g C A R T cells, we will use t he 
f oll o wi n g gra di n g f or C R S T o xicit y.  T he start d ate of C R S is a retr os pecti ve assess me nt of t he 
date of o nset of persiste nt fe vers a n d/ or m yal gia c o nsiste nt wit h C R S a n d n ot e x plai ne d b y ot her 
e ve nts (i.e. s e psis). T he st o p date of C R S is defi ne d as t he date w h e n t he patie nt has bee n afe brile 
f or 2 4 h o urs a n d off vas o press ors f or 2 4 h o urs.   F or t he p ur p oses of defi ni n g t he C R S start date, a 
fe ver is defi ne d as a te m perat ur e of 1 0 0. 4⁰ F/ 3 8 ⁰ C.  
 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 7 8  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
T a ble 8- 1: C R S Gr a di n g Criteri a 
 
C R S T o xi cit y Gr a d e  ( M o difi e d) 
1  
2  
3  
4  
5  
Mil d reacti o n: 
Treate d wit h 
s u p p orti ve care 
s uc h as a nti-
p yretics, a nti -
e metics 
M o derate 
reacti o n 
re q uiri n g I V 
fl ui ds or 
pare nteral 
n utriti o n ; s o me 
si g ns of or ga n 
d ysf u n cti o n ( i.e. 
gra de 2 
creati ni ne or 
gra de 3 li ver 
f u ncti o n tests 
[ L F Ts] relate d t o 
C R S a n d n ot 
attri b uta ble t o 
a n y ot h er 
c o n diti o n).  
H os pitalizati o n 
f or ma na ge me nt 
of C R S  relate d 
s y m pt o ms 
i ncl u di n g fe v ers 
wit h ass ociate d 
ne utr o pe nia .  
M ore se vere reacti o n:  
H os pitaliz ati o n re q uire d 
f or ma na ge me nt of 
s y m pt o ms relate d t o 
or ga n d ysf u ncti o n  
i ncl u di n g gra d e 4 L F Ts 
or gra de 3 creati ni ne 
relate d t o C R S a n d n ot 
attri b uta ble t o a n y ot her 
c o n diti o ns .  T his 
e x cl u des ma na ge me nt of 
fe ver or m yal gias.  
I n cl u des h y p ote nsi o n 
treate d wit h I V Fs*  or 
l o w-d ose press ors, 
c oa g ul o pat h y re q uiri n g 
fres h fr oze n plas ma 
( F F P) or cr y o preci pitate, 
a n d h y p o xia re q uiri n g 
s u p ple me ntal o x y ge n 
(nasal ca n n ula o x y ge n, 
hi g h fl o w o x y ge n, 
C o nti n u o us P ositi ve 
Air wa y Press ur e [ C P A P] 
or Bilateral P ositi ve 
Air wa y Press ur e 
[Bi P A P ].  Patie nts 
a d mitte d f or ma na ge me nt 
of s us pecte d i nfecti o n 
d ue t o fe vers a n d/ or 
ne utr o pe nia ma y h a ve 
gra de 2 C R S.  
Lif e -t hreate ni n g 
c o m plicati o ns 
s uc h as 
h y p ote nsi o n 
re q uiri n g hi g h 
d ose  press ors  
( See Ta ble 8-2) , 
or  h y p o xia 
re q uiri n g 
mec ha nic al 
ve ntilati o n  
Deat h  
* C R S Gra d e 3 la n g ua ge clarificati o n: “ h y p ote nsi o n treate d wit h i ntra ve n o us fl ui ds” is f urt her defi ne d as 
h y p ote nsi o n re q uiri n g m ulti ple fl ui d b ol uses f or bl o o d press ure s u p p ort. 
 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 7 9  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
T a ble 8- 2  
Hi g h D ose V as o press or Use 
Defi niti o n of “ Hi g h -D ose ” V as o press ors  
Vas o press or  
D ose f or ≥ 3 h o urs  
N ore pi ne p hri n e m o n ot hera p y  
≥ 0. 2  mc g/ k g/ mi n  
or ≥ 2 0 mc g/ mi n (if i nstit uti o nal practice is t o use flat 
d osi n g)  
D o pa mi ne m o n ot hera p y  
≥ 1 0 mc g/ k g/ mi n  
or ≥ 1 0 0 0 mc g/ mi n (if i nstit uti o nal practice is t o use flat 
d osi n g)  
P he n yle p hri ne m o n ot hera p y  
≥ 2  mc g/ k g/ mi n  
or ≥ 2 0 0 mc g/ mi n (if i nstit uti o nal practice is t o use flat 
d osi n g)  
E pi ne p hri ne m o n ot hera p y  
≥ 0. 1  mc g/ k g/ mi n  
or ≥ 1 0 mc g/ mi n (if i nstit uti o nal practice is t o use flat 
d osi n g)  
If o n vas o pr essi n 
Hi g h -d o s e if vas o +  N ore pi ne p hri ne E q ui val e nt ( N E) of 
> 0. 1  mc g/ k g/ mi n ( or 1 0 mc g/ mi n) ( usi n g Vas o pressi n a n d 
Se ptic S h oc k Trial ( V A S S T) f or m ula)  
If o n c o m bi nati o n vas o pr ess ors 
( n ot vas o pressi n) 
N ore pi ne p hri n e e q ui vale nt of ≥ 0. 2 mc g/ k g/ mi n  
( or ≥ 2 0 mc g/ mi n) ( u si n g V A S S T f or m ula) 
 
Vas o pressi n a n d Se ptic S h oc k Trial ( V A S S T) E q ui vale nt E q uati o n: 
N ore pi ne p hri ne e q ui vale nt d ose = [ n ore pi ne p hri ne ( mc g/ mi n)] + [ d o pa mi ne ( mc g/ k g/ mi n) ÷ 2] + [e pi ne p hri ne 
( mc g/ mi n)] + [ p he n yle p hri ne ( mc g/ mi n) ÷ 1 0]  
Criteria fr o m R ussell et al, 2 0 0 8 1 0 6. 
Pr e g n a n ci e s  
T o e ns ure patie nt safet y, eac h pre g na n c y o cc urri n g w hile t he patie nt is o n st u d y treat me nt m ust be 
re p orte d t o pr ot oc ol s p o ns or wit hi n 2 4 h o urs of lear ni n g of its occ urre nce. T he pre g na n c y s h o ul d 
be f oll o we d u p t o deter mi ne o utc o me, i ncl u di n g s p o nta ne o us or v ol u ntar y ter mi nati o n, details of 
t he birt h, a n d t he prese n ce or a bs e nce of a n y birt h defects, c o n ge nital a b n or malities, or mater nal 
a n d/ or ne w b or n c o m plicati o ns. 
 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 8 0  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
Pre g n a nc y s h o ul d be rec or de d o n a Cli nical Trial Pre g na nc y F or m a n d re p orte d b y t he i n vesti gat or 
t o t he pr ot oc ol s p o ns or Pre g n a nc y f oll o w- u p s h o ul d be rec or de d o n t h e sa me f or m a n d s h o ul d 
i ncl u de a n assess me nt of t he p ossi ble relati o ns hi p t o t he st u d y dr u g f or a n y pre g n a nc y o utc o me. 
A n y S A E e x perie nce d d uri n g pre g na n c y m ust be re p orte d o n t he S A E Re p ort F or m. 
 
Pre g n a nc y o utc o mes m ust be c ollecte d f or t he fe male part ners of a n y males w h o t o o k st u d y 
treat me nt i n t his st u d y. C o nse nt t o re p ort i nf or mati o n re gar di n g t hes e pre g n a nc y o utc o mes s h o ul d 
be o btai ne d fr o m t he m ot her. 
8. 3. R e p orti n g of S eri o u s A d v er s e E v e nt s 
E ver y S A E, re g ar dless of s us pecte d c a us alit y , occ urri n g d uri n g t he a d verse e ve nt re p orti n g 
peri o d defi ne d i n Secti o n 8. 1 a b o v e m ust be re p ort e d t o t he s p o ns or wit hi n 2 4 h o urs of lear ni n g of 
its occ urre n ce.   T he ori gi nal S A E n otificati o n ma y t a ke place b y e mail t o meet t he 2 4- h o ur 
re p orti n g wi n d o w.  H o we ver, wit hi n 3 b usi ness da ys of k n o wle d ge of t he e ve nt, t he i n vesti gat or 
m ust s u b mit a c o m plete S A E f or m t o t he S p o ns or al o n g wit h a n y ot her dia g n ostic i nf or mati o n t hat 
will assist t he u n dersta n di n g of t he e ve nt.  T he I n v esti gat or will kee p a c o p y of t his S A E F or m o n 
file at t he st u d y site.   
F oll o w- u p i nf or m ati o n o n S A Es s h o ul d be re p ort e d w he n u p dates are a vaila ble, as a f oll o w- u p t o 
t he i nitial S A E f or m, a n d s h o ul d i ncl u de b ot h t he f oll o w- u p n u m ber a n d re p ort date.  Ne w 
i nf or mati o n o n o n g oi n g seri o us a d verse e ve nts s h o ul d be pr o vi de d pr o m ptl y t o t h e s p o ns or. T he 
f oll o w- u p i nf or mati o n s h o ul d descri be w het h er t h e e v e nt has res ol ve d or c o nti n ues, if t here are 
a n y c h a n ges i n assess m e nt, if a n d h o w it was treate d, a n d w het h er t he patie nt c o nti n ue d or 
wit h dre w fr o m st u d y partici pati o n.  
 
Re p ort seri o us a d verse e ve nts b y e mail t o: 
Atte nti o n: S p o ns or Cli nical Safet y Ma n a ger or desi g nee 
Ce nter f or Cell ular I m m u n ot hera pies ( C CI)   
  
 
At t he ti me of t he i nitial re p ort, t he f oll o wi n g i nf or mati o n s h o ul d be pr o vi de d: 
 St u d y i d e ntifier 
 S u bject n u m ber 
 A descri pti o n of t he e v e nt 
 Date of o nset  
 C urre nt stat us  
 W het her st u d y treat me nt was disc o nti n ue d  
 T he reas o n t he e ve nt is cl assifie d as seri o us  
 I n v esti gat or assess me nt of t he ass ociati o n bet w ee n t he e ve nt a n d t he st u d y 
treat me nt 
 E x pecte d ness relati ve t o i n vesti gati o nal pr o d u ct(s)  
8. 3. 1. I n v e sti g at or r e p orti n g: n otif yi n g t h e P e n n I R B s 
T his secti o n descri bes t he re q uire me nts f or safet y re p orti n g b y i n vesti gat ors w h o are Pe n n fac ult y, 
affiliate d wit h a Pe n n researc h site, or ot her wise res p o nsi ble f or safet y re p orti n g t o t he I R B. T h e 
I R B re q uires e x pe dite d re p orti n g of t h ose e v e nts relate d t o st u d y p artici pati o n t hat are u nf oresee n 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 8 1  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
a n d i n dicate t hat partici pa nts or ot hers are at i ncreas e d ris k of har m.  T he I R B will n ot 
ac k n o wle d ge safet y re p orts or b ul k a d verse e v e nt s u b missi o ns t hat d o n ot meet t he criteria 
o utli ne d bel o w.  T he I R B re q uires researc hers t o s u b mit re p orts of t he f oll o wi n g pr o ble ms wit hi n 
1 0 w or ki n g d a ys fr o m t h e ti me t he i n vesti gat or b ec o mes a ware of t h e e ve nt: 
 
A n y a d verse e ve nt (re gar dless of w h et her t he e ve nt is seri o us or n o n-seri o us, o n-site or off- site) 
t hat occ urs a n y ti me d uri n g or after t he researc h st u d y, w hic h i n t he o pi ni o n of t he pri nci pal 
i n vesti gat or is: 
 
U ne x pecte d ( A n e ve nt is “ u ne x pecte d” w he n its s pecificit y a n d se verit y are n ot acc urat el y 
reflecte d i n t he pr ot oc ol-relate d d oc u me nts, s u c h as t he I R B-a p pr o ve d researc h pr ot o c ol, a n y 
a p plica ble i n vesti gat or br oc h ure, a n d t he c urre nt I R B-a p pr o ve d i nf or me d c o nse nt d oc u me nt a n d 
ot her rele v a nt s o urces of i nf or mati o n, s uc h as pr o d uct la beli n g a n d pac ka ge i nserts.) 
A N D  
Relate d t o t he researc h pr oce d ures ( A n e v e nt is “relate d t o t he researc h pr oce d ures” if 
i n t he o pi ni o n of t he princ i pal i n vesti gat or or s po ns or, t he ca use of t he e ve nt is dee me d pr o ba bl y 
or defi nitel y relate d t o t he i n vesti gati o nal pr o d uct or a pr oce d ure t hat was perf or me d f or t he 
p ur p oses of t he researc h .) 
 
Re p orti n g Pr ocess  
U na ntici pate d pr o ble ms p osi n g ris ks t o p atie nts or ot hers as n ote d a b o ve will be re p orte d t o t he 
I R B.   T his will i ncl u de a writte n re p ort of t h e e v e nt (i ncl u di n g a des cri pti o n of t he e ve nt wit h 
i nf or mati o n re gar di n g its f ulfill me nt of t he a b o ve criteria, f oll o w- u p/res ol uti o n a n d nee d f or 
re visi o n t o c o nse nt f or m a n d/ or ot her st u d y d oc u me ntati o n). 
 
C o pies of eac h re p ort a n d d oc u me ntati o n of I R B n otificati o n a n d recei pt will be ke pt i n t he 
Cli nical I n vesti gat or’s st u d y file. 
 
Re p orti n g de at hs:  m ore r a pi d re p orti n g re q uire me nts  
C o ncer ni n g deat hs t hat o cc ur d uri n g t he c o urse of a researc h st u d y, t he f oll o wi n g des cri bes t h e 
m ore ra pi d r e p orti n g re q uire me nt of t he Pe n n I R B f or s p ecific sit uati o ns: 
  Re p ort t he e v e nt wit hi n 7 2 h o urs, w he n t he d eat h is u nf ores ee n ( u ne x pecte d) a n d 
i n dicates partici pa nts or ot hers are at i ncrease d ris k of har m (i ncl u di n g deat h of 
s u bjects off-st u d y). 
 
F or re p orta bl e deat hs, t he i nitial s u b missi o n t o t he I R B ma y be ma de b y c o ntacti n g t he I R B 
Direct or or Ass ociate Direct or.  
 
Ot her Re p ort a ble e ve nts:  
F or cli nical dr u g trials, t he f oll o wi n g e ve nts are als o re p orta ble t o t he I R B: 
 
  A n y a d vers e e x perie nce t hat, e ve n wit h o ut detaile d a nal ysis, re prese nts a s eri o us 
u ne x pecte d a d vers e e v e nt t hat is rare i n t he a bs e nce of dr u g e x p os ure (s uc h as a 
gra n ul oc yt osis, he patic n ecr osis, Ste ve ns-J o h ns o n s y n dr o me). 
  A n y a d vers e e ve nt t hat w o ul d ca us e t he s p o ns or t o m o dif y t he i n vesti gat ors 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 8 2  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
br oc h ure, pr ot oc ol or i nf or me d c o nse nt f or m, or w o ul d pr o m pt ot her acti o n b y t he 
I R B t o ass ure pr otecti o n of h u ma n patie nts. 
  I nf or mati o n t hat i n dicates a c ha n ge t o t he ris ks or p ote ntial be nefits of t he researc h, 
i n ter ms of se verit y or fre q ue nc y. F or e x a m ple: 
– 
A n i nteri m a nal ysis i n dicates t hat partici pa nts ha v e a l o wer rate of res p o ns e 
t o treat me nt t ha n i nitiall y e x pecte d. 
– 
Safet y m o nit ori n g i n dicat es t hat a partic ular si de effect is m ore s e vere, or 
m ore fre q u e nt t ha n i nitiall y e x pecte d. 
– 
A pa per is p u blis he d fr o m a n ot her st u d y t h at s h o ws t hat a n ar m of y o ur 
researc h st u d y is of n o t h era pe utic v al ue. 
  C ha n ge i n F D A s afet y la beli n g or wit h dra wal fr o m mar keti n g of a dr u g, d e vice, or 
bi ol o gic use d i n a researc h pr ot oc ol. 
  Breac h of c o nfi de ntialit y 
  C ha n ge t o t he pr ot oc ol ta ke n wit h o ut pri or I R B re vie w t o eli mi nate a p pare nt 
i m me diate hazar d t o a researc h p artici pa nt. 
  I n carcerati o n of a p artici pa nt w he n t he researc h was n ot pre vi o usl y a p pr o ve d u n der 
S u b part C a n d t he i n vesti gat or b elie ves it is i n t he best i nterest of t he patie nt t o 
re mai n o n t he st u d y. 
  C o m plai nt of a partici pa nt w he n t he c o m plai nt i n dicates u ne x pecte d ris ks or t he 
c o m plai nt ca n n ot be res ol ve d b y t he researc h t ea m. 
  Pr ot oc ol vi olati o n ( mea ni n g a n acci de ntal or u ni nt e nti o nal de viati o n fr o m t he I R B 
a p pr o ve d pr ot o c ol) t hat i n t he o pi ni o n of t he i n vesti gat or place d o ne or m ore 
partici pa nts at i ncrease d ris k, or affects t he ri g hts or welfare of patie nts. 
 
F oll o w- u p re p ort  
If a n S A E has n ot res ol ve d at t he ti me of t h e i nitial re p ort a n d ne w i nf or mati o n arises t hat c ha n ges 
t he i n vesti gat or’s assess me nt of t he e ve nt, a f oll o w- u p re p ort i ncl u di n g all rele va nt ne w or 
reassess e d i nf or mati o n (e. g., c o n c o mita nt me dicati o n, me dical hist or y) s h o ul d be s u b mitte d t o t he 
I R B. T he i n vesti gat or is res p o nsi ble f or e ns uri n g t hat all S A Es are f oll o w e d u ntil eit her res ol ve d 
or sta ble. 
8. 3. 2. I n v e sti g at or R e p orti n g :  N otif yi n g t h e D S M C of t h e A br a m s o n C a n c er 
C e nt er ( A C C ) 
All e ve nts t hat meet t h e A C C D S M C defi niti o n of re p orta ble A E’s m ust b e pr o m ptl y re p orte d t o 
t he A C C D S M C t hr o u g h Vel os.   
 
T he D S M C re q uires A E/ S A E s u b missi o n as f oll o ws:  
 U nless c o vere d b y e x cl usi o ns bel o w, gra d e 3 or hi g her e v e nts m ust be re p orte d wit hi n 
1 0 da ys of k n o wle d ge of t he a d verse e ve nt.   
E x ce pti o ns: 
o  Gra de 3 a n d 4 e ve nts t hat are t y pical i n t he disease p o p ulati o n-  wit h t he 
e x ce pti o n of t h ose t hat c o ul d be s y m pt o ms/earl y i n dicat ors of a n y of t he t o xicities 
defi ne d i n t he T o xicit y Ma na ge me nt secti o n of t he pr ot oc ol, si g ns/s y m pt o ms of 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 8 3  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
a n aller gic res p o nse, se v ere h y p ote nsi ve crisis or a n y ot her reacti o n t o t he 
i nf usi o n.  
o  All gra d e 3 or 4 e ve nts t h at are j u d ge d b y a st u d y i n vesti gat or t o be clearl y u nrelate d 
t o pr ot oc ol t hera p y. 
o  Gra de 3 or 4 e ve nts t hat are pr o ba bl y or d efi nitel y relate d t o pr o gressi o n of disease 
as j u d ge d b y t he st u d y i n vesti gat or.  
o  Gra de 3 or 4 e ve nts t hat are pr o ba bl y or defi nitel y relate d t o a n F D A a p pr o ve d 
a ge nt. 
 All u ne x pecte d deat hs wit hi n o ne b usi ness da y of k n o wle d ge 
 All ot hers deat hs wit hi n 3 0 da ys of k n o wle d ge. Deat hs of s u bjects off -st u d y f or 
greater t ha n 3 0 da ys fr o m t he last st u d y treat me nt/i nter ve nti o n are n ot re p ort a ble 
u nless a l o n ger ti me fra me is s pecifie d i n t he pr ot o c ol. 
 
I n t he e ve nt of a gra d e 4 or 5 u ne x pecte d e v e nt re gar dless of attri b uti o n, t h e st u d y tea m m ust meet 
or ha ve a tel ec o nfere n ce wit hi n 2 4 b usi ness h o urs of k n o wle d ge of t h e e v e nt t o ha ve a t h or o u g h 
disc ussi o n of t he e ve nt. T hese t y p es of e ve nts will n ot be vette d via e- mail. T he s p o ns or s h o ul d 
n ot be i n v ol ve d i n disc ussi o ns a b o ut attri b uti o n. T he PI a n d Researc h C o or di nat or will sc he d ul e a 
me eti n g wit h t he st u d y tea m t o disc uss t he gra de 4 or 5 u ne x pecte d e ve nt. Meeti n g mi n utes 
ca pt uri n g t he re vie w of a n y o n g oi n g i n vesti gati o ns of t he gra d e 4 or 5 u ne x pecte d e v e nt, i ncl u di n g 
ne xt ste ps i n t he ma n a ge me nt of t he s u bject a n d a n y pr o p ose d c ha n ges t o t he pr ot o c ol will be 
d oc u me nte d a p pr o priatel y. 
8. 3. 3. I B C N otifi c ati o n b y I n v e sti g at or  
N otif y t he I nstit uti o nal Bi osafet y C o m mittee of seri o us a d verse e ve nts a cc or di n g t o i nstit uti o nal 
re q uire me nts. 
8. 3. 4. F D A N otifi c ati o n b y S p o n s or 
T he st u d y s p o ns or is re q uire d t o re p ort cert ai n st u d y e v e nts i n a n e x pe dite d fas hi o n t o t he F D A. 
T hese writte n n otificati o ns of a d verse e ve nts are referre d t o as I N D safet y re p orts. T he s p o ns or 
m ust re p ort a n I N D safet y re p orts as descri be d i n: 
 
htt p:// w w w.f da. g o v/ d o w nl oa ds/ Dr u gs/ G ui da nce C o m plia nce Re g ulat or yI nf or mati o n/ G ui da nces/ U C M 2 2 7 3 5 1
. p df 
 
T he f oll o wi n g d escri b es t he safet y re p orti n g re q uire me nts b y ti meli ne f or re p orti n g a n ass ociate d 
t y pe of e ve nt: 
 
 Wit hi n 7 C ale n d ar D ays  
 
A n y st u d y e v e nt t hat is:  
o  U nex pecte d fatal or life-t hreate ni n g s us pecte d a dverse re a cti o n. 
o  E x pecte d a n d u ne x pecte d Gra de 3  or hi g h er e ve nts of c yt o ki n e rel ease s y n dr o me 
per t he m o difie d C R S gra di n g scale i n Ta bl e 8- 1 
o  All fatal e ve nts occ urri n g wit hi n 3 0 da ys of T-cell i nf usi o n, re gar dless of 
attri b uti o n a n d e x pecte d ness 
 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 8 4  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
A n y st u d y e ve nt o cc urri n g after retreat me nt wit h eit her h u ma nize d or m uri n e C A R T 1 9 T-
cells t hat is:  
o  U nex p ecte d fatal or life-t hreate ni n g s us pecte d a dverse re a cti o n. 
o  E x pecte d a n d u ne x pecte d Gra de 3 or hi g h er e ve nts of c yt o ki n e rel ease s y n dr o me 
per t he m o difie d C R S gra di n g scale i n Ta bl e 8- 1 
o  All gra d e 4 ne ur ol o gi c e v e nts 
o  All fatal e ve nts oc c urri n g wit hi n 3 0 da ys of T-cell i nf usi o n, re gar dless of 
attri b uti o n a n d e x pecte d ness 
o  A n y a d vers e e ve nt re q uiri n g t he st u d y t o be pa us e d a n d/ or st o p pe d  
 
 
 Wit hi n 1 5 C ale n d ar D ays  
 
A n y st u d y e v e nt t hat is: 
 
o  u ne x pecte d 
o  S us pecte d a d verse reacti o n t hat is seri o us, b ut n ot fatal or life-t hr eate ni n g 
- or- 
 
o  a pre vi o us a d v erse e v e nt t hat was n ot i nitiall y dee me d re p orta ble b ut is later 
f o u n d t o fit t he criteria f or re p orti n g (re p orti n g wit hi n 1 5 cale n dar da ys fr o m 
w he n e ve nt w as dee me d re p orta ble). 
 
A n y fi n di n g fr o m tests i n la b orat or y a ni mals t hat: 
 
o  s u g gest a si g nifica nt ris k f or h u ma n patie nts i ncl u di n g re p orts of m uta ge ni cit y, 
terat o ge nicit y, or carci n o ge ni cit y or re p orts of si g nifica nt or ga n t o xicit y at or 
near t he e x pecte d h u ma n e x p os ure. 
 
I n crease i n r ate of occ urre nce of s eri o us s us pect e d a d verse reacti o ns: 
o  a n y cli nicall y i m p orta nt i ncrease i n t he rate of a seri o us s us pect e d 
a d verse reacti o n o ver t hat liste d i n t he pr ot oc ol or i n vesti gat or br o c h ure. 
 
A d diti o n al Re p orti n g Re q uire me nts  
 
S p o ns ors are als o re q uir e d t o re vie w all a d verse e ve nts t o ma ke a ca usalit y deter mi nati o n o n t he 
basis of i nf or mati o n fr o m i n vesti gat ors a n d re p ort t hese fi n di n gs t o t he F D A i n acc or da nce wit h 
2 1 C F R 3 1 2. 3 2. 
 
If t he a d v erse e v e nt d oes n ot meet e x pe dite d re p orti n g re q uir e me nts, t he S p o ns or will re p ort t he 
S A E as i n t he I N D A n n u al Re p ort 
8. 4. T o xi cit y M a n a g e m e nt, St o p pi n g R ul e s a n d St u d y T er mi n ati o n 
It is e x pecte d t hat A Es will occ ur fre q ue ntl y i n t his p o p ulati o n base d o n t he u n derl yi n g a d v a nce d 
he mat ol o gic mali g n a nc y a n d t hat t hese ca n be S A Es. T heref ore, t here is n o s pecific occ urre n ce 
of S A Es t hat defi ne a st o p pi n g r ule, b ut t he re vie w of S A Es will f or m t he basis f or p ote ntial earl y 
st o p pi n g of t he st u d y. O nl y u ne x pecte d S A Es t hat are relate d t o t he C A R T- 1 9 cells w o ul d defi ne 
a st o p pi n g r ule.  

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 8 5  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
Pre mat ure ter mi nati o n of t he cli nical trial ma y occ ur beca use of a re g ulat or y a ut h orit y decisi o n, 
c ha n ge i n o pi ni o n of t he I R B, t he D S M B, Me dical M o nit or, deter mi nati o n t hat t here are pr o ble ms 
i n t he cell pr o d uct ge nerati o n, as a res ult of safet y c o ncer ns, or at t he discreti o n of t he S p o ns or or 
st u d y i n vesti gat ors. A d diti o nall y, recr uit me nt ma y be st o p pe d f or reas o ns of partic ularl y l o w 
recr uit me nt, pr ot oc ol vi olati o ns, or i na de q uate data rec or di n g. 
8. 4. 1. Crit eri a f or st o p pi n g or p a u si n g t h e st u d y 
T he st u d y will be st o p pe d if: 
 
A n y p atie nt de vel o ps u nc o ntr olle d T cell pr oliferati o n t hat d oes n ot res p o n d t o 
ma na ge me nt. 
 Pre mat ure st u d y ter mi nati o n ma y occ ur if t he I n vesti gat or, St u d y F u n der, S p o ns or, 
D S M B, D S M C or a n y a p pr o priate i n de pe n de nt re vie w b oar d or re g ulat or y b o d y 
deci des f or a n y reas o n t h at patie nt safet y ma y b e c o m pr o mise d b y c o nti n ui n g t he 
st u d y. 
 Pre mat ure st u d y ter mi nati o n ma y occ ur if t he S p o ns or or St u d y F u n der deci des t o 
disc o nti n ue t he de vel o p me nt of t he i nter ve nti o n t o be use d i n t his st u d y. 
 
T he st u d y will be p a use d if: 
 
T he pr ot oc ol will be pa us e d pe n di n g s u b missi o n t o t he F D A a n d re vi e w b y I R B, 
D S M C, C T S R M C a n d t he D S M B if a n y p atie nt e x perie nces a n y of t he f oll o wi n g 
e ve nts wit hi n t w o wee ks of t he first C A R T- 1 9 i nf usi o n: 
o  life-t hreat e ni n g ( gra d e 4) t o xicit y attri b uta ble t o pr ot oc ol t hera p y t hat is 
u n ma na gea bl e, u ne x pect e d a n d u nrel ate d t o c he m ot hera p y a n d attri b uta ble t o 
pr ot oc ol t hera p y.  Hi g h fe vers, h y p ote nsi o n, p ossi ble I C U a d missi o n a n d 
e ve n mec h a nical ve ntilati o n are e x pecte d.  T hese si de effects ca n res ult i n 
gr a de I V li ver t o xicit y, n e p hr ot o xicit y a n d ot her or ga n i n v ol ve me nt. 
o  Deat h. 
If t he st u d y is pa us e d f or t he reas o ns a b o ve, t he PI, me m bers of t he st u d y tea m a n d Pr ot oc ol 
A d vis or will meet i n pers o n or b y telec o nfere n ce wit hi n 2 4 h o urs of t he e ve nt t o ha ve a t h or o u g h 
disc ussi o n of t he e ve nt. T hese t y pes of e ve nts will n ot be vette d via e- mail. T he Re g ul at or y 
S p o ns or or desi g nee s h o ul d be prese nt, b ut s h o ul d n ot be i n v ol ve d i n a n y disc ussi o ns relate d t o 
attri b uti o n. Meeti n g mi n utes ca pt uri n g t he re vie w of a n y o n g oi n g i n vesti gati o ns, i ncl u di n g ne xt 
ste ps i n t he ma na ge me nt of s u bjects a n d a n y pr o p ose d c ha n ges t o t he pr ot o c ol will be f or war de d 
t o t he F D A, I R B, A C C D S M C, Me dical M o nit or  a n d D S M B. If all parties are i n a gree m e nt as t o 
t he e ve nt res ol uti o n a n d a n y pr o p ose d m o dificati o ns, t he n t he pa use will be lifte d. 
 
T he pr ot oc ol ma n ufact uri n g will be pa use d t o re vie w t he ma n ufact uri n g pr ocess s h o ul d t here be 
> 3 3 % pri mar y efficac y n o n-e val ua ble p atie nts (i.e. t he ma n ufact uri n g pr ocess fails t o meet t he 
pr ot oc ol-s pecifi e d d ose ra n ge of 1- 5 x 1 0 7 C A R T- 1 9 cells). 
 
If t he st u d y is pa use d f or ma n ufact uri n g reas o ns, t he PI, me m bers of t he st u d y tea m, Pr ot oc ol 
A d vis or, Cli nical O perati o ns a n d Cell Ma n ufact uri n g will meet t o i de ntif y ma n ufact uri n g fail ure. 
T he tea m will ma ke r ec o m me n dati o ns f or pr ocess i m pr o ve me nts t o be i m ple me nte d. Pe n di n g 
s uccessf ul c o m pleti o n of a pr ocess v ali dati o n r u n, t he ma n ufact uri n g p a use will be lifte d. 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 8 6  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
8. 4. 2. G e n er al T o xi cit y M a n a g e m e nt C o n si d er ati o n s 
Re plic ati o n-c o m pete nt le nti vir us ( R C L)  ma y b e ge n erat e d d uri n g t he C A R T- 1 9 ma n ufact uri n g 
p hase or s u bse q u e ntl y aft er i ntr o d ucti o n of vect or tra ns d uce d cells i nt o t he patie nt. H o we ver, a n 
R C L res ulti n g fr o m t he pr o d ucti o n p hase is hi g hl y u nli kel y si nce ele m e nts are i nc or p orate d i n t he 
desi g n of t he v ect or s yste m t hat mi ni mize vect or rec o m bi nati o n a n d ge n erati o n of R C L. 
F urt her m ore, t he v ect or use d t o tra ns d uce t he pr o d uct u n der g oes se nsiti ve assa ys f or det ecti o n of 
R C L b ef ore it ca n be rele ase d t o a patie nt. Ne v ert h eless, ge nerati o n of a n R C L f oll o wi n g i nf usi o n 
of t he vect or pr o d uct re mai ns a t he oretical p ossi bilit y. T he c o ns e q ue nces of s uc h rec o m bi nati o n 
e ve nts i n p atie nts wit h o ut a k n o w n le nti viral i nf ecti o n are u n k n o w n, a n d t h eref ore patie nts wit h 
c oe xiste nt HI V i nfecti o n are e x cl u de d fr o m parti ci pati o n i n t his st u d y i n or der t o mi ni mize t his 
p ossi bilit y. T he d e vel o p me nt of R C L c o ul d p os e a ris k t o b ot h t he p atie nt a n d t heir cl os e 
c o ntact(s), a n d t heref ore, m o nit ori n g f or R C L will be c o n d ucte d d uri n g t h e c o urse of t he trial. 
 
Re g ulat or y a ge n cies a n d t he ge ne t h era p y c o m m u nit y ha v e pre vi o usl y disc usse d meas ures t o be 
ta ke n s h o ul d a n R C L b e c o nfir me d i n a patie nt. H o we ver, beca use t h e pr o ba bilit y of d e vel o pi n g, 
a n d c haracteristics of,  a n R C L are u n k n o w n, n o g ui deli nes ha ve bee n p ut i n place. 
 
Ne vert hel ess, all a gr ee t h at t he patie nt m ust be is olate d u ntil a n u n dersta n di n g of h o w t o 
ma na ge t he p atie nt bec o mes clear. S o me c o nsi derati o ns are 
o  I nt e nsi ve f oll o w- u p of patie nt i n c o ns ultati o n wit h ge ne t h era p y e x perts, 
st u d y i n vesti gat ors, F D A a n d NI H. 
o  I nf or m l ocal p u blic healt h officials a n d C D C. 
o  I d e ntif y se x ual part ners a n d pr o vi de a p pr o priate c o u nseli n g a n d i nter ve nti o n. 
 
R C L will be m o nit ore d b y a s uita ble Q- P C R assa y f or t he detecti o n of t he le nti vir us ( V S V- g 
D N A).  If a p ositi ve V S V-g D N A assa y res ult is o btai ne d, t he I n v esti gat or will be i nf or me d a n d 
t he patie nt resc he d ule d f or a retest f or t he D N A test.  If t he sec o n d D N A test is p ositi ve, t he n 
i nf usi o ns will be te m p oraril y halte d.  T he p atie nt will u n der g o a bl o o d dra w f or is olati o n of HI V 
fr o m his/ her cells.   T he vir us will be se q u e nce d a n d c o m pare d t o se q u e nces of t he tr a nsfer vect or 
a n d pac ka gi n g c o nstr ucts, as w ell as t o a vaila ble HI V s e q ue n ces t o d eter mi ne t he ori gi n of t he 
vir us.  Deter mi nati o n of t he ori gi n of t he vir us ca n be easil y perf or me d b y e val uati o n f or HI V 
access or y ge nes s u c h as vif, v pr a n d v p u w hic h are n ot prese nt i n t he p ac ka gi n g c o nstr ucts. If t h e 
se q ue nce is deri v e d fr o m wt- HI V t he n i nf usi o ns f or all patie nts ca n res u m e, a n d t h e patie nt will 
be referre d t o treat me nt f or HI V.  If a n R C L is c o nfir me d, or t he vir us ca n n ot be is olate d fr o m t he 
bl o o d dra w, t he patie nt will be sc he d ule d f or a p heresis a n d will u n der g o a f ull bi ol o gical R C R/ L 
testi n g f or d etecti o n a n d/ or c haracterizati o n of t he R C R L. 
 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 8 7  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
Cl o n alit y a n d i nserti o n al o nc o ge nesis :  T he occ urre nce of a d v erse e ve nts ca use d b y i nserti o nal 
m uta ge n esis i n fi ve patie nts i n a ge ne t hera p y trial f or X-li n ke d S CI D f oll o wi n g ste m cell t hera p y 
e m p hasizes t he p ote ntial f or pr o ble ms i n tra nslati n g t his a p pr oac h t o t he cli nic 1 1 8. T o date, 
cli nicall y e vi de nt i nserti o nal m uta ge nesis has n ot b ee n re p orte d f oll o wi n g a d o pti ve of e n gi neere d 
T cells. Le nti viral vect ors ma y ha v e a l o wer ris k t ha n o nc oretr o viral vect ors base d o n se veral 
c o nsi derati o ns 1 1 9.  M o nit ori n g f or T cell cl o nal o ut gr o wt h will be perf or me d b y fl o w c yt o metric 
a nal ysis f or C A R- e x pressi n g cells, a n d b y C B C c o u nt.  If t he n u m b er of c hi m eric i m m u ne rece pt or 
cells c o nti n ues t o i n creas e aft er 6 wee ks, a V β re pert oire a nal ysis will be perf or me d t o e v al uate 
cl o nalit y, or if t he C B C a nal ysis re veals a b n or m al T cell c o u nts, t he n t he V β a nal ysis will be 
perf or me d earlier.   If a patie nt's V  re pert oire is f o u n d t o b e m o n ocl o n al or oli g ocl o nal, t he 
patie nt's T cells will be e val uate d f or t he patter n of vect or i ns erti o n. If t h e patter n of i nserti o n is 
f o u n d t o fa v or a si n gle d o mi na nt i nserti o n site patter n t he cli nical tri al will be place d o n h ol d f or 
d osi n g t o all o w e v al uati o n of t he patie nt i n c o ns ultati o n wit h ge ne t hera p y e x perts, st u d y 
i n vesti gat ors, D S M B, F D A a n d NI H. F urt her e val u ati o n of t he patie nt will c o m prise c o nfir m ati o n 
of t he persiste nce of t he cl o nalit y wit hi n a 3 m o nt h peri o d, a n d m o nit ori n g of t he patie nt f or 
he mat ol o gic mali g na n cies.  O pti o nall y, a se q ue n ce a nal ysis of t he d o mi na nt i nserti o n site(s) will 
be perf or me d, i n or der t o l ocate a n y ass o ciati o n of t he i ns erti o n sites wit h k n o w n h u ma n 
o nc o ge nes. 
 
U nc o ntr olle d T cell pr olifer ati o n:  C A R T- 1 9 cells c o ul d pr oliferate wit h o ut c o ntr ol of n or mal 
h o me ostatic mec ha nis ms. I n pre-cli nical st u dies, C A R T- 1 9 cells ha ve o nl y pr oliferate d i n 
res p o nse t o p h ysi ol o gic si g nals or u p o n e x p os ure t o C D 1 9. I n t he c o nte xt of t his pr ot oc ol it is 
p ossi ble t hat t he T cells will pr oliferate i n res p o ns e t o si g n als fr o m t h e mali g na nt t u m or or n or m al 
B cells. T his c o ul d be be neficial or har mf ul de p e n di n g o n t he e xte nt  of pr oliferati o n. Cl o nal 
d o mi na nce of a d o pti vel y tra nsferre d T cells has bee n ass ociate d wit h t u m or re d ucti o n i n a d o pti ve 
tra nsfer tri als 7 5, 1 0 3. If a n y patie nt de vel o ps e x cessi ve C A R T- 1 9 cell acc u m ulati o n, c ortic oster oi ds 
will be a d mi nistere d t o era dicate t he i nf us e d cells. 
 
T o xicit y ass ociate d wit h all o ge n eic or a ut ol o g o us T cell i nf usi o ns has bee n ma na ge d wit h a c o urse 
of p har mac ol o gic i m m u n os u p pressi o n. T b o d y ass ociate d t o xicit y h as bee n re p orte d t o res p o n d t o 
s yste mic c ortic oster oi ds 1 0 4.  If u nc o ntr olle d T cell pr oliferati o n occ urs ( gra d e 3 or 4 t o xicit y relate d 
t o C A R T- 1 9 cells), p atie nts ma y b e tr eate d wit h c ortic oster oi ds. Patie nts will be treate d wit h p ulse 
met h yl pre d nis ol o ne ( 2 m g/ k g i. v. di vi de d q 8 hr x 2 da ys), f oll o we d b y a ra pi d ta per. 
 
B cell de pleti o n: It is p ossi ble t hat B cell de pl eti o n a n d h y p o ga m ma gl o b uli n e mia will occ ur. T his 
is c o m m o n 
wit h a nti- C D 2 0 directe d t hera pi es1 0 5. I n t he e ve nt of cli nicall y si g nifica nt 
h y p o ga m ma gl o b uli ne mia (i.e. s yste mic i nfecti o ns), patie nts 
ma y be gi ve n i ntra ve n o us 
i m m u n o gl o b uli n (I VI G) b y esta blis he d cli nical d osi n g g ui deli nes t o rest ore n or mal le vels of ser u m 
i m m u n o gl o b uli n le vels, as has bee n d o ne wit h Rit u xi ma b. 
 
I nf usi o n re acti o n: Aceta mi n o p he n a n d di p he n h y dra mi ne h y dr oc hl ori de ma y be re p eate d e v er y 6 
h o urs as n ee d e d. A c o urs e of n o n-ster oi dal a nti-i nfla m mat or y m e dicati o n m a y be pres cri be d if t he 
patie nt c o nti n ues t o ha ve fe ver n ot relie ve d b y acet a mi n o p he n. It is rec o m me n de d t hat patie nts n ot 
recei v e c ortic oster oi ds at a n y ti me, e x ce pt i n t he case of a life t hreate ni n g e mer ge nc y, si nc e t his 
ma y h a ve a n a d vers e effect o n C A R T- 1 9 cells.  
 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 8 8  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
Fe brile re a cti o n: I n t he e ve nt of fe brile reacti o n, a n e val uati o n f or i nf ecti o n s h o ul d be i nitiate d, 
a n d patie nts m a na ge d a p pr o priatel y wit h a nti bi otics, fl ui ds a n d ot her s u p p orti ve care as m e dicall y 
i n dicate d a n d deter mi ne d b y t he treati n g p h ysicia n.  I n t he e v e nt t hat t he patie nt de vel o ps se psis or 
s yste mic b actere mia f oll o wi n g C A R T cell i nf usi o n, a p pr o priat e c ult ures a n d me dical ma na ge me nt 
s h o ul d be i nitiate d.  If a c o nta mi nate d C A R T- 1 9 T cell pr o d uct is s us pect e d, t he pr o d uct ca n b e 
reteste d f or st erilit y usi n g arc hi ve d sa m ples t hat are st ore d i n t he C V P F.  C o nsi derati o n of a 
c yt o ki ne rele ase s y n dr o m e (see b el o w) s h o ul d be gi ve n.   
 
C yt o ki ne Rele ase S y n dr o me ( C R S) / M acr o p h a ge Acti v ati o n S y n dr o me ( M A S):  
C R S has bee n o bser ve d i n patie nts after treat me nt wit h C A R T- 1 9 . Patie nts wit h cli nical res p o nses 
e x hi bite d s o me le vel of C R S t hat ra n ge d fr o m mil d t o se vere c o nsisti n g of fe vers, h y p ote nsi o n, 
ca pillar y le a k, h y p o xia or ot her s y m pt o ms ( See Secti o n 1. 5. 2 a n d 8. 2).  All patie nts w h o h a ve 
res p o n de d t o C A R T- 1 9 cells ha ve e x perie nce d a C R S.  
 
C yt o ki ne pr o d ucti o n is re q uire d f or t he acti vati o n, e x pa nsi o n a n d c yt ol ytic f u ncti o n of T cells a n d 
f or C A R T- 1 9 T cells.  T heref ore, s o me d e gree of C R S ma y b e a desire d cli nical o utc o me. 
Pre mat ure or earl y i nter ve nti o n wit h a nti-c yt o ki ne t hera p y ma y t heref ore a br o gate t he a nti-t u m or 
effic ac y of C A R T- 1 9 . S u bse q ue nt t o t his e x perie nce, selecti ve t ociliz u ma b (a n a nti-I L 6-rece pt or 
a nti b o d y) t hera p y h as bee n utilize d ( descri be d bel o w) wit h effecti ve t o xicit y ma na ge me nt a n d 
s uccessf ul o n g oi n g C A R T- 1 9 T cell e x pa nsi o n i n patie nts. Please n ote, ster oi ds or ot her 
i m m u n os u p pressa nt dr u gs s h o ul d N O T  be use d as pre- me dicati o n f or C A R T- 1 9 t hera p y b ut ma y 
be c o nsi dere d i n t he ma n a ge me nt of C R S.   
 
T h e m o derat e t o se vere cases of C R S o bser ve d re q uire d i nter ve nti o n wit h t ociliz u ma b,  wit h or 
wit h o ut hi g h d ose c ortic oster oi ds, bet wee n 2 a n d 9 da ys after T cell i nf usi o n. T his res ulte d i n ra pi d 
re vers al of t he hi g h persiste nt fe vers ass ociate d wit h C R S i n m ost b ut n ot all patie nts.   
 
Gi ve n t he dra matic cli nical i m pr o ve me nt of m ost patie nts treate d wit h a nti-c yt o ki n e t hera p y, 
patie nts wit h m o derate t o se vere c yt o ki ne t o xicities s h o ul d be first ma na ge d wit h a d mi nistrati o n 
of t ociliz u ma b. 
 
T ociliz u ma b s h o ul d be use d as a si n gle, wei g ht- b as e d d ose of 8 m g/ k g at t he ti me of he m o d y na mic 
i nsta bilit y (i nitial d ose of t ociliz u ma b wit hi n o ne h o ur of or deri n g dr u g is hi g hl y rec o m me n d e d). 
T his ma na ge me nt a p pr oac h is desi g ne d t o a v oi d life-t hreate ni n g t o xicities, w hile atte m pti n g t o 
all o w t he C A R T- 1 9 cells t o esta blis h a pr oliferati ve p hase t h at a p pears t o c orrelate wit h a nti-t u m or 
effic ac y. T h us, t he ti mi n g of t he t ociliz u ma b s h o ul d be i n di vi d ualize d, i n cl ose c o ns ultati o n wit h 
t he Pri nci pal I n vesti gat or a n d/ or e x pert c o ns ulta nts f or t he trial.  Ster oi ds ha ve n ot al wa ys b ee n 
effecti ve i n t his setti n g a n d ma y n ot be necessar y gi ve n t he ra pi d res p o nse t o t ociliz u ma b. Beca use 
ster oi ds will i nterfere wit h C A R T- 1 9 f u ncti o n a n d efficac y, if use d, t he y s h o ul d be ra pi dl y ta pere d.  
 
U p o n de vel o pi n g t he pr o dr o me of hi g h- p ersiste nt fe vers f oll o wi n g C A R T- 1 9 i nf usi o n, patie nts 
s h o ul d t he n be f oll o we d cl osel y. I nfecti o n a n d t u m or l ysis s y n dr o m e w or k u p s h o ul d be 
i m me diatel y u n derta ke n.  T he p har mac y s h o ul d be n otifie d of t he p ote ntial n ee d f or t o ciliz u ma b.  
Patie nt ma na ge me nt i n a n i nte nsi ve care u nit ma y be re q uir e d a n d t he ti mi n g is de pe n d e nt u p o n 
l ocal i nstit uti o nal practice. I n a d diti o n t o s u p p orti ve care, t ociliz u ma b ma y be a d mi nistere d i n 
cases of m o derate t o se v ere C R S, es peciall y if t he patie nt e x hi bits a n y of t he f oll o wi n g: 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 8 9  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
 He m o d y n a mic i nsta bilit y des pite i ntra ve n o us fl ui d c halle n ges a n d m o d erat e sta ble 
vas o press or s u p p ort 
 W orse ni n g res pirat or y distress, i ncl u di n g p ul m o n ar y i nfiltrates, i ncreasi n g o x y ge n 
re q uire me nt i ncl u di n g hi g h-fl o w O 2, a n d/ or n ee d f or mec h a nical ve ntilati o n. 
 A n y ot her si g ns or s y m pt o ms of ra pi d deteri orati o n des pite me dical ma na ge me nt 
 
T he rec o m me n d e d d osi n g f or t ociliz u ma b is 8  m g/ k g i. v. si n gle d ose. N ot all Gra de 4 C R S 
reacti o ns f oll o wi n g C A R T- 1 9 ha ve b ee n i m me diatel y tr eate d wit h t ociliz u ma b a n d decisi o ns are, 
i n part, base d u p o n t he ra pi dit y of t he s y n dr o me o nset a n d u n derl yi n g patie nt reser ve. 
 
Silt u xi ma b, a n a nti-I L 6 t hera p y, m a y be a d mi nistere d b e gi n ni n g 2- 2 4 h o urs after t he first d os e of 
t ociliz u ma b, at t he p h ysicia n-i n vesti gat or’s discreti o n.  Ot her a nti-c yt o ki ne t hera pies, s u c h as 
re peat a d mi nistrati o n of t ociliz u ma b or silt u xi ma b, or eta nerce pt, ma y als o be c o nsi dere d if t he 
patie nt d oes n ot res p o n d t o i nitial t hera p y.  If t he patie nt e x perie nces o n g oi n g C R S des pite 
a d mi nistrati o n of a nti-c yt o ki ne directe d t hera pies, a nti T-cell t hera pies s u c h as c ycl o p h os p ha mi de , 
A T G, or ale mt uz u ma b ( Ca m pat h) ma y als o be c o nsi dere d.   
 
C R S has bee n ass ociate d wit h bi oc he mical a n d p h ysi ol o gic a b n or malities c o nsiste nt wit h M A S.  
M o derate t o e xtre me ele v ati o ns i n ser u m C-reacti v e pr otei n ( C R P) a n d ferriti n ha ve bee n see n wit h 
C A R T- 1 9 ass ociate d C R S, h o we ver t he ma g nit u d e a n d ki netics var y greatl y b et wee n i n di vi d ual 
patie nts.  C R S ma na ge me nt decisi o ns s h o ul d be base d u p o n cli nical si g ns a n d s y m pt o ms a n d 
res p o nse t o i nter ve nti o ns, n ot t hese la b orat or y v al ues per se . Refer t o Fi g ure 8- 1 bel o w f or a 
C R S M a n a ge me nt Al g o rit h m.  
 
C T C A E gra di n g of C R S relates t o its occ urre nce wit h ac ute i nf usi o nal t o xicities, w hereas t he C R S 
ass ociate d wit h C A R T- 1 9 t hera p y is n ot ac ute, b ut rat her dela ye d. Refer t o Secti o n 8. 2 a n d T a ble 
8 - 1 f or m o difie d defi niti o ns of gra di n g of C A R T- 1 9 dela ye d C R S e ve nts.  
 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 9 0  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
Fi g ur e 8- 1  
C R S M a n a g e m e nt Al g orit h m 
 
 
 
T u m or l ysis s y n dr o me:  Patie nts will recei ve all o p uri n ol pr o p h ylacticall y f or 2 8 da ys t o pre ve nt 
c o m plicati o ns fr o m T L S.  T L S res ulti n g i n re nal i ns ufficie nc y, or ra pi dl y risi n g uric aci d, or 
e vi de nce of or ga n d ysf u ncti o n will be ma na ge d wit h fl ui ds a n d ras b uricas e as cli nicall y i n dicat e d 
a n d deter mi ne d b y t he treati n g p h ysicia ns. 
 
G V H D:  T he c ha nce of G V H D occ urri n g is l o w, b ut it is a p ote ntial ris k wit h C T L 0 1 9 t h era p y. A 
pri or st u d y of acti vate d d o n or l y m p h o c yt e i nf usi o ns (e x vi v o acti vate d cells c ollecte d fr o m t he 
d o n or a n d gr o w n i n t he sa me fas hi o n as C A R T - 1 9 b ut wit h o ut t he C A R i ntr o d ucti o n) di d n ot s h o w 
hi g h rat es of G V H D ( 2/ 1 8 patie nts wit h gra de 3 G V H D a n d n o n e wit h gra de 4) 9 7. Ei g ht A L L 
patie nts treate d t o dat e wit h a ut ol o g o us C A R T- 1 9 t hera p y h a d pri or all o ge n eic he mat o p oietic S C T 
wit h resi d ual d o n or c hi meris m. N o ne of t h ese p atie nts ha ve d e vel o pe d G V H D after a ut ol o g o us 
C A R T- 1 9 i nf usi o n 
8. 4. 3. Crit eri a f or Di s c o nti n ui n g a P ati e nt’ s P arti ci p ati o n i n t h e St u d y 
If a patie nt de vel o ps a c o n diti o n t hat precl u des C A R T- 1 9 i nf usi o n after e nr oll me nt b ut bef ore 
i nf usi o n, t he patie nt will be pre mat urel y disc o nti n ue d. T his will be d o ne at t he j u d g me nt of t he PI, 
a n d c o ul d i ncl u de f or e x a m ple, t he occ urre nce of a n i nterc urre nt ill ness re q uiri n g t he i nstit uti o n of 
s yste mic i m m u n os u p pressi o n 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 9 1  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
8. 5. Pr ot o c ol E x c e pti o n s a n d D e vi ati o n s 
E xce pti o n  
A o ne ti me, i nte nti o n al acti o n or pr ocess t hat de parts fr o m t he a p pr o ve d st u d y pr ot oc ol, i nte n de d 
f or o ne  o cc urre nce. If t he acti o n disr u pts t he st u d y pr o gress, s uc h t hat t he st u d y d esi g n or o utc o m e 
(e n d p oi nts) ma y be c o m pr o mise d, or t he acti o n c o m pr o mises t he safet y a n d welf are of st u d y 
s u bjects, a d v a nce  d oc u me nte d I R B a n d D S M C a p pr o val is re q uire d.    
 
N o e x ce pti o n w o ul d be gra nte d if t he acti o n disr u pts t he st u d y pr o gress, s uc h t hat t he st u d y desi g n 
or o utc o me (e n d p oi nts) ma y b e c o m pr o mise d, or t he acti o n c o m pr o mises t he safet y a n d welfare 
of st u d y s u bjects 
 
E x ce pti o ns will be a p pr o ve d b y t he Me dical M o nit or a n d Re g ul at or y S p o ns or pri or t o s u b missi o n 
t o t he I R B a n d D S M C.  D oc u me ntati o n of a p pr o val b y t he M e dical M o nit or a n d Re g ulat or y 
S p o ns or will be s u b mitte d wit h t he i nitial re q uest f or a n e x ce pti o n t o t he I R B a n d D S M C.  All 
e x ce pti o ns re q uire a d v a nce  d oc u me nte d I R B, A C C D S M C, a n d ot her a p plica ble re g ulat or y 
re vie w c o m mittees f or a p pr o val. 
 
N o exce pti o ns t o eli gi bility will be gr a nte d f or t his st u dy.   
 
De vi ati o n 
A o ne ti me, u ni nte nti o n al  acti o n or pr ocess t hat de parts fr o m t he I R B a n d D S M C a p pr o ve d st u d y 
pr ot oc ol, i n v ol vi n g o ne i nci de nt a n d i de ntifie d retr os pecti vel y, after t he e ve nt occ urre d. If t he 
i m pact o n t he pr ot oc ol disr u pts t he st u d y desi g n, ma y affect t he o utc o me (e n d p oi nts) or 
c o m pr o mises t he safet y a n d welfare of t he s u bj ects, t he de viati o n m ust be re p orte d t o t he D S M C 
wit hi n 5 b usi ness da ys a n d t he I R B wit hi n 1 0 b usi ness da ys.  
 
A n y d e part ure fr o m t he pr ot oc ol t hat meets t he f oll o wi n g criteria s h o ul d b e s u b mitte d t o t he 
re g ulat or y s p o ns or, A C C D S M C a n d I R B: 
 I m pa cts s u bject safet y 
 I m pa cts t he i nte grit y of t he st u d y d esi g n or o utc o me 
 Base d o n t h e PI’s j u d g me nt is re p orta ble 
 
Ot her de viati o ns s h o ul d be e x plai ne d i n a me m o t o file (s uc h as a patie nt missi n g a visit is n ot a n 
iss ue u nless a critical/i m p orta nt treat me nt or pr oce d ure was misse d a n d m ust ha ve bee n d o ne at 
t hat s pecific ti me). 
 
I n cl u de t he f oll o wi n g i nf or mati o n o n t he S p o ns or s u p plie d e x ce pti o n/ de viati o n f or m:  Pr ot oc ol 
n u m ber, s u bject st u d y n u m ber, descri pti o n of t he e x ce pti o n/ de viati o n fr o m t he pr ot oc ol, a n d 
rati o nale.  E ns ure all c o m plete d e x ce pti o n/ de viati o n f or ms are si g ne d b y t he Pri nci pal I n vesti gat or 
( or s u b-i n vesti gat or) a n d s u b mitt e d t o t he S p o ns or Pr oject Ma na ger f or re vi e w. 
 
Atte nti o n: S p o ns or Pr oject Ma na ger 
Ce nter f or Cell ular I m m u n ot hera pies ( C CI) 
U ni versit y of Pe n ns yl v a nia  
 
 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 9 2  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
T he S p o ns or Pr oject Ma n a ger will s u b mit t he e x ce pti o n/ de viati o n f or m t o t he Re g ulat or y S p o ns or 
f or re vie w a n d a p pr o val.  O nce a p pr o val of t he e x ce pti o n re q uest or ac k n o wle d ge me nt of t he 
de viati o n has bee n gra nte d b y t h e Re g ulat or y S p o ns or, t he e x ce pti o n or de vi ati o n will be s u b mitte d 
t o t he I R B, A C C D S M C a n d all ot her a p plica ble c o m mittees f or re vie w a n d a p pr o val.  
 
8. 6. M e di c al M o nit ori n g 
It is t he res p o nsi bilit y of t he Pri nci pal I n vesti gat or t o o versee t he safet y of t h e st u d y at his/ her site.  
T his safet y m o nit ori n g will i ncl u de caref ul assess m e nt a n d a p pr o pri ate re p orti n g of a d v erse e v e nts 
as n ote d a b o ve, as well as t he c o nstr ucti o n a n d i m ple me ntati o n of a site data a n d safet y- 
m o nit ori n g pla n (see secti o n 1 0 A u diti n g, M o nit ori n g a n d I ns pecti n g).  Me dical m o nit ori n g will 
i ncl u de a re g ul ar ass ess me nt of t he n u m ber a n d t y pe of seri o us a d v erse e ve nts. 
 
A pr ot oc ol-s pecific i n d e p e n de nt Me dical M o nit or wit h a p pr o priat e e x pertise has b ee n recr uite d i n 
a d diti o n t o t he D S M B t o re vie w s u bjects’ safet y data a n d e ns ure t he safet y of partici pa nts.  T h e 
Me dical M o nit or will recei ve real-ti me re p orti n g of a n y e v e nt t hat c o ul d p ote ntiall y i m pact s u bject 
safet y (i ncl u di n g d ose-li miti n g t o xicities).  T he Me dical M o nit or will als o recei ve all of t he 
f oll o wi n g:   
 
 All Seri o us A d verse E v e nts (re gar dl ess of e x pecte d ness/relate d ness).  T he S A E will 
be re p ort e d t o t he Me dic al M o nit or wit hi n 2 4 h o urs of bec o mi n g a ware of t he S A E. 
 De viati o ns re p orte d t o t h e Re g ul at or y S p o ns or, A C C D S M C a n d I R B as t h e y o cc ur 
 E x ce pti o ns pri or t o s u b missi o n t o t he I R B a n d A C C D S M C 
 I R B C o nti n ui n g Re vie ws  
 M o nt hl y listi n g of S A E’s w hic h occ ur after T cell i nf usi o n 
 All q ueries iss ue d b y t he D S M C (i ncl u di n g t h ose relate d t o gra di n g, attri b uti o n a n d 
e x pecte d ness of a d v erse e ve nts).  
 
T he Me dical M o nit or will c orres p o n d via e mail t o c o m m u nicate: 
 S A E ac k n o wle d ge me nt a n d i n q uiries 
 De viati o n ac k n o wl e d ge me nt, i n q uiries, rec o m me n dati o ns 
 E x ce pti o n ac k n o wle d ge me nt, i n q uiries a n d a p pr o val/ disa p pr o val 
 C o nti n ui n g re vie w ac k n o wle d ge me nt, i n q uiries  
 
T he Me dical M o nit or will re vie w t he a b o v e a n d ma ke rec o m me n d ati o ns t o c o nti n ue wit h t he st u d y, 
a me n d t he st u d y, a n d/ or st o p/ pa use t he st u d y as n ee de d.   
 
D oc u me ntati o n of M e dical M o nit or re vi e w will be mai ntai ne d i n t he st u d y re g ulat or y bi n d er. 
D oc u me ntati o n of M e dic al M o nit or re vie w will als o be se nt t o t he A C C D S M C a n d Re g ulat or y 
S p o ns or as s o o n as a res p o nse is recei v e d fr o m t he Me dical M o nit or. 
8. 6. 1. I n d e p e n d e nt D at a a n d S af et y M o nit ori n g B o ar d 
A n I n de p e n de nt D ata a n d Safet y M o nit ori n g B oar d ( D S M B) will be c o nstit ute d pri or t o e nr oll me nt 
of t he first patie nt. Please n ote t hat t he D S M B is se parat e fr o m t he A C C D S M C (refer t o secti o n 
9. 3. 3).  T he D S M B will be c o m prise d of a mi ni m u m of f o ur i n di vi d uals, i ncl u di n g p h ysicia ns wit h 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 9 3  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
e x perie nce i n o nc ol o g y a n d/ or ge n e tra nsfer t hera p y a n d a statisticia n a n d will w or k u n der a c harter 
s pecificall y d e vel o pe d f or safet y o versi g ht of t his st u d y. T h e D S M B will pr o vi de g ui da nce/a d vice 
t o t he Re g ulat or y S p o ns or. T he D S M B will e val uate patie nt-s u bject safet y as s pecifi e d i n t he 
D S M B C harter.  
 
T he D S M B will meet a p pr o xi matel y e ver y 4 m o nt hs.  If necessar y, a d diti o nal meeti n g of t h e 
D S M B ma y be hel d if s afet y iss ues arise i n bet wee n sc he d ule d meeti n gs. 
 
It is e n visi o ne d t hat t he D S M B ma y ma ke f o ur t y pes of rec o m me n dati o ns, na mel y: 
• N o safet y or effi cac y iss ues, et hical t o c o nti n ue t he st u d y as pla n ne d 
• Seri o us safet y c o n cer ns precl u di n g f urt her st u d y treat me nt, re gar dless of efficac y 
• O ver w h el mi n g e vi de n ce f or f utilit y, rec o m me n d st o p pi n g t he st u d y. 
• Rec o m me n dati o n t o c o nti n ue t he st u d y b ut pr o p osi n g a n a me n d me nt t o t h e pr ot oc ol (e. g., 
i nc or p orate a n a d diti o nal safet y assess me nts) 
 
A s p o ns or re pres e ntati ve will s hare t he o utc o me of t he D S M B meeti n g wit h t he PI via e mail, f or 
s u b missi o n t o l ocal re g ul at or y re vie w c o m mittees as re q uire d p er i nstit uti o nal p olic y.   
9.  D A T A H A N D LI N G A N D R E C O R D K E E PI N G 
9. 1. C o nfi d e nti alit y 
T he i n vesti gat or m ust e ns ure a n o n y mit y of t he patie nts; patie nts m ust n ot be i de ntifie d b y na mes 
i n a n y d o c u me nts s u b mitte d t o t he s p o ns or.  Si g n e d i nf or me d c o nse nt f or ms a n d patie nt e nr oll me nt 
l o g m ust be ke pt strictl y c o nfi de ntial t o e na ble patie nt i de ntificati o n at t he site.   
 
I nf or mati o n a b o ut st u d y s u bjects will be ke pt c o nfi de ntial a n d ma na ge d acc or di n g t o t he 
re q uire me nts of t he Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act of 1 9 9 6 ( HI P A A).  T h ose 
re g ulati o ns re q uir e a si g n e d s u bject a ut h orizati o n i nf or mi n g t he s u bject of t he f oll o wi n g: 
 
 
W hat pr otecte d healt h i nf or mati o n ( P HI) will be c ollecte d fr o m patie nts i n t his st u d y 
 
W h o will ha ve access t o t hat i nf or mati o n a n d w h y 
 
W h o will use or discl ose t hat i nf or mati o n 
 
T he ri g hts of a researc h p atie nt t o re v o ke t heir a ut h orizati o n f or use of t heir P HI. 
 
I n t he e v e nt t hat a patie nt re v o kes a ut h orizati o n t o c ollect or use P HI, t he i n vesti gat or, b y 
re g ulati o n, retai ns t he a bilit y t o use all i nf or mati o n c ollecte d pri or t o t h e re v ocati o n of patie nt 
a ut h orizati o n.   F or patie nts t hat ha ve re v o k e d a ut h orizati o n t o c ollect or us e P HI, atte m pts s h o ul d 
be ma de t o o btai n per missi o n t o c ollect at least vital stat us (i.e. t hat t he patie nt is ali ve) at t he e n d 
of t heir sc he d ule d st u d y peri o d. 
 
T he data c ollecti o n s yst e m f or t his st u d y uses b uilt-i n sec urit y feat ures t o e ncr y pt all data f or 
tra ns missi o n i n b ot h directi o ns, pre ve nti n g u n a ut h orize d access t o c o nfi de ntial partici pa nt 
i nf or mati o n. Access t o t he s yste m will be c o ntr olle d b y a se q u e nce of i n di vi d uall y assi g n e d user 
i de ntificati o n c o des a n d pass w or ds, ma de a vaila ble o nl y t o u na ut h orize d pers o n nel w h o ha ve 
c o m plete d t he prere q uisite trai ni n g.  

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 9 4  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
If c o u ntr y r ules or et hics c o m mittee sta n dar ds d o n ot per mit c ollecti o n of patie nt i nitials a n d t he 
e x act date of birt h, ge n eric i nitials will be use d a n d o nl y t he year of birt h will be c ollecte d. 
9. 2. S o ur c e D o c u m e nt s 
S o urce dat a is all i nf or mati o n, ori gi nal rec or ds of cli nical fi n di n gs, o bser vati o ns, or ot her acti vities 
i n a cli nical tri al necess ar y f or t he rec o nstr ucti o n a n d e v al uati o n of t he trial.  S o urce data are 
c o ntai ne d i n s o urce d oc u me nts  E x a m ples of t hese ori gi nal d oc u m e nts, a n d d ata rec or ds i ncl u de:  
h os pital  rec or ds,  cli nical  a n d  office  c harts,  la b orat or y n ot es,  me m ora n da,  patie nts’ diaries or 
e val uati o n c hec klists, p har mac y dis pe nsi n g rec or ds, rec or de d data fr o m a ut o mate d i nstr u me nts, 
c o pies or tr a nscri pti o ns certifie d after verificati o n as bei n g acc urate a n d c o m plete, micr ofic hes, 
p h ot o gra p hic ne gati ves, micr ofil m or ma g netic m e dia, x-ra ys, p atie nt files, a n d rec or ds k e pt at t h e 
p har mac y, at t he la b orat ories, a n d at me dic o-tec h nical de part me nts i n v ol ve d i n t he cli nical trial. 
 
T he i n vesti gat or m ust mai ntai n s o urce d oc u me nts f or eac h p atie nt i n t he st u d y, c o nsisti n g of case 
a n d visit n otes ( h os pital or cli nical me dical rec or ds) c o nt ai ni n g d e m o gra p hic a n d me dical 
i nf or mati o n, la b orat or y d ata, ele ctr ocar di o gra ms a n d t he res ults of a n y ot her tests or assess me nts. 
All i nf or mati o n rec or de d o n t he e C R Fs m ust be tracea ble t o s o urce d o c u me nts i n t he patie nt’s file. 
T he i n vesti gat or m ust als o kee p t he ori gi nal si g ne d i nf or me d c o ns e nt f or m, a n d a si g ne d c o p y m ust 
be gi v e n t o t he patie nt. 
9. 3. C a s e R e p ort F or m s 
F or st u dies usi n g el ectr o nic data ca pt ure ( E D C), t he desi g n ate d i n vesti gat or staff will e nter t h e 
data re q uir e d b y t he pr ot oc ol i nt o t he electr o nic case re p ort f or m (e C R Fs). T he e C R Fs ha ve b ee n 
b uilt usi n g f ull y vali dat e d sec ure we b-e na ble d s oft ware t hat c o nf or ms t o 2 1 C F R Part 1 1 
re q uire me nts.  I n vesti gat or site staff will n ot be gi ve n access t o t he E D C s yste m u ntil t he y h a ve 
bee n f ull y trai ne d. A ut o matic vali dati o n pr o gra ms c hec k f or data discre pa ncies i n t he e C R Fs a n d 
all o w m o dificati o n or verificati o n of t he e ntere d d ata b y t he i n vesti gat or staff.  
 
T he Pri nci pal I n v esti gat or is res p o nsi ble f or ass uri n g t hat t he data e ntere d i nt o t he e C R F is 
c o m plete, acc urat e, a n d t hat e ntr y a n d u p d ates are perf or m e d i n a ti mel y ma n ner. T h e desi g n ate d 
C R O will re vie w t he data e ntere d b y i n vesti gati o nal staff f or c o m plete ness a n d acc urac y. 
Electr o nic dat a q ueries stati n g t he mat ure of t he pr o ble m a n d re q uesti n g clarificati o n will be 
creat e d f or discre pa ncies a n d missi n g val ues a n d se nt t o t he i n vesti gati o nal site via t he E D C 
s yste m. D esi g n ate d i n vesti gat or site staff is re q uir e d t o res p o n d pr o m ptl y t o q ueries a n d t o ma ke 
a n y n ecessar y c h a n ges t o t he data. 
 
C o nc o mita nt treat me nts e ntere d i nt o t he dat a base will be c o d e d usi n g t he W H O Dr u g refere n ce 
list. Me dical hist or y/ c urre nt me dical c o n diti o ns a n d a d verse e v e nts will be c o d e d usi n g t h e 
Me dical dicti o nar y f or re g ulat or y acti vities ( Me d R A) ter mi n ol o g y. 
 
At t he c o ncl usi o n of t h e st u d y t he o cc urre nce of a n y pr ot o c ol vi olati o ns will be deter mi ne d, a n d 
all u n use d s u p plies are t o be ret ur n e d. Aft er t his has bee n c o m plet e d a n d t he data has b ee n verifie d 
t o be c o m plete a n d acc urate, t he d ata bas e will be decl are d l o c ke d. After data base l oc k, all 
i n vesti gat ors will recei v e a C D- R O M or pa p er c o pies of t he p atie nt dat a f or arc hi vi n g at t he 
i n vesti gati o nal site. 
 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 9 5  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
1 0.  
S T U D Y M O NI T O RI N G, A U DI TI N G, A N D I N S P E C TI N G 
1 0. 1.  
Sit e M o nit ori n g 
All m o nit ori n g will be c o n d ucte d b y r e prese ntati ves of t he S p o ns or as des cri be d i n t he M o nit ori n g 
Pla n.   At t he site i nitiati o n visit, m o nit ors will ass ure t hat pr o per st u d y relate d d oc u me ntati o n 
e xists, pr o vi de trai ni n g t o i n vesti gat ors a n d ot her site pers o n nel i n t h e G C P g ui deli nes, a n d ass ure 
t hat acce pta ble facilities a n d a de q u atel y trai ne d st aff are a v aila ble t o c o n d uct t he st u d y. 
 
D uri n g t he st u d y, t he s p o ns or m o nit or will visit t he site re g ularl y t o c hec k t he c o m plete ness of 
patie nt rec or ds, t he acc urac y of e ntries o n t he C R Fs, t he a d here nce t o t he pr ot oc ol t o G o o d Cli nical 
Practice, t he pr o gress of e nr oll me nt, a n d t o e ns ure t hat st u d y treat me nt is bei n g st ore d, dis pe nse d, 
a n d acc o u nt e d f or acc or di n g t o s pecificati o ns. Ke y st u d y p ers o n nel m ust be a vaila ble t o assist t he 
s p o ns or m o nit or d uri n g t hese visits. 
 
T he i n vesti gat or m ust mai ntai n s o urce d oc u me nts f or eac h p atie nt i n t he st u d y, c o nsisti n g of case 
a n d visit n otes ( h os pital or cli nic 
me dical rec or ds) c o ntai ni n g de m o gra p hic a n d 
me dical 
i nf or mati o n, la b orat or y d ata, ele ctr ocar di o gra ms, a n d t he res ults of a n y ot her tests or assess me nts. 
All i nf or mati o n rec or de d o n C R Fs m ust be tracea ble t o s o urce d oc u me nts i n t he patie nt's file. T he 
i n vesti gat or m ust als o k ee p t he ori gi nal si g ne d i nf or me d c o nse nt f or m (a si g ne d c o p y is gi ve n t o 
t he patie nt). 
 
T he i n vesti gat or m ust gi ve t he m o nit or access t o all rele va nt s o urc e d oc u me nts t o c o nfir m t heir 
c o nsiste nc y wit h t he C R F e ntries. T he m o nit ori n g sta n dar ds f or t his st u d y will re q uire f ull 
verificati o n f or t he pres e nce of i nf or me d c o nse nt, a d here n ce t o t he i ncl usi o n/e xcl usi o n criteria a n d 
d oc u me ntati o n of S A Es. A d diti o nal c hec ks of t h e c o nsiste nc y of t he s o urce dat a wit h t he C R Fs 
are perf or m e d acc or di n g t o t he st u d y-s pecific m o nit ori n g pla n. 
1 0. 2.  
A u diti n g a n d I n s p e cti n g 
T he i n vesti gat or will per mit st u d y-relat e d m o nit ori n g, a u dits, a n d i ns pecti o ns b y t he I R B, t h e 
s p o ns or, g o ver n m e nt re g ulat or y b o dies, a n d U ni v ersit y c o m plia nce a n d q u alit y ass ura n ce gr o u ps 
of all st u d y-relate d d o c u me nts (e. g. s o urce d oc u me nts, re g ulat or y d oc u me nts, data c ollecti o n 
i nstr u me nts, st u d y data, etc.). T h e i n vesti gat or will e ns ure t he ca pa bilit y f or i ns p ecti o ns of 
a p plica ble st u d y-relate d facilities (e. g. p har m ac y, dia g n ostic la b orat or y, et c.). 
 
Partici pati o n as a n i n vesti gat or i n t his st u d y i m plies acce pta nce of p ote ntial i ns pecti o n b y 
g o ver n me nt re g ulat or y a ut h orities a n d a p plica ble U ni versit y c o m plia nc e a n d q ualit y ass ur a nce 
offices. 
 
Please n otif y t h e S p o ns or i n real-ti me if a n a u dit/i ns pecti o n n otificati o n is recei ve d. 
 
1 1.  
E T HI C A L C O N SI D E R A TI O N S 
T his st u d y is t o be c o n d ucte d acc or di n g t o U S a n d i nter nati o nal sta n d ar ds of G o o d Cli nical 
Practice ( F D A Title 2 1 part 3 1 2 a n d I nter n ati o nal C o nfere n ce o n Har m o nizati o n g ui deli nes), 
a p plica ble g o ver n me nt re g ulati o ns a n d I nstit uti o nal researc h p olicies a n d pr oce d ures. 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 9 6  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
T his pr ot oc ol a n d a n y a me n d me nts will be s u b mitte d t o a pr o perl y c o nstit ute d i n d e pe n de nt 
I nstit uti o nal Re vie w B oar d (I R B), i n a gree me nt wit h l ocal le gal prescri pti o ns, f or f or mal a p pr o val 
of t he st u d y c o n d u ct.  T he decisi o n of t he I R B c o ncer ni n g t he c o n d uct of t he st u d y will be ma de 
i n writi n g t o t he i n vesti gat or a n d a c o p y of t his decisi o n will be pr o vi de d t o t he s p o ns or bef ore 
c o m me nce me nt of t his st u d y.   
 
All patie nts f or t his st u d y will be pr o vi de d a c o nse nt f or m des cri bi n g t his st u d y a n d pr o vi di n g 
s ufficie nt i nf or mati o n f or patie nts t o ma ke a n i nf or me d decisi o n a b o ut t heir partici pati o n i n t his 
stu d y.  T his c o nse nt f or m will be s u b mitte d wit h t he pr ot oc ol f or re vie w a n d a p pr o val b y t he I R B 
f or t he st u d y.  T h e f or mal c o nse nt of a patie nt, usi n g t he I R B-a p pr o ve d c o nse nt f or m, m ust b e 
o btai ne d bef ore t hat patie nt is s u b mitte d t o a n y st u d y pr oce d ure.  T his c o nse nt f or m m ust be si g ne d 
b y t he p atie nt a n d t he i n v esti gat or- desi g nate d researc h pr ofessi o nal o btai ni n g t he c o nse nt. 
 
T he pr ot oc ol is liste d u n der cli nicaltrials. g o v. 
 
1 2.  
S T U D Y FI N A N C E S 
1 2. 1.  
F u n di n g S o ur c e 
T his st u d y will be f u n de d b y N o v artis P har mace uticals. 
1 2. 2.  
C o nfli ct of I nt er e st 
All U ni versit y of Pe n ns yl va nia i n vesti gat ors will f oll o w t he U ni versit y o f P e n ns yl va nia P olic y o n 
C o nflicts of I nterest Relate d t o Researc h. 
1 2. 3.  
P ati e nt Sti p e n d s or P a y m e nt s 
T here is t here is n o patie nt sti pe n d/ pa y me nt f or partici pati o n i n t his pr ot oc ol. 
1 2. 4.  
St u d y Di s c o nti n u ati o n 
T he st u d y ma y be disc o nti n ue d at a n y ti me b y t h e I R B, t he S p o ns or, t he F D A, or ot her g o v er n me nt 
a ge ncies as part of t h eir d uties t o e ns ure t hat res earc h patie nts are pr otecte d. 
 
1 3.  
P U B LI C A TI O N P L A N 
P u blicati o n of t he res ults of t his trial will be g o ver ne d b y U ni versit y of Pe n ns yl va nia p olici es. 
Neit her t he c o m plete n or a n y part of t he res ults of t he st u d y carri e d o ut u n der t his pr ot oc ol, n or 
a n y of t he i nf or mati o n pr o vi de d b y t he s p o ns or f or t he p ur p oses of p erf or mi n g t he st u d y, will be 
p u blis he d or passe d o n t o a n y t hir d part y wit h o ut t he c o nse nt of t he st u d y s p o ns or.  A n y 
i n vesti gat or i n v ol ve d wit h t his st u d y is o bli gate d t o pr o vi de t he s p o ns or wit h c o m plete test res ults 
a n d all data deri ve d fr o m t he st u d y. 
 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 9 7  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
 
1 4.  R E F E R E N C E LI S T 
 
  
1.  S ur veilla nce, E pi de mi ol o g y, a n d E n d Res ults ( S E E R) Pr o gra m of t he N CI.  2 0 0 6.  
             Ref T y pe: I nter n et C o m m u nicati o n 
  
2.  P ui C H, Ca m pa na D, E va ns W E. C hil d h o o d ac ute l y m p h o blastic le u kae mia--c urre nt 
stat us a n d f ut ure pers pecti ves. La ncet O n c ol 2 0 0 1; 2( 1 0): 5 9 7- 6 0 7. 
  
3.  Ver ma A, St oc k W. Ma n a ge me nt of a d ult ac ute l y m p h o blastic le u ke mia: m o vi n g t o war d 
a ris k-a da pt e d a p pr oac h. C urr O pi n O nc ol 2 0 0 1; 1 3( 1): 1 4- 2 0. 
  
4.  K ol b HJ, Sc hatte n ber g A, G ol d ma n J M et al. Graft- vers us-le u ke mia effect of d o n or 
l y m p h oc yte tra nsf usi o ns i n marr o w grafte d patie nts. E ur o pea n Gr o u p f or Bl o o d a n d 
Marr o w Tra ns pla ntati o n W or ki n g Part y C hr o nic Le u k e mia. Bl o o d 1 9 9 5; 8 6( 5): 2 0 4 1-
2 0 5 0.  
  
5.  A p pel ba u m F R. H ae mat o p oietic cell tra ns pla ntati o n as i m m u n ot hera p y. Nat ure 
2 0 0 1; 4 1 1( 6 8 3 5): 3 8 5- 3 8 9. 
  
6.  S ulli va n K M, St or b R, B uc k ner C D et al. Graft- vers us- h ost disease as a d o pti ve 
i mm u n ot hera p y i n patie nts wit h a d va nce d he m at ol o gic ne o plas ms. N E n gl J Me d 
1 9 8 9; 3 2 0( 1 3): 8 2 8- 8 3 4.  
  
7.  Billi n g ha m R E, Bre nt L, Me da war P B. Q ua ntitati ve st u dies o n tiss ue tra ns pla ntati o n 
i m m u nit y. II. T he ori gi n, stre n gt h a n d d urati o n of acti vel y a n d a d o pti vel y ac q uire d 
i m m u nit y. Pr ocee di n gs R o yal S oc 1 9 5 4; 1 4 3: 5 8- 8 0. 
  
8.  Gree n b er g P D. A d o pti ve T cell t hera p y of t u m ors: mec ha nis ms o perati ve i n t he 
rec o g niti o n a n d eli mi nati o n of t u m or cells. A d v I m m u n ol 1 9 9 1; 4 9: 2 8 1- 3 5 5. 
  
9.  Yee C, Ri d dell S R, Gree n ber g P D. Pr os pects f or a d o pti ve T cell t hera p y. C urr O pi n 
I m m u n ol 1 9 9 7; 9( 5): 7 0 2- 7 0 8. 
 
1 0.  R ose n ber g S A, Restif o N P, Ya n g J C, M or ga n R A, D u dle y M E. A d o pti ve cell tra nsfer: a 
cli nical pat h t o effecti ve ca ncer i m m u n ot hera p y. Nat Re v Ca ncer 2 0 0 8; 8( 4): 2 9 9- 3 0 8.  
 
1 1.  J u ne C H. A d o pti ve T cell t hera p y f or ca ncer i n t h e cli nic. J Cli n I n vest 
2 0 0 7; 1 1 7( 6): 1 4 6 6- 1 4 7 6. 
 
1 2.  J u ne C H. Pri nci ples of a d o pti ve T cell ca n cer t hera p y. J Cli n I n vest 2 0 0 7; 1 1 7( 5): 1 2 0 4-
1 2 1 2.  
 
1 3.  P orter D L, J u ne C H. T-cell rec o nstit uti o n a n d e x pa nsi o n after he mat o p oietic ste m cell 
trans pla ntati o n: ' T' it u p! B o ne Marr o w Tra ns pla nt 2 0 0 5; 3 5( 1 0): 9 3 5- 9 4 2. 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 9 8  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
 
1 4.  Fear o n D T, Carr oll M C. Re g ulati o n of B l y m p h o c yt e res p o nses t o f orei g n a n d self-
a nti ge ns b y t he C D 1 9/ C D 2 1 c o m ple x. A n n u Re v I m m u n ol 2 0 0 0; 1 8: 3 9 3- 4 2 2.: 3 9 3- 4 2 2.  
 
1 5.  Free d ma n A S, B o y d A W, Bie ber F R et al. N or mal cell ular c o u nter parts of B cell c hr o nic 
l y m p h oc ytic le u k e mia. Bl o o d 1 9 8 7; 7 0( 2): 4 1 8- 4 2 7. 
 
1 6.  Uc k u n F M, Le d better J A. I m m u n o bi ol o gi c differe nces bet wee n n or mal a n d le u ke mic 
h u ma n B- cell prec urs ors. Pr oc Natl Aca d Sci U S A 1 9 8 8; 8 5( 2 2): 8 6 0 3- 8 6 0 7. 
 
1 7.  Le d b etter J A, Ra bi n o vitc h P S, J u ne C H, S o n g C W, Clar k E A, Uc k u n F M. A nti ge n-
i n de pe n de nt re g ul ati o n of c yt o pl as mic calci u m i n B cells wit h a 1 2- k Da B-cell gr o wt h 
fact or a n d a nti- C D 1 9. Pr oc Natl Aca d Sci U S A 1 9 8 8; 8 5: 1 8 9 7- 1 9 0 1. 
 
1 8.  Sta me n k o vic I, See d B. C D 1 9, t he earliest differe ntiati o n a nti ge n of t he B cell li nea ge, 
bears t hree e xtracell ular i m m u n o gl o b uli n-li ke d o mai ns a n d a n E pstei n- Barr vir us-relate d 
c yt o plas mic tail. J E x p Me d 1 9 8 8; 1 6 8( 3): 1 2 0 5- 1 2 1 0. 
 
1 9.  Te d der T F, Is aacs C M. Is olati o n of c D N As e n c o di n g t he C D 1 9 a nti ge n of h u ma n a n d 
m o use B l y m p h o c ytes. A ne w me m ber of t he i m m u n o gl o b uli n s u perfa mil y. J I m m u n ol 
1 9 8 9; 1 4 3( 2): 7 1 2- 7 1 7. 
 
2 0.  Uc k u n F M, J aszcz W, A m br us J L et al. Detaile d st u dies o n e x pressi o n a n d f u ncti o n of 
C D 1 9 s urface deter mi na nt b y usi n g B 4 3 m o n ocl o nal a nti b o d y a n d t he cli nical p ote ntial 
of a nti- C D 1 9 i m m u n ot o xi ns. Bl o o d 1 9 8 8; 7 1( 1): 1 3- 2 9.  
 
2 1.  Sc he uer ma n n R H, Racila E. C D 1 9 a nti ge n i n le u k e mia a n d l y m p h o m a dia g n osis a n d 
i m m u n ot hera p y. Le u k L y m p h o ma 1 9 9 5; 1 8( 5- 6): 3 8 5- 3 9 7. 
 
2 2.  Sc h w o nze n M, P o hl C, Stei n metz T et al. I m m u n o p he n ot y pi n g of l o w- gra d e B-cell 
l y m p h o ma i n bl o o d a n d b o ne marr o w: p o or c orrelati o n bet wee n i m m u n o p he n ot y p e a n d 
c yt ol o gic al/ hist ol o gical classificati o n. Br J Hae mat ol 1 9 9 3; 8 3( 2): 2 3 2- 2 3 9. 
 
2 3.  E k O, Rea ma n G H, Cr a n ks ha w D L, C helstr o m L M, M yers D E, Uc k u n F M. C o m bi ne d 
t hera pe utic effic ac y of t h e t h y mi d ylate s y nt has e i n hi bit or Z D 1 6 9 4 ( T o m u d e x) a n d t he 
i m m u n ot o xi n B 4 3(a nti- C D 1 9)- P A P i n a S CI D m o use m o del of h u ma n B-li nea ge ac ute 
l y m p h o blastic le u ke mia. Le u k L y m p h o m a 1 9 9 8; 2 8( 5- 6): 5 0 9- 5 1 4. 
 
2 4.  E k O, Ga y n o n P, Zere n T, C helstr o m L M, M yers D E, Uc k u n F M. Treat me nt of h u ma n 
B-cell prec urs or le u k e mia i n S CI D mice b y usi n g a c o m bi nati o n of t he a n ti- C D 1 9 
i m m u n ot o xi n B 4 3- P A P wit h t he sta n dar d c h e m ot hera pe utic dr u gs vi ncristi ne, 
met h yl pre d nis ol o ne, a n d L- as para gi nase. Le u k L y m p h o ma 1 9 9 8; 3 1( 1- 2): 1 4 3- 1 4 9.  
 
2 5.  Gri b be n J G, H osi n g C, Mal o ne y D G. Ste m cell tra ns pla ntati o n f or i n d ole nt l y m p h o m a 
an d c hr o nic l y m p h oc ytic le u ke mia. 2 0 1 1; 2 0 1 1/ 0 1/ 1 4( 1 S u p pl): S 6 3- S 7 0. 
 
2 6.  Li Q, H u ds o n W, Wa n g D, Ber ve n E, Uc k u n F M, Kerse y J H. P har mac o ki n etics a n d 
bi o distri b uti o n of ra di oi m m u n oc o nj u gates of a nti- C D 1 9 a nti b o d y a n d si n gle-c hai n F v f or 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 9 9  of 1 0 8 
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
treat me nt of h u ma n B- cell mali g na nc y. Ca n cer I m m u n ol I m m u n ot her 1 9 9 8; 4 7( 3): 1 2 1-
1 3 0.  
 
2 7.  
Messi n ger Y, Ya nis h e vs ki Y, A vra mis VI et al. Treat me nt of h u ma n B-cell prec urs or 
le u ke mia i n S CI D mic e usi n g a c o m bi nati o n of t h e i n vesti gati o nal bi ot hera p e utic a ge nt 
B 4 3 - P A P wit h c yt osi n e ara bi n osi de. Cli n Ca ncer Res 1 9 9 6; 2( 9): 1 5 3 3- 1 5 4 2. 
 
2 8.  Bejc e k B E, Wa n g D, Ber ve n E et al. De v el o p me nt a n d c haracterizati o n of t hree 
rec o m bi na nt si n gle c h ai n a nti b o d y fra g me nts (sc F vs) directe d a gai nst t he C D 1 9 a nti ge n. 
Ca ncer Res 1 9 9 5; 5 5( 1 1): 2 3 4 6 -2 3 5 1.  
 
2 9.  Bre ntje ns RJ, Lat o u c he J B, Sa nt os E et al. Era dicati o n of s yste mic B -cell t u m ors b y 
ge n eticall y tar gete d h u m a n T l y m p h oc yt es c o -sti m ulate d b y C D 8 0 a n d i nt erle u ki n-1 5. 
Nat Me d 2 0 0 3; 9( 3 ): 2 7 9-2 8 6.  
 
3 0.  C he n C L, Le vi n e A, Ra o A et al. Cli nical p har mac o ki netics of t he C D 1 9 rece pt or-
directe d t yr osi ne ki nas e i n hi bit or B 4 3- Ge nistei n i n patie nts wit h B-li nea ge l y m p h oi d 
mali g na n cies. J Cli n P har mac ol 1 9 9 9; 3 9( 1 2): 1 2 4 8- 1 2 5 5.  
 
3 1.  C o o per LJ, T o p p M S, Serra n o L M et al. T-cell cl o nes ca n be re n d ere d s p ecific f or C D 1 9: 
t o war d t he sele cti ve a u g me ntati o n of t he graft- vers us- B-li nea ge le u ke mia effect. Bl o o d 
2 0 0 3; 1 0 1( 4): 1 6 3 7- 1 6 4 4. 
 
3 2.  Ki pri ya n o v S M, M ol de n ha uer G, Stra uss G, Little M. Bis pecific C D 3 x C D 1 9 dia b o d y 
f or T cell- m e diate d l ysis of mali g na nt h u ma n B cells. I nt J Ca ncer 1 9 9 8; 7 7( 5): 7 6 3- 7 7 2. 
 
3 3.  Ki pri ya n o v S M, M ol de n ha uer G, Bra u na gel M et al. Effect of d o mai n or der o n t he 
acti vit y of bacteri all y pr o d uce d bis pecifi c si n gle-c hai n F v a nti b o dies. J M ol Bi ol 
2 0 0 3; 3 3 0( 1): 9 9- 1 1 1. 
 
3 4.  Le Gall F, Ki pri ya n o v S M, M ol de n ha uer G, Littl e M. Di-, tri- a n d tetra meric si n gle c hai n 
F v a nti b o d y fra g me nts a gai nst h u ma n C D 1 9: effect of vale nc y o n cell bi n di n g. F E B S Lett 
1 9 9 9; 4 5 3( 1- 2): 1 6 4- 1 6 8.  
 
3 5.  
Messi n ger Y, Ya nis h e vs ki Y, E k O et al. I n vi v o t o xicit y a n d p h ar mac o ki n etic feat ures of 
B 4 3 (a nti- C D 1 9)- ge nistei n i m m u n oc o nj u gate i n n o n h u ma n pri mates. Cli n Ca ncer Res 
1 9 9 8; 4( 1): 1 6 5- 1 7 0. 
 
3 6.  Nic h ols o n I C, Le nt o n K A, Little DJ et al. C o nstr ucti o n a n d c haracterisati o n of a 
f u ncti o nal C D 1 9 s pecific si n gle c h ai n F v fra g me nt f or i m m u n ot hera p y of B li nea ge 
le u kae mia a n d l y m p h o m a. M ol I m m u n ol 1 9 9 7; 3 4( 1 6 -1 7): 1 1 5 7 -1 1 6 5.  
 
3 7.  Uc k u n F M, Y a nis he vs ki Y, T u mer N et al. P har mac o ki netic feat ures, i m m u n o ge ni cit y, 
a n d t o xicit y of B 4 3 (a nti-C D 1 9) -p o ke wee d a nti vir al pr otei n i m m u n ot o xi n i n c y n o m ol g us 
m o n ke ys. Cli n Ca ncer Res 1 9 9 7; 3( 3): 3 2 5 -3 3 7.  

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 1 0 0 of 1 0 8  
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
 
3 8.  
Wa n g D, Li Q, H u ds o n W, Ber ve n E, Uc k u n F, Kerse y J H. Ge nerati o n a n d 
c haracteriz ati o n of a n a nti- C D 1 9 si n gle-c hai n F v i m m u n ot o xi n c o m p ose d of C-ter mi nal 
dis ulfi de-li n ke d d g R T A. Bi oc o nj u g C he m 1 9 9 7; 8( 6): 8 7 8- 8 8 4.  
 
3 9.  Gr oss G, Wa ks T, Es h har Z. E x pressi o n of i m m u n o gl o b uli n- T-cell rece pt or c hi meric 
m olec ules as f u ncti o nal rece pt ors wit h a nti b o d y-t y pe s pecificit y. Pr oc Natl Aca d Sci U S 
A 1 9 8 9; 8 6( 2 4): 1 0 0 2 4- 1 0 0 2 8. 
 
4 0.  Pi nt h us J H, Wa ks T, Ka uf ma n- Fra ncis K et al. I m m u n o- Ge ne T h era p y of Esta blis he d 
Pr ostate T u m ors Usi n g C hi meric Rece pt or-re dir ecte d H u ma n L y m p h o c ytes. Ca ncer Res 
2 0 0 3; 6 3( 1 0): 2 4 7 0- 2 4 7 6. 
 
4 1.  
M ulla ne y B P, Palla vici ni M G. Pr otei n- pr otei n i nteracti o ns i n he mat ol o g y a n d p ha ge 
dis pla y. E x p He mat ol 2 0 0 1; 2 9( 1 0): 1 1 3 6- 1 1 4 6. 
 
4 2.  Br oc k er T, K arjalai n e n K. A d o pti ve t u m or i m m u nit y me diate d b y l y m p h oc ytes beari n g 
m o difie d a nti ge n-s pecific rece pt ors. A d va nces i n i m m u n ol o g y 1 9 9 8; 6 8: 2 5 7- 2 6 9.  
 
4 3.  J une C H, Blazar B R, Rile y J L. L y m p h o c yt e S u bset E n gi neeri n g: t o ols, trials a n d 
tri b ulati o ns. Nat ure Re vi e ws I m m u n ol o g y 2 0 0 9; 9: 7 0 4- 7 1 6. 
 
4 4.  K o h n D B, D otti G, Bre ntje ns R et al. C A R S o n Trac k i n t he Cli nic: Re p ort of a Meeti n g 
Or ga niz e d b y t h e Bl o o d a n d Marr o w Tra ns pla nt Cli nical Trials Net w or k ( B M T C T N) 
S u b- C o m mittee o n Cell a n d Ge ne T hera p y. Was hi n gt o n D. C., Ma y 1 8, 2 0 1 0. 2 0 1 1;i n 
press. 
 
4 5.  Sa delai n M, Ri viere I, Bre ntje ns R. Tar geti n g t u m o urs wit h ge n eticall y e n h a nce d T 
l y m p h oc ytes. Nat Re v Ca ncer 2 0 0 3; 3( 1): 3 5- 4 5. 
 
4 6.  Fiel di n g A K, Ric har ds S M, C h o pra R et al. O utc o me of 6 0 9 a d ults after rel a pse of ac ute 
l y m p h o blastic le u ke mia ( A L L); a n M R C U K A L L 1 2/ E C O G 2 9 9 3 st u d y. Bl o o d 
2 0 0 7; 1 0 9( 3): 9 4 4- 9 5 0. 
 
4 7.  Gr u p p S A, Kal os M, Barrett D et al. C hi meric A nti ge n Rece pt or- M o difi e d T Cells f or 
Ac ute L y m p h oi d Le u ke mia. N E n gl J Me d 2 0 1 3. 
 
4 8.  P orter D L, Le vi ne B L, K al os M, Ba g g A, J u ne C H. C hi meric a nti ge n rece pt or- m o difie d 
T cells i n c hr o nic l y m p h oi d le u ke mia. N E n gl J Me d 2 0 1 1; 3 6 5( 8): 7 2 5- 7 3 3. 
 
4 9.  Nic h ols o n I C, Le nt o n K A, Little DJ et al. C o nstr ucti o n a n d c haracterisati o n of a 
f u ncti o nal C D 1 9 s pecific si n gle c h ai n F v fra g me nt f or i m m u n ot hera p y of B li nea ge 
le u kae mia a n d l y m p h o m a. M ol I m m u n ol 1 9 9 7; 3 4( 1 6- 1 7): 1 1 5 7- 1 1 6 5. 
 
5 0.  I mai C, Mi hara K, A n drea ns k y M et al. C hi meri c rece pt ors wit h 4- 1 B B si g n ali n g 
ca pacit y pr o v o k e p ote nt c yt ot o xicit y a gai nst ac ute l y m p h o blastic le u ke mia. Le u k e mia 
2 0 0 4; 1 8( 4): 6 7 6- 6 8 4. 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 1 0 1 of 1 0 8  
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
 
5 1.  
Mil o ne M C, Fis h J D, Car pe nit o C et al. C hi meric Rece pt ors C o ntai ni n g C D 1 3 7 Si g nal 
Tra ns d ucti o n D o mai ns Me diate E n ha n ce d S ur vi val of T Cells a n d I ncrease d 
A ntile u ke mic Efficac y I n Vi v o. M ol T her 2 0 0 9; 1 7( 8): 1 4 5 3- 1 4 6 4. 
 
5 2.  Gr oss G, Es h har Z. E n d o wi n g T cells wit h a nti b o d y s pecificit y usi n g c hi meric T cell 
rece pt ors. F A S E B J 1 9 9 2; 6( 1 5): 3 3 7 0- 3 3 7 8. 
 
5 3.  Sa delai n M, Ri viere I, Bre ntje ns R. Tar geti n g t u m o urs wit h ge n eticall y e n h a nce d T 
l y m p h oc ytes. Nat Re v Ca ncer 2 0 0 3; 3( 1): 3 5- 4 5. 
 
5 4.  
M u ul L M, T usc h o n g L M, S oe ne n S L et al. Persiste nce a n d e x pressi o n of t he a de n osi ne 
dea mi nase ge n e f or 1 2 ye ars a n d i m m u ne reacti o n t o ge n e tra nsfer c o m p o n e nts: l o n g-
ter m res ults of t he first cli nical ge ne t hera p y trial. Bl o o d 2 0 0 3; 1 0 1( 7): 2 5 6 3- 2 5 6 9. 
 
5 5.  Yee C, T h o m ps o n J A, B yr d D et al. A d o pti ve T cell t hera p y usi n g a nti ge n-s pecific C D 8 + 
T cell cl o nes f or t he treat me nt of patie nts wit h metastatic mela n o ma: i n vi v o persiste nce, 
mi grati o n, a n d a ntit u m or effect of tra nsferre d T cells. Pr oc Natl Aca d Sci U S A 
2 0 0 2; 9 9( 2 5): 1 6 1 6 8- 1 6 1 7 3. 
 
5 6.  D u dle y M E, W u n derlic h J R, R o b bi ns P F et al. Ca ncer re gressi o n a n d a ut oi m m u nit y i n 
patie nts after cl o nal re p o p ulati o n wit h a ntit u m or l y m p h oc ytes. Scie n ce 
2 0 0 2; 2 9 8( 5 5 9 4): 8 5 0- 8 5 4. 
 
5 7.  
Mits u yas u R T, A nt o n P A, Dee ks S G et al. Pr ol o n ge d s ur vi val a n d tiss ue traffic ki n g 
f oll o wi n g a d o pti ve tr a nsf er of C D 4zeta ge n e- m o difie d a ut ol o g o us C D 4( +) a n d C D 8( +) T 
cells i n h u ma n  i m m u n o deficie nc y vir us-i nfecte d s u bjects. Bl o o d 2 0 0 0; 9 6( 3): 7 8 5- 7 9 3. 
 
5 8.  
Wal ker R E, Bec htel C M, Nataraj a n V et al. L o n g-ter m i n vi v o s ur vi val of rece pt or-
m o difie d s y n ge n eic T cells i n patie nts wit h h u ma n i m m u n o deficie nc y vir us i nfecti o n. 
Bl o o d 2 0 0 0; 9 6( 2): 4 6 7- 4 7 4. 
 
5 9.  Ri d dell S R, Elli ott M, Le wi ns o h n D A et al. T- cell me diate d rejecti o n of ge n e- m o difie d 
HI V-s pecific c yt ot o xic T l y m p h oc ytes i n HI V-i nf ecte d patie nts. N at Me d 1 9 9 6; 2( 2): 2 1 6-
2 2 3.  
 
6 0.  D u m mer W, Niet ha m mer A G, Baccala R et al. T cell h o me ostatic pr oliferati o n elicits 
effecti ve a ntit u m or a ut oi m m u nit y. J Cli n I n vest 2 0 0 2; 1 1 0( 2): 1 8 5- 1 9 2. 
 
6 1.  S ur h C D, S pre nt J. H o me ostatic T cell pr oliferati o n: h o w far ca n T cells be acti vate d t o 
self-li ga n ds? J E x p Me d 2 0 0 0; 1 9 2( 4): F 9- F 1 4. 
 
6 2.  G ol drat h A W, Be v a n MJ. Selecti n g a n d mai ntai ni n g a di v erse T-cell re pert oire. Nat ur e 
1 9 9 9; 4 0 2( 6 7 5 9): 2 5 5- 2 6 2. 
 
6 3.  Kle ba n off C A, K h o n g H T, A nt o n y P A, Pal mer D C, Restif o N P. Si n ks, s u p press ors a n d 
a nti ge n prese nt ers: h o w l y m p h o de pleti o n e n ha nces T cell- me diate d t u m or 
i m m u n ot hera p y. Tre n ds I m m u n ol 2 0 0 5; 2 6( 2): 1 1 1- 1 1 7. 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 1 0 2 of 1 0 8  
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
 
6 4.  Ra p o p ort A, Sta dt ma uer E A, A q ui N et al. Rest or ati o n of i m m u nit y i n l y m p h o pe nic 
i n di vi d uals wit h ca ncer b y vacci nati o n a n d a d o pti ve T-cell tra nsfer. Nat M e d 
2 0 0 5; 1 1( 1 1): 1 2 3 0- 1 2 3 7. 
 
6 5.  P orter D L, Le vi ne B L, K al os M, Ba g g A, J u ne C H. C hi meric a nti ge n rece pt or- m o difie d 
T cells i n c hr o nic l y m p h oi d le u ke mia. N E n gl J Me d 2 0 1 1; 3 6 5( 8): 7 2 5- 7 3 3. 
 
6 6.  La p ort G G, Le vi ne B L, Sta dt ma uer E A et al. A d o pti ve tra nsfer of c osti m ulate d T cells 
i n d uces l y m p h oc yt osis i n patie nts wit h rela pse d/r efract or y n o n- H o d g ki n l y m p h o ma 
f oll o wi n g C D 3 4 +-select e d he mat o p oietic cell tra ns pla ntati o n. Bl o o d 2 0 0 3; 1 0 2( 6): 2 0 0 4-
2 0 1 3.  
 
6 7.  Kal os M, Le vi ne B L, P orter D L et al. T cells wit h c hi meric a nti ge n rece pt ors ha ve p ote nt 
a ntit u m or effects a n d ca n esta blis h me m or y i n pati e nts wit h a d va nce d l e u ke mia. Sci 
Tra nsl Me d 2 0 1 1; 3( 9 5): 9 5ra 7 3. 
 
6 8.  Cal o ger o A, De Leij Y F M H, M ul der N H, H os p ers G A P. Rec o m bi na nt T-cell rece pt ors: 
A n i m m u n ol o gic li n k t o ca ncer t hera p y. J o ur nal of I m m u n ot hera p y 2 0 0 0; 3 9 3- 4 0 0.  
 
6 9.  Cla y T M, M orse M, L yerl y H K. Re dir ecti n g c yt ot o xic T l y m p h oc yte res p o nses wit h T-
cell rece pt or tra ns ge nes. E x pert O pi ni o n o n Bi ol o gical T hera p y 2 0 0 2 2 0 0 2; 3 5 3- 3 6 0.  
 
7 0.  H o m bac h A, He user C, A b ke n H. T he rec o m bi na nt T cell rece pt or strate g y: i nsi g hts i nt o 
str uct ure a n d f u ncti o n of rec o m bi na nt i m m u n orece pt ors o n t he wa y t o w ar ds a n o pti mal 
rece pt or desi g n f or cell ular i m m u n ot hera p y. C urr Ge ne T her 2 0 0 2; 2( 2): 2 1 1- 2 2 6. 
 
7 1.  P ule M, Fi n ne y H, La ws o n A. Artificial T-cell rece pt ors. C yt ot hera p y 2 0 0 3; 5: 2 1 1- 2 2 6. 
 
7 2.  Sa delai n M, Ri viere I, Bre ntje ns R. Tar geti n g t u m o urs wit h ge n eticall y e n h a nce d T 
l y m p h oc ytes. Nat Re v Ca ncer 2 0 0 3; 3( 1): 3 5- 4 5. 
 
7 3.  Bre ntje ns RJ, Lat o u c he J B, Sa nt os E et al. Era dicati o n of s yste mic B-cell t u m ors b y 
ge n eticall y tar gete d h u m a n T l y m p h oc yt es c o-sti m ulate d b y C D 8 0 a n d i nt erle u ki n- 1 5. 
Nat Me d 2 0 0 3; 9( 3): 2 7 9- 2 8 6.  
 
7 4.  C o o per LJ, T o p p M S, Serra n o L M et al. T-cell cl o nes ca n be re n d ere d s p ecific f or C D 1 9: 
t o war d t he sele cti ve a u g me ntati o n of t he graft- vers us- B-li nea ge le u ke mia effect. Bl o o d 
2 0 0 3; 1 0 1( 4): 1 6 3 7- 1 6 4 4. 
 
7 5.  R ossi g C, B ollar d C M, N uc hter n J G, Merc ha nt D A, Bre n ner M K. Tar geti n g of G( D 2)-
p ositi ve t u m or cells b y h u ma n T l y m p h oc ytes e n gi neere d t o e x press c hi meric T-cell 
rece pt or ge nes. I nter nati o nal J o ur nal of Ca ncer 2 0 0 1 2 0 0 1; 9 4: 2 2 8- 2 3 6. 
 
7 6.  Serra n o L M, Pfeiffer T, Oli vares S et al. Differe ntiati o n of nai ve c or d- bl o o d T cells i nt o 
C D 1 9-s pecific c yt ol ytic effect ors f or p osttra ns pla ntati o n a d o pti ve i m m u n ot hera p y. Bl o o d 
2 0 0 6; 1 0 7( 7): 2 6 4 3- 2 6 5 2. 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 1 0 3 of 1 0 8  
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
 
7 7.  
Wille mse n R A, Weijte ns M E, R o ntelta p C et al. Grafti n g pri mar y h u ma n T l y m p h oc ytes 
wit h ca ncer-s pecific c hi meric si n gl e c hai n a n d t w o c hai n T C R. Ge ne T h er 
2 0 0 0; 7( 1 6): 1 3 6 9- 1 3 7 7. 
 
7 8.  Bre ntje ns R, Y e h R, Ber nal Y, Ri viere I, Sa del ai n M. Treat me nt of C hr o ni c L y m p h o c yti c 
Le u k e mia Wit h Ge neticall y Tar gete d A ut ol o g o us T Cells: Case Re p ort of a n U nf ores ee n 
A d verse E v e nt i n a P hase I Cli nical Tri al. 2 0 1 0; 1 8( 4): 6 6 6- 6 6 8. 
 
7 9.  Es h har Z, Wa ks T, Be n d a vi d A, Sc hi n dler D G. F u ncti o nal e x pressi o n of c hi meric 
rece pt or ge nes i n h u ma n T cells. J o ur nal of I m m u n ol o gical Met h o ds 2 0 0 1; 2 4 8: 6 7- 7 6. 
 
8 0.  Fi n ne y H M, La ws o n A D G, Be b bi n gt o n C R, Weir A N C. C hi meric rece pt ors pr o vi di n g 
b ot h pri mar y a n d c osti m ulat or y si g nali n g i n T cells fr o m a si n gle ge ne pr o d uct. J o ur nal 
of I m m u n ol o g y 1 9 9 8; 1 6 1: 2 7 9 1- 2 7 9 7.  
 
8 1.  Fi n ne y H M, A k b ar A N, La ws o n A D G. Acti vati o n of resti n g h u ma n pri mar y T cells wit h 
c hi meric rece pt ors: C osti m ulati o n fr o m C D 2 8, i n d uci ble c osti m ulat or, C D 1 3 4, a n d 
C D 1 3 7 i n series wit h si g nals fr o m t he T C R zeta c hai n. J o ur nal of I m m u n ol o g y 
2 0 0 4; 1 7 2( 1): 1 0 4- 1 1 3. 
 
8 2.  Frie d ma n n- M or vi ns ki D, Be n da vi d A, Wa ks T, Sc hi n dler D, Es h har Z. Re directe d 
pri mar y T cells har b ori n g a c hi meric rece pt or re q uire c osti m ulati o n f or t heir a nti ge n-
s pecific acti vati o n. Bl o o d 2 0 0 5; 1 0 5( 8): 3 0 8 7- 3 0 9 3. 
 
8 3.  Kra use A, G u o H F, Lat o uc he J B, Ta n C, C he u n g N K, Sa delai n M. A nti ge n- de pe n de nt 
C D 2 8 si g nali n g selecti vel y e n h a nces s ur vi val a n d pr oliferati o n i n ge neticall y m o difie d 
acti vate d h u ma n pri mar y T l y m p h oc ytes. J E x p Me d 1 9 9 8; 1 8 8( 4): 6 1 9- 6 2 6. 
 
8 4.  
Ma her J, Bre ntje ns RJ, G u nset G, Ri viere I, Sa del ai n M. H u ma n T-l y m p h o c yt e 
cyt ot o xicit y a n d pr oliferati o n directe d b y a si n gle c hi meric T C R zeta/ C D 2 8 rece pt or. 
Nat ure Bi otec h n ol o g y 2 0 0 2; 2 0( 1): 7 0- 7 5. 
 
8 5.  Car pe nit o C, Mil o ne M C, Hassa n R et al. C o ntr ol of lar ge esta blis he d t u m or xe n o grafts 
wit h ge n eticall y re-tar get e d h u ma n T cells c o nt ai ni n g C D 2 8 a n d C D 1 3 7 d o mai ns. Pr oc 
Natl Aca d Sci U S A 2 0 0 9; 1 0 6( 9): 3 3 6 0- 3 3 6 5. 
 
8 6.  J u ne C H, Blazar B R, Rile y J L. L y m p h o c yt e S u bset E n gi neeri n g: t o ols, trials a n d 
tri b ulati o ns. Nat ure Re vi e ws I m m u n ol o g y 2 0 0 9; 9: 7 0 4- 7 1 6. 
 
8 7.  
Wa n g G P, Le vi ne B L, Bi n der G K et al. A nal ysis of le nti viral vect or i nte grati o n i n HI V + 
st u d y s u bjects r ecei vi n g a ut ol o g o us i nf usi o ns of ge ne m o difie d C D 4 + T cells. M ol T her 
2 0 0 9; 1 7( 5): 8 4 4- 8 5 0. 
 
8 8.  Ra p o p ort A P, Le vi ne B L, Ba dr os A et al. M olec ul ar re missi o n of C M L after 
a ut otra ns pla ntati o n f oll o we d b y a d o pti ve tra nsfer of c osti m ulate d a ut ol o g o us T cells. 
B o ne Marr o w Tra ns pla nt 2 0 0 4; 3 3( 1): 5 3- 6 0. 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 1 0 4 of 1 0 8  
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
 
8 9.  Ra p o p ort A P, Sta dt ma uer E A, A q ui N et al. Ra pi d i m m u ne rec o ver y a n d graft- vers us-
h ost disease-li ke e n graft m e nt s y n dr o me f oll o wi n g a d o pti ve tr a nsfer of C osti m ulate d 
a ut ol o g o us T cells. Cli n Ca ncer Res 2 0 0 9; 1 5( 1 3): 4 4 9 9- 4 5 0 7.  
 
9 0.  Le vi n e B L, Ber nstei n W B, Ar o ns o n N E et al. A d o pti ve Tra nsfer of C osti m ulate d C D 4 + 
T cells I n d uces E x pa nsi o n of Peri p heral T Cells a n d Decrease d C C R 5 E x pressi o n i n HI V 
I nfecti o n. N at Me d 2 0 0 2; 8( 1): 4 7- 5 3. 
 
9 1.  La p ort G G, Le vi ne B L, Sta dt ma uer E A et al. A d o pti ve tra nsfer of c osti m ulate d T cells 
i n d uces l y m p h oc yt osis i n patie nts wit h rela pse d/r efract or y n o n- H o d g ki n l y m p h o ma 
f oll o wi n g C D 3 4 +-select e d he mat o p oietic cell tra ns pla ntati o n. Bl o o d 2 0 0 3; 1 0 2( 6): 2 0 0 4-
2 0 1 3.  
 
9 2.  Cr uz C R, Ha nle y PJ, Li u H et al. A d verse e v e nts f oll o wi n g i nf usi o n of T cells f or 
a d o pti ve i m m u n ot hera p y: a 1 0- year e x perie nce. 2 0 1 0; 2 0 1 0/ 0 5/ 0 1( 6): 7 4 3- 7 4 9.  
 
9 3.  He nter JI, H or ne A, Aric o M et al. H L H- 2 0 0 4: Di a g n ostic a n d t hera pe utic g ui deli nes f or 
he m o p ha g oc ytic l y m p h o histi oc yt osis. Pe diatr Bl o o d Ca ncer 2 0 0 7; 4 8( 2): 1 2 4- 1 3 1.  
 
9 4.  Bre ntje ns R, Y e h R, Ber nal Y, Ri viere I, Sa del ai n M. Treat me nt of c hr o nic l y m p h oc ytic 
le u ke mia wit h ge neticall y tar gete d a ut ol o g o us T cells: case re p ort of a n u nf oresee n 
a d verse e ve nt i n a p h ase I cli nical trial. M ol T her 2 0 1 0; 1 8( 4): 6 6 6- 6 6 8. 
 
9 5.  
M or ga n R A, Ya n g J C, Kita n o M, D u dle y M E, La ure nc ot C M, R ose n ber g S A. Case 
re p ort of a s eri o us a d v ers e e ve nt f oll o wi n g t he a d mi nistrati o n of T cells tra ns d uce d wit h a 
c hi meric a nti ge n rece pt or rec o g nizi n g E R B B 2. M ol T her 2 0 1 0; 1 8( 4): 8 4 3- 8 5 1. 
 
9 6.  Press M F, C or d o n- Car d o C, Sla m o n DJ. E x pressi o n of t he H E R- 2/ ne u pr ot o- o nc o ge ne i n 
n or mal h u ma n a d ult a n d fetal tiss ues. O nc o ge n e 1 9 9 0; 5( 7): 9 5 3- 9 6 2. 
 
9 7.  P orter D L, Le vi ne B L, B u ni n N et al. A p hase 1 trial of d o n or l y m p h o c yt e i nf usi o ns 
e x pa n de d a n d acti vate d e x vi v o via C D 3/ C D 2 8 c osti m ulati o n. Bl o o d 2 0 0 6; 1 0 7( 4): 1 3 2 5-
1 3 3 1.  
 
9 8.  Cella D, J e nse n S E, We bster K et al. Meas uri n g h ealt h-rel ate d q ualit y of life i n le u ke mia: 
t he F u ncti o nal Assess me nt of Ca ncer T h era p y--Le u ke mia ( F A C T- Le u) q uesti o n naire. 
Val ue Healt h 2 0 1 2; 1 5( 8): 1 0 5 1- 1 0 5 8.  
 
9 9.  A cli nical e val uati o n of t he I nter n ati o nal L y m p h o ma St u d y Gr o u p classificati o n of n o n-
H o d g ki n's l y m p h o ma. T h e N o n- H o d g ki n's L y m p h o ma Classificati o n Pr oject. Bl o o d 
1 9 9 7; 8 9( 1 1): 3 9 0 9- 3 9 1 8. 
 1 0 0.  C hes o n B D, Gree n b er g P L, Be n n ett J M et al. Cli nical a p plicati o n a n d pr o p osal f or 
m o dificati o n of t he I nter nati o nal W or ki n g Gr o u p (I W G) res p o nse criteri a i n 
m yel o d ys plasia. Bl o o d 2 0 0 6; 1 0 8( 2): 4 1 9- 4 2 5. 
 1 0 1.  A p pel ba u m F R, R ose n bl u m D, Arceci RJ et al. E n d p oi nts t o esta blis h t he efficac y of 
ne w a ge nts i n t he treat me nt of ac ute le u k e mia. Bl o o d 2 0 0 7; 1 0 9( 5): 1 8 1 0- 1 8 1 6. 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 1 0 5 of 1 0 8  
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
 1 0 2.  C hes o n B D, Be n nett J M, K o pec k y KJ et al. Re vise d rec o m me n d ati o ns of t he 
I nter nati o nal W or ki n g Gr o u p f or Dia g n osis, Sta n dar dizati o n of Res p o nse Criteria, 
Treat me nt O utc o m es, a n d Re p orti n g Sta n dar ds f or T hera p e utic Trials i n Ac ute M yel oi d 
Le u k e mia. J Cli n O nc ol 2 0 0 3; 2 1( 2 4): 4 6 4 2- 4 6 4 9. 
 1 0 3.  D u dle y M E, W u n derlic h J R, Ya n g J C et al. A d o pti ve cell tra nsfer t hera p y f oll o wi n g n o n-
m yel oa bl ati ve b ut l y m p h o de pleti n g c he m ot hera p y f or t he treat me nt of patie nts wit h 
refract or y met astatic mel a n o ma. J Cli n O nc ol 2 0 0 5; 2 3( 1 0): 2 3 4 6- 2 3 5 7. 
 1 0 4.  La m ers C H, Sleijfer S, V ult o A G et al. Treat me nt of metastatic re n al cell carci n o ma wit h 
aut ol o g o us T-l y m p h oc yt es ge neticall y retar gete d a gai nst car b o ni c a n h y drase I X: first 
cli nical e x perie nce. J Cli n O nc ol 2 0 0 6; 2 4( 1 3):e 2 0-e 2 2. 
 1 0 5.  Cartr o n G, Watier H, G ol a y J, S olal- Celi g n y P. Fr o m t he be nc h t o t he be dsi de: wa ys t o 
i mpr o ve rit u xi ma b efficac y. Bl o o d 2 0 0 4; 1 0 4( 9): 2 6 3 5- 2 6 4 2.  
1 0 6.     R ussell J A, Walle y K R, Si n ger J et al. Vas o pressi n vers us n ore pi ne p hri n e i nf usi o n i n 
patie nts  wit h se ptic s h oc k. N E n gl J Me d 2 0 0 8; 3 5 8( 9): 8 7 7 -8 8 7.  
 
 
 
 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 1 0 7 of 1 0 8  
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
A p p e n di x 2 .  Cl a s sifi c ati o n of Gr aft- V er s u s- H o st- Di s e a s e 
 
Cl assific ati o n of C hr o nic Gr aft- Vers us- H ost Dise ase 
 
Li mite d C hr o nic G V H D 
 
Eit her or B ot h: 
1.  L ocalize d s ki n i n v ol ve me nt 
 
2.  He patic d ysf u n cti o n d ue t o c hr o nic G V H D 
 
E xte nsi ve C hr o nic G V H D 
  
Eit her: 
1.    Ge neral s ki n i n v ol ve me nt 
  
  
 
  
 
Or  
  
  
 
2.    L ocalize d s ki n i n v ol ve me nt a n d/ or he patic d ysf u ncti o n d ue t o c hr o nic G V H D 
 
 
Pl us: 
3a).   Li ver hist ol o g y s h o wi n g a g gressi ve h e patitis, bri d gi n g necr osis or cirr h osis 
 
 Or  
 
  3 b).  I n v ol ve me nt of e yes:  Sc hir mer’s test wit h less t ha n 5 m m wetti n g 
 
  
 
Or  
  
 
  
  
3c).  I n v ol ve me nt of mi n or sali var y gla n ds or oral m uc osa de m o nstrate d o n 
                       la bial bi o ps y s peci me n 
 
  
 
Or  
 
  
  
3 d).  I n v ol ve me nt of a n y ot her or ga n 
 
 

C D 1 9 C A R T- 1 9 Pr ot o c ol f or A L L 
P a ge 1 0 8 of 1 0 8  
V ersi o n V 1 2. 0 4 - 1 4-2 0 1 7   
 
C O N FI D E N TI A L  
T hi s material is t he pr opert y o f t he Uni vers ity o f Pe n n s yl va ni a.  D o n ot di scl ose or u se e xc e pt as a ut hor ized i n wr iti n g b y t he stu d y s p o ns o r. 
 
Cl assific ati o n of Ac ute Gr aft- Vers us- H ost Dise ase 
 
Ac ute G V H D will be gra de d usi n g t he c o nse ns us c o nfere nce criteria. T he first da y of ac ute 
G V H D o nset at a certai n gra de will be use d t o calc ulate c u m ulati ve i nci de n ce c ur ves. T his e n d-
p oi nt will be e val uate d t hr o u g h d a y 1 8 0 p ost-tra ns pla nt t o acc o u nt f or d ela ye d o nset. 
   
  
E xte nt of or g a n i n v ol ve me nt  
  
S ki n a 
Li ver b  
G ut c 
St a ge  
  
  
  
1  
Ras h o n < 2 5 % of s ki n  
Bilir u bi n 2 -3 m g/ d L  
Diarr hea > 5 0 0 ml/ da y or 
persiste nt na usea d 
2  
Ras h o n 2 5 -5 0 % of s ki n  
Bilir u bi n 3 -6 m g/ d L  
Diarr hea > 1 0 0 0 ml/ da y  
3  
Ras h o n > 5 0 % of  s ki n 
Bilir u bi n 6 -1 5 m g/ d L  
Diarr hea > 1 5 0 0 ml/ da y  
4  
Ge neralize d er yt hr o der ma 
wit h b ull o us f or mati o n  
Bilir u bi n > 1 5 m g/ d L  
Se vere a b d o mi nal pai n wit h 
or wit h o ut ile us  
  
  
  
  
Gr a de e 
  
  
  
I 
Sta ge 1 -2  
N o ne  
N o ne  
II 
Sta ge 3 or  
Sta ge 1 or  
Sta ge 1  
III 
- 
Sta ge 2 -3 or  
Sta ge 2 -4  
I V f 
Sta ge 4 or  
Sta ge 4  
- 
a Use ‘ R ule of Ni nes’ or b ur n c hart t o deter mi ne e xte nt of ras h.  
b Ra n ge gi ve n as t otal bilir u bi n. D o w n gra de o ne sta ge if a n a d diti o nal ca use of ele vate d bilir u bi n has bee n 
d oc u me nte d.  
c V ol u me of diarr hea a p plies t o a d ults. D o w n gra de o ne sta ge if a n a d diti o nal ca use of diarr hea has bee n 
d oc u me nte d.  
d Persiste nt na usea wit h hist ol o gic e vi de nce of G V H D i n t he st o mac h or d u o de n u m.  
e Criteria f or gra di n g gi ve n as mi ni m u m de gree of or ga n i n v ol ve me nt re q uire d t o c o nfer t hat gra de.  
f Gra de I V ma y als o i ncl u de lesser or ga n i n v ol ve me nt b ut wit h e xtre me decrease i n perf or ma nce stat us.