A Pilot Study of E7 TCR T Cell Induction Immunotherapy for Stage IIB-IVA Cervical Cancer
Phase: EARLY_PHASE1
Conditions: Uterine Cervical Neoplasms
Sponsor: National Cancer Institute (NCI)

Abbreviated Title:  E7 Induction Cervical Cancer 
 
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Version Date:  11/4/2020 
 
Abbreviated Title: E7 Induction Cervical Cancer 
NIH Protocol #: 20C0116 
Version Date: 11/4/2020 
IBC Number: RD-20-III-01 
NCT Number: NCT04476251 
 
Title: A Pilot Study of E7 TCR T Cell Induction Immunotherapy for Stage IIB-IVA Cervical 
Cancer    
 
NCI Principal Investigator:   Scott Norberg, DO 
 
Genitourinary Malignancies Branch 
 
National Cancer Institute 
 
10 Center Drive, Room 6B09 
 
Bethesda, MD 20892 
 
Phone:  301-275-9668 
 
Email:  scott.norberg@nih.gov  
 
Investigational Agents: 
Drug Name: 
E7 TCR T cells 
IND Number: 
19564 
Sponsor: 
Center for Cancer Research 
Manufacturer: 
CC DTM 
 
Investigational Device: 
Name: 
HPV16 Genotyping Assay 
Device: 
Nonsignificant Risk Device (NSR) 
Sponsor: 
Center for Cancer Research 
Lab: 
MolecularMD 
 
Commercial Agents: Fludarabine, Cyclophosphamide, IL-2 (Aldesleukin) 
 
 

Abbreviated Title:  E7 Induction Cervical Cancer 
 
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PRÉCIS  
 
Background: 
• Cervical cancer is the third most common cause of death among women with 
gynecologic cancers in the United States. Worldwide, cervical cancer accounts for nearly 
300,000 deaths annually.  
• Virtually all cases of cervical cancer result from chronic infection with high-risk human 
papillomavirus (HPV), the most common type being HPV16. 
• The treatment of locally advanced cervical cancer consists of chemoradiation +/- 
extended field radiation therapy. Participants with FIGO (revised 2018) stage III-IVA 
have the worse prognosis with approximately 50% of the participants dying from their 
disease within 5 years. 
• Induction chemotherapy is an active area of study in this type of cancer. The aim of 
induction therapy is to reduce the risk of disease recurrence and improve overall survival.  
• E7 TCR T cells, administered as a single infusion, have demonstrated safety and clinical 
activity in advanced, treatment-refractory metastatic HPV+ cancers.  
Objectives: 
• To determine the feasibility of induction E7 TCR T cell therapy for FIGO (2018) stage 
IIB-IVA, HPV16+ cervical cancer 
Eligibility: 
• Participants greater than or equal to 18 years old with FIGO (2018) stage IIB-IVA 
cervical cancer.  
• The cancer must be HPV16+ and participant must be HLA-A*02:01+. 
• Participants must be treatment-naïve (i.e., no prior local or systemic treatment, including 
radiation; prior LEEP procedure or cone biopsy is allowed). 
Design: 
• This is a single arm, pilot study, testing the feasibility of induction E7 TCR T cell 
therapy.  
• Participants will receive a conditioning regimen of cyclophosphamide and fludarabine, a 
single infusion of E7 TCR T cells, and systemic aldesleukin. 
• Participants will be referred for standard of care definitive therapy (i.e., chemoradiation 
+/- extended field radiation therapy) within 6 weeks after infusion of E7 TCR T cells.  

Abbreviated Title:  E7 Induction Cervical Cancer 
 
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TABLE OF CONTENTS  
PRÉCIS .......................................................................................................................................... 2 
TABLE OF CONTENTS ................................................................................................................ 3 
STATEMENT OF COMPLIANCE ................................................................................................ 6 
1. 
INTRODUCTION ............................................................................................................... 6 
1.1 
Study Objectives .............................................................................................................. 6 
1.2 
Background and Rationale ............................................................................................... 6 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT .................................................... 15 
2.1 
Eligibility Criteria .......................................................................................................... 15 
2.2 
Screening Evaluation...................................................................................................... 17 
2.3 
Participant Registration and Status Update Procedures ................................................. 18 
2.4 
Baseline Evaluation ........................................................................................................ 19 
3 
STUDY IMPLEMENTATION ......................................................................................... 20 
3.1 
Study Design .................................................................................................................. 20 
3.2 
Drug Administration ...................................................................................................... 23 
3.3 
Safety Protocol Stopping Rules ..................................................................................... 25 
3.4 
Study Calendar ............................................................................................................... 25 
3.5 
On-Study Evaluations .................................................................................................... 29 
3.6 
Cost and Compensation .................................................................................................. 29 
3.7 
Criteria for Removal from Protocol Therapy and Off Study Criteria ............................ 29 
4 
CONCOMITANT MEDICATIONS/MEASURES ........................................................... 30 
4.1 
Prohibited Medications .................................................................................................. 30 
4.2 
Infection Prophylaxis ..................................................................................................... 31 
4.3 
Blood Product Support ................................................................................................... 31 
4.4 
Neutrophil Recovery ...................................................................................................... 32 
4.5 
Other Concomitant medications to control side effects ................................................. 32 
5 
BIOSPECIMEN COLLECTION ....................................................................................... 32 
5.1 
Correlative Studies for Research/Pharmacokinetic Studies ........................................... 32 
5.2 
Summary of Sample Collection ..................................................................................... 34 
5.3 
Gene Therapy-Specific Follow-Up ................................................................................ 35 
5.4 
Sample Storage, Tracking and Disposition .................................................................... 36 
5.5 
Samples for Genetic/Genomic Analysis ........................................................................ 37 

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DATA COLLECTION AND EVALUATION .................................................................. 37 
6.1 
Data Collection ............................................................................................................... 37 
6.2 
Data Sharing Plans ......................................................................................................... 38 
6.3 
Genomic Data Sharing Plan ........................................................................................... 39 
6.4 
Response Criteria ........................................................................................................... 39 
6.5 
Toxicity Criteria ............................................................................................................. 46 
6.6 
Feasibility Assessment ................................................................................................... 47 
7 
NIH Reporting REQUIREMENTS/DATA AND SAFETY MONITORING PLAN ....... 47 
7.1 
Definitions ...................................................................................................................... 47 
7.2 
OHSRP Office of Compliance and Training.................................................................. 47 
7.3 
NCI Clinical Director Reporting .................................................................................... 47 
7.4 
Institutional Biosafety Committee (IBC) Reporting Criteria ......................................... 48 
7.5 
NIH Required Data and Safety Monitoring Plan ........................................................... 49 
8 
SPONSOR PROTOCOL/SAFETY REPORTING ............................................................ 50 
8.1 
Definitions ...................................................................................................................... 50 
8.2 
Assessment of Safety Events.......................................................................................... 51 
8.3 
Reporting of Serious Adverse Events ............................................................................ 51 
8.4 
Waiver of expedited reporting to CCR .......................................................................... 52 
8.5 
Safety Reporting Criteria to the Pharmaceutical Collaborators ..................................... 53 
8.6 
Reporting Pregnancy ...................................................................................................... 53 
8.7 
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND .................. 53 
8.8 
Sponsor Protocol Non-Adherence Reporting ................................................................. 54 
9 
CLINICAL MONITORING .............................................................................................. 54 
10 
STATISTICAL CONSIDERATIONS............................................................................... 55 
10.1 
Statistical Hypotheses ................................................................................................. 55 
10.2 
Sample Size Determination ........................................................................................ 55 
10.3 
Populations for Analysis ............................................................................................. 56 
10.4 Statistical Analyses ........................................................................................................... 56 
11 
COLLABORATIVE AGREEMENTS........................................................................... 57 
11.1 
Cooperative Research and Development Agreement (CRADA) ............................... 57 
12 
HUMAN SUBJECTS PROTECTIONS ............................................................................ 57 
12.1 
Rationale For Subject Selection ................................................................................. 57 

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12.2 
Participation of Children ............................................................................................ 57 
12.3 
Risk/Benefit Assessment ............................................................................................ 58 
12.4 
Consent Process and Documentation ......................................................................... 60 
13 
REGULATORY AND OPERATIONAL CONSIDERATIONS ...................................... 60 
13.1 
Study Discontinuation and Closure ............................................................................ 60 
13.2 
Quality Assurance and Quality Control ...................................................................... 61 
13.3 
Conflict of Interest Policy........................................................................................... 61 
13.4 
Confidentiality and Privacy ........................................................................................ 61 
14 
PHARMACEUTICAL INFORMATION .......................................................................... 62 
14.1 
Aldesleukin ................................................................................................................. 62 
14.2 
Fludarabine ................................................................................................................. 63 
14.3 
Cyclophosphamide ..................................................................................................... 64 
14.4 
Cell Preparation (E7 TCR Transduced PBL) (IND # 19564) .................................... 66 
14.5 
HPV16 Genotyping Assay (NSR Device) .................................................................. 66 
15 
REFERENCES .................................................................................................................. 68 
16 
APPENDICES ................................................................................................................... 71 
16.1 
Appendix 1: Performance Status Criteria ................................................................... 71 
16.3 
Appendix 2: Adverse Events Occurring in ≥ 10% of Participants Treated with 
Aldesleukin (N=525) ................................................................................................................ 72 
16.4 
Appendix 3: Expected IL-2 Toxicities and Their Management ................................. 74 
16.5 
Appendix 4: Interleukin-2 Toxicities Observed in Participants Treated at the NIH .. 77 
 

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STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following:  
• United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
 
1. INTRODUCTION 
1.1 
STUDY OBJECTIVES 
1.1.1 Primary Objective 
• To determine the feasibility of induction E7 TCR T cell therapy for FIGO (2018) stage 
IIB-IVA, HPV16+ cervical cancer 
1.1.2 Secondary Objective 
• To assess relapse-free survival (RFS) at 2 years and 5 years  
• To evaluate the safety of induction E7 TCR T cell therapy for FIGO (2018) stage IIB-
IVA, HPV16+ cervical cancer 
• To determine the percentage of E7 TCR T cells following completion of chemoradiation 
• To assess objective response rate following E7 TCR T cell induction therapy  
1.1.3 Exploratory Objective(s) 
• To perform laboratory research to begin to understand treatment response and to develop 
biomarkers that predict response  
• To determine the percentage of participants able to receive standard chemoradiation 
without requiring dose-reduction due to hematologic toxicities 
1.2 
BACKGROUND AND RATIONALE 
There are more than 12,000 new cases of cervical cancer diagnosed in the United States each 
year and the incidence is rising [1, 2]. Virtually all cases (99.7%) of cervical cancer are 
associated with the human papillomavirus (HPV) [3]. HPV types 16 and 18 account for over 

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70% of all cervical cancers with more than half of all cases of squamous cell carcinoma caused 
by HPV type 16 [4]. The primary therapy for FIGO (2018) stages IIB to IVA cervical cancer is 
chemoradiation +/- extended field radiation therapy [5]. Despite this therapy, 42% of participants 
with FIGO (2018) stage III cervical cancer will die of their disease within 5 years [6, 7]. These 
participants are also at a high risk of developing recurrent disease at distant sites [8]. Despite 
improvements in the treatment of metastatic cervical cancer, more than 90% of participants who 
develop distant recurrence will die of their disease within five years [9]. While there is no well-
established approach to induction chemotherapy in this disease, it is an active area of 
investigation. The goals of induction chemotherapy are to reduce the risk of disease recurrence 
and improve overall survival. In a multicenter, phase II trial of 46 women, 68% of participants 
with locally advanced cervical cancer responded to induction chemotherapy with carboplatin + 
paclitaxel prior to chemoradiation [10]. The overall survival and progression free survival at 3 
years was 66%. This has led to a multicenter, randomized phase III clinical trial (termed the 
INTERLACE trial) of induction chemotherapy with weekly carboplatin + paclitaxel for 6 cycles 
followed by standard chemoradiation versus standard chemoradiation alone in participants with 
locally advanced cervical cancer (NCT01566240). Another clinical trial is testing induction 
chemotherapy with 3 cycles of carboplatin + paclitaxel every 3 weeks followed by standard 
therapy in cervical cancer participants with paraaortic lymph node involvement (NCT03534713). 
In this clinical trial, we are studying induction therapy with E7 TCR T cells followed by standard 
therapy with chemoradiation +/- extended field radiation therapy in participants with FIGO 
(2018) stage IIB-IVA cervical cancer.  
1.2.1 T Cell Therapy  
T cell therapy is a type of treatment in which tumor-targeted T cells are administered for the 
treatment of cancer. T cells are a part of the adaptive immune system that is specialized for the 
highly specific cell-mediated killing of other cells, particularly cells that are infected by a virus 
or other intracellular pathogen. Through mechanisms similar to those by which T cells fight 
infected cells, T cells can also attack cancer cells. HPV+ cancers are attractive candidates for T 
cell therapy because they express viral antigens that can be targeted by T cells [11]. The primary 
antigens for targeting with immunotherapy are the HPV E6 and E7 oncoproteins, which are viral 
proteins that are constitutively expressed by HPV+ cancers and not expressed by healthy human 
tissues. E6 and E7 contribute to malignant transformation and to survival of cancer cells, and this 
functional importance also makes them attractive therapeutic targets. 
Previously, our group has conducted clinical trials of T cell therapy for metastatic HPV+ cancers. 
Our initial clinical trial employed as treatment a single infusion of autologous tumor-infiltrating 
T cells (TIL), which were preferentially generated from TIL subcultures with E6 and/or E7 
reactivity [12, 13]. Participants received a conditioning regimen of cyclophosphamide 60 mg/kg 
for two days and fludarabine 25 mg/m2 for five days. Cell infusion was followed by high-dose 
aldesleukin. In this study, 5/18 participants with cervical cancer experienced tumor responses 
and 2/11 participants with other HPV+ cancers experienced tumor responses. Within the cervical 
cancer participants, two participants had complete responses, while the other participants had 
partial responses. A participant with oropharyngeal cancer experienced complete regression of 
multiple tumors in his lungs. He had a recurrence of the metastatic cancer in his brain, which was 
resected, and he is without disease several years after treatment. The magnitude of the HPV-
oncoprotein-reactivity of the infused treatment cells correlated with response in participants in 
this clinical trial. However, both viral and non-viral tumor antigens were targeted by the TIL 

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administered to two participants with cervical cancer who each had a complete tumor response 
[12]. Thus, the results of this trial support the ability of T cells to mediate regression of HPV+ 
cancers, but they do not necessarily validate E6 and E7 as therapeutic targets. 
We subsequently conducted a clinical trial in which the E6 antigen was specifically targeted with 
T cell therapy. To accomplish E6 targeting, autologous peripheral blood T cells were genetically 
engineered to express an HLA-A*02:01-restricted, HPV16 E629-38-specific T cell receptor (TCR) 
[14]. The trial was a phase I/II, dose-escalation study. Participants had metastatic HPV16+ 
cancer that, in most participants, was refractory to multiple systemic agents. Participants 
received a conditioning regimen of cyclophosphamide 60 mg/kg for two days and fludarabine 25 
mg/m2 for five days. Cell infusion was followed by high-dose aldesleukin. Here, 2/12 
participants experienced partial tumor responses; one subsequently had residual disease resected 
by surgery, and she is without evidence of cancer several years later. Pre-treatment tumor 
biopsies from three participants were available to study to understand disease response and 
resistance. One participant who did not respond had loss of HLA-A*02:01 expression by the 
tumor, which likely made the tumor unable to present the E629-38 epitope to E6 TCR T cells. A 
second participant who did not respond had a truncating mutation in interferon-gamma receptor 
1, a crucial molecule for tumor sensitivity to T-cell-mediated tumor recognition and killing [15, 
16]. A participant who responded to treatment did not have mutations, deletions, or loss of 
heterozygosity in a defined panel of genes related to antigen processing and presentation, and 
interferon-gamma response. These findings suggest that – in the setting of previously treated, 
metastatic HPV+ cancer – tumors may acquire mutations that confer resistance to T cell 
immunotherapy. Tumors appear to acquire mutations that confer resistance to T cell immunity as 
they progress [17-20]. Awareness of this progressive resistance is driving a movement in 
oncology toward the earlier application of immunotherapy [21, 22].  
1.2.2 E7 TCR T cell preclinical development 
We identified an HLA-A*02:01-restricted TCR that targets HPV16 E711-19 from the cervix-
infiltrating T cells of a participant with cervical intraepithelial neoplasia who received a 
therapeutic cancer vaccine targeting HPV-16 E7 [23]. The nucleotide sequence of the TCR was 
codon optimized for expression in human tissues and the TCR constant regions were swapped 
for their mouse counterparts, which in other receptors has improved TCR alpha/beta chain 
pairing. TCR expression was further improved by reversing the order of the alpha and beta 
genes, and by making cysteine substitutions in the TCR constant regions and hydrophobic 
substitutions in the transmembrane region of the alpha chain constant region. The TCR sequence 
insert was cloned into the MSGV1 retroviral vector (Figure 1), which was chosen for this 
clinical trial based on its excellent safety record in treating greater than 200 participants.  
 

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Figure 1:  E7 TCR vector map. A TCR targeting E711-19 was isolated from the cervix-infiltrating lymphocytes 
of a participant with cervical intraepithelial neoplasia. The nucleotide sequence of the alpha and beta chains was 
determined, codon optimized for expression in human tissues, and the constant regions swapped for their mouse 
counterparts. A MSGV1 retroviral vector encoding this TCR was constructed. This retroviral vector consists of 
7,310 base pairs and includes a 5’LTR from the murine stem cell virus (promoter), packaging signal including the 
splicing donor (SD) and splicing acceptor sites (SA).  Alpha and beta chains of the E7 TCR are linked by a furin 2A 
peptide. 
  
Peripheral blood T cells transduced to express the E7 TCR display high avidity for the E711-19 
peptide (Figure 2) and CD8-independent HLA-A*02:01/E711-19 tetramer binding (Figure 3). 
They specifically recognize a panel of HPV-16+ HLA-A*02:01+ cervical and oropharyngeal 
cancer cell lines but not cell lines that lack HLA-A*02:01 or HPV-16 (Figure 4). Thus, gene 
engineered T cells expressing the E7 TCR can specifically target HPV-16+ HLA-A*02:01+ 
cancers. In contrast to TCRs that have had unexpected cross-reactivity against normal human 
proteins, this TCR was isolated directly from a human T cell. Hence, it was subjected to thymic 
selection and is unlikely to possess avid reactivity against self-antigens. The complementarity 
determining regions of the TCR have not been modified; therefore, there is no chance that cross-
reactivity has been artificially introduced.  The target epitope is derived from a viral protein, and 
no more than 6 of its 9 amino acids are shared with any human protein (Table 1). There is no 
cross reactivity of this TCR with epitopes of human proteins that share six amino acids or five 
amino acids plus a conservative amino acid substitution (Figure 5). In addition, alanine scanning 
of E711-19 identified four important residues for recognition (Figure 6). Cross reactivity was not 
detected against epitopes of human proteins that shared these residues (Table 1).  
E7 TCR
7310 bp
AmpR
SD
SA
3' LTR
5' LTR
Furin 2A linker
Beta Chain
Alpha Chain
EcoRI (1804)
Nco I (2)

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I F N - γ  ( p g / m L )
6
7
8
9
1 0
1 1
1 2
N o  p e p t i d e
0
5 0 0 0
1 0 0 0 0
E 7  T C R
E 6  T C R
>
- l o g [ E 7 1 1 - 1 9 ]  ( M )
 
Figure 2:  T cells transduced to express the E7 TCR demonstrated high avidity for the E711-19 peptide. T cells 
from PBMCs were transduced to express the E7 TCR.  Functional avidity was tested by co-culture with T2 cells 
pulsed with titrated concentrations of E711-19 peptide. 
 
 
 
Figure 3:  Peripheral blood T cells transduced to express the E7 TCR display CD8-independent HLA-
A*02:01/E711-19 tetramer binding. T cells from PBMCs were transduced to express the E7 TCR. Dot plots shown 
are gated on PI- lymphocytes and either CD8+ or CD8- cells as indicated above the dot plots. The x-axis is mouse T 
cell receptor beta chain expression. The y-axis is tetramer binding. 
Donor 1
CD8 +
CD8 -
Donor 2
79
2
0
19
84
1
0
15
70
2
0
27
68
3
0
29
HLA-A2/E711-19 tetramer
mTRBC

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I F N - γ  ( p g / m
L )
2 9 3 - A 2  +  E 7 ( 1 1 - 1 9 )
2 9 3 - A 2  +  E 6 ( 2 9 - 3 8 )
C a S k i
S C C 9 0
S C C 1 5 2
6 2 4  E 7
6 2 4  E 6
A l b
P a n c 1
S i H a
A n e
0
5 0 0 0
1 0 0 0 0
1 0 0 0 0
5 0 0 0 0
U n t r a n s d u c e d
E 7  T C R
+    +    +    +    -    -    -    +    -
H P V - 1 6
>
+    +    +    +    +    +    -    -    -
H L A - A 2
         
 
Figure 4:  T cells transduced to express the E7 TCR specifically recognized HPV-16+ HLA-A*02:01+ tumor 
lines   T cells transduced with E7 TCR were cocultured with targets expressing HPV-16 and HLA-A2 or with 
negative controls. Target cell line expression of HPV-16 and HLA-A2 is indicated below each label on the x-axis.   
 
 
 
 
 
 

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Figure 5: E7 TCR transduced T cells did not show cross reactivity against human peptides. E7 TCR 
transduced human T cells were tested for recognition of peptides identified by the BLAST search shown in Table 1. 
Target cells were T2 cells loaded with either the E7 peptide (E7) as a positive control, peptides identified by number 
in Table 1, or no peptide (A).  Peptides which elicited a weak response by E7TCR were further tested for 
recognition at titrated concentrations (B). 
 
 
 
 
 
IFN-γ (pg/mL)
E7
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
no peptide
0
5000
10000
15000
20000
IFN-γ (pg/mL)
E7
1
6
7
9
12
17
no peptide
0
10000
20000
30000
1
0.1
0.01
0.001
>
Peptide Conc. [uM]

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Figure 6: Serial alanine substitutions to the E711-19 target peptide revealed positions 4-7 to be the most crucial 
for recognition by E7 TCR transduced T cells. Human T cells were transduced to express the E7 TCR. The 
transduced cells were co-cultured with T2 cells loaded with varying concentrations of E711-19 peptide (E7) or E711-19 
with an alanine substitution at the position indicated by the x-axis labels. E7 peptide (E7) is an HLA-A2 restricted 
negative control peptide. 
 
 
 
Table 1: BLAST search for peptides with at least 6 (or at least 5 identical + 1 conservative change) amino 
acids shared with E711-19.  Capital/Underlined = Amino Acid Identical to E7 epitope, Capital/Not Underlined = 
Conservative change. *=Peptides that demonstrates weak cross-reactivity only at supraphysiological concentrations. 
IF N -γ  (p g/m L)
E 7
1 A
2 A
3 A
4 A
5 A
6 A
7 A
8 A
9 A
E 6
0
4 0 0 0
8 0 0 0
1 2 0 0 0
1 6 0 0 0
1
0 .1
0 .0 1
0 .0 0 1
>
P e p tid e  C o n c. [u M ]

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1.2.3 E7 TCR T cell clinical trial 
We conducted a phase I dose-escalation study of HPV-16 E7 TCR T cells for participants with 
metastatic HPV16+ cancers (e.g., cervical cancer, anal cancer, head and neck cancer, etc.). 
Participants received a conditioning regimen of cyclophosphamide 60 mg/kg or 30 mg/kg daily 
for two days and fludarabine 25 mg/m2 daily for five days. Cell infusion was followed by high-
dose aldesleukin. Objective tumor responses were experienced in 6 of 12 participants. One dose-
limiting toxicity occurred in a participant with impaired lung function from rapidly progressing 
cancer in the lungs.  The participant experienced severe lung, cardiovascular, and kidney toxicity 
that required temporary mechanical ventilation, pressors, and hemodialysis, that resulted in soft 
tissue injury to the distal lower extremities. No T-cell-mediated off-target toxicity was observed. 
The maximum administered dose, 1 x 1011 TCR+ E7 T cells, was selected as the dose for the 
phase II portion of the study which is currently ongoing. Six participants have been treated in the 
phase II portion of the study as of the writing of this protocol, with 3 participants having 
experienced objective responses. 
1.2.4 Safety Considerations 
The safety of infusion of large numbers of retrovirally modified tumor reactive T cells has been 
demonstrated in prior clinical studies. Protocols at the NIH Clinical Center have administered 
over 1 X 1011 tumor infiltrating lymphocytes (TIL) with widely heterogeneous reactivity 
including CD4, CD8, and NK cells. Further, after treating more than 200 participants with 
advanced cancers with genetically engineered T cells, NIH studies have not identified a risk of 
malignant transformation in this setting to date.  
The risk of insertional mutagenesis is a known possibility using retroviral vectors. It has been 
observed in the setting of CD34+ hematopoietic stem cells for the treatment of XSCID, WAS, 
and X-CGD. It has also been reported with lentiviral transduction in a participant who received 
CD19 CAR-T cells (it did not cause malignant transformation and may have enhanced the 
efficacy of the T cells) [24]. With retroviral vector-mediated gene transfer into mature T cells, 
there has been no evidence of malignancy due to genotoxicity since the first NCI sponsored gene 
transfer study in 1989. Although continued follow-up of all gene therapy participants will be 
required, data support the safety of retrovirally transduced mature T cells [25]. While the risk of 
insertional mutagenesis is low, the proposed protocol follows all current FDA guidelines 
regarding testing and follow up of participants receiving gene transduced cells [26]. To increase 
the safety of this protocol, the dose of E7 TCR T cells will be approximately 3.0 x 1010, which is 
several-fold lower than the maximum dose that was found to be safe in the phase I/II protocol. In 
addition, the dose of cyclophosphamide will be 30 mg/kg, which is half the dose administered to 
some participants in the prior phase I/II study, and the maximum doses of aldesleukin will be 
decreased by 50% to 6.  
 
 
 

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2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT  
2.1 
ELIGIBILITY CRITERIA 
2.1.1 Inclusion Criteria 
2.1.1.1 Participants with histologically or cytologically confirmed carcinoma of the cervix that 
has not been treated, with clinical staging as follows:   
• Lead-in safety cohort:  FIGO stage IIIC-IVA (2018 International FIGO Staging 
System)  
• After lead-in safety cohort:  FIGO stage IIB-IVA (2018 International FIGO 
Staging System) 
2.1.1.2 HPV16+ tumor and HLA-A*02:01+ HLA type.  Note:  HLA-A*02 is also acceptable 
for enrollment but not for treatment.  
2.1.1.3 Measurable disease by RECIST 1.1 criteria or PERCIST (if not eligible by RECIST 
1.1). 
2.1.1.4 Age 18 years. Because no dosing or adverse event data are currently available on the 
use of E7 TCR T cells in participants <18 years of age, children are excluded from this 
study. Note: This age range is consistent with the age of participants with the disease 
being studied.  
2.1.1.5 ECOG performance status 0 or 1 (see Appendix 1). 
2.1.1.6 Women of child-bearing potential must have a negative pregnancy test because E7 TCR 
T cells have unknown potential for teratogenic or abortifacient effects. Women of child-
bearing potential are defined as all women who are not post-menopausal or who have 
not had a hysterectomy.  Note:  Postmenopausal will be defined in this study as women 
over the age of 55 who have not had a menstrual period in at least 1 year. 
2.1.1.7 The effects of E7 TCR T cells on the developing human fetus are unknown.  For this 
reason and because the chemotherapy agents used in this trial are known to be 
teratogenic, women of child-bearing potential must agree to use adequate contraception 
(e.g., intrauterine device, hormonal or barrier method of birth control; abstinence; tubal 
ligation or vasectomy) prior to study entry and for four months after treatment.  Should 
a woman become pregnant or suspect she is pregnant while she is participating in this 
study, she should inform her treating physician immediately. 
2.1.1.8 Seronegative for HIV antibody. The experimental treatment being evaluated in this 
protocol depends on an intact immune system.  Participants who are HIV seropositive 
can have decreased immune-competence and thus be less responsive to the 
experimental treatment. 
2.1.1.9 Seronegative for hepatitis B antigen and hepatitis C antibody.  If hepatitis C antibody 
test is positive, then the participant must be tested for the presence of antigen by RT-
PCR and be HCV RNA negative. 
2.1.1.10 Must be willing to participate in Gene Therapy Long Term Follow up Protocol 
(20C0051), which will follow participants for up to 15 years per Food and Drug 

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Administration (FDA) requirements. 
2.1.1.11 Participants must have organ and marrow function as defined below: 
• leukocytes 
>3,000/mcL 
• absolute neutrophil count 
>1,500/mcL 
• platelets 
>100,000/mcL 
• hemoglobin  
>9.0 g/dL 
• total bilirubin 
within normal institutional limits except in 
participants with Gilbert’s Syndrome who must 
have a total bilirubin < 3.0 mg/dL 
• AST(SGOT)/ALT(SGPT) 
Serum ALT/AST < 2.5X ULN 
• creatinine clearance 
Calculated creatinine clearance (CrCl) >50 
mL/min/1.73 m2 for participants with creatinine 
levels above institutional normal (by the Chronic 
Kidney Disease Epidemiology Collaboration (CKD-
EPI) equation) 
2.1.1.12 Ability of subject to understand and the willingness to sign a written informed consent 
document. 
2.1.2 Exclusion Criteria 
2.1.2.1 Previous treatment for invasive cervical cancer including: 
• Chemotherapy or other systemic treatments 
• Radiation therapy 
• Hysterectomy (prior LEEP procedure or cone biopsy is allowed) 
2.1.2.2 Participants who are receiving any other investigational agents. 
2.1.2.3 History of severe allergic reactions attributed to compounds of similar chemical or 
biologic composition to agents used in study. 
2.1.2.4 Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations at the time of treatment that would 
limit compliance with study requirements. 
2.1.2.5 Because there is an unknown but potential risk for adverse events in nursing infants 
secondary to treatment of the mother with E7 TCR T cells, breastfeeding should be 
discontinued if the mother is treated with E7 TCR T cells.  These potential risks may 
also apply to other agents used in this study. 
2.1.2.6 Participants with any form of systemic immunodeficiency, including acquired 
deficiency such as HIV or primary immunodeficiency such as Severe Combined 
Immunodeficiency Disease, are ineligible. The experimental treatment being evaluated 
in this protocol depends on an intact immune system. Participants who have decreased 

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immune competence may be less responsive to the treatment. 
2.1.2.7 Participants on immunosuppressive drugs including corticosteroids. 
2.1.2.8 Participants with autoimmune diseases such as Crohn’s disease, ulcerative colitis, 
rheumatoid arthritis, autoimmune hepatitis, autoimmune pancreatitis, or systemic lupus 
erythematosus. Hypothyroidism, vitiligo and other minor autoimmune disorders are not 
exclusionary. 
2.1.2.9 Participants with a second invasive malignancy requiring treatment within the last 2 
years are not eligible with the following exceptions: 
• Ductal carcinoma in situ (DCIS) of the breast 
• Cutaneous skin cancers requiring only local excision 
2.1.3 Recruitment Strategies 
Participants for this protocol will be recruited via standard CCR mechanisms, including that this 
protocol may be abstracted into a plain lay language announcement posted on NIH websites and 
social media platforms, physician and self-referrals as well as various advertising venues. All 
other specific recruitment advertisements and letters will be submitted to the IRB for approval 
prior to their implementation.  
2.2 
SCREENING EVALUATION 
2.2.1 Screening activities performed prior to obtaining informed consent 
Minimal risk activities that may be performed before the subject has signed a consent include the 
following:  
• Email, written, in person or telephone communications with prospective subjects  
• Review of existing medical records to include H&P, laboratory studies, etc.   
• Review of existing MRI, x-ray, or CT images 
• Review of existing photographs or videos 
• Review of existing pathology specimens/reports from a specimen obtained for diagnostic 
purposes 
2.2.2 Screening activities performed after a consent for screening has been signed 
The following activities will be performed only after the subject has signed the consent for this 
study for screening. Results from outside laboratories are accepted for screening evaluations 
provided that they were performed in the appropriate timeframe. 
2.2.2.1 Any time prior to initiation of study therapy: 
• HLA-A*02:01 testing. Tests from CLIA approved laboratories outside the NIH are 
acceptable. Note:  HLA-A*02 is also acceptable for determination of eligibility but 
HLA-A*02:01 is required prior to initiation of treatment.  
• HPV16 genotype testing. Tissue from a previous surgery or biopsy may be used or a new 
biopsy may be obtained. Tests from MolecularMD laboratories outside the NIH are 
acceptable.   
• Confirmation of cervical cancer (pathology report from outside institution is acceptable)  

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2.2.2.2 Any time within 3 months prior to confirmation of eligibility:   
• HBsAg, anti-HCV Antibody, and anti-HIV-1/2 Antibody. Results from outside the NIH 
are acceptable. (Within 3 months prior to initiation of study therapy or 7 days prior to cell 
product collection if results are from outside the NIH) 
• Anti-HTLV-I/II, Anti-Hbc Antibody, West Nile Virus, HIV-1/HCV/HBV NAT, T.cruzi 
Antibody.  
• Anti CMV antibody titer, HSV serology, and EBV panel (unless known to be positive by 
a prior test).  
2.2.2.3 Any time within 4 weeks prior to confirmation of eligibility:   
• History and physical exam, including vital signs, review of performance status and 
concomitant medications, and a review of the medical record to confirm disease 
diagnosis and stage.  
• Chem 20 equivalent: (Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 
(Bicarbonate), Creatinine, Glucose, Urea nitrogen (BUN), Albumin, Calcium total, 
Magnesium total (Mg), Inorganic Phosphorus, Alkaline Phosphatase, ALT/GPT, 
AST/GOT, Total Bilirubin, Direct Bilirubin, LDH, Total Protein, Total CK, Uric Acid). 
• Thyroid Panel 
• CBC with differential and TBNK 
• PT/PTT 
• Imaging studies including CT scans, MRI scans*, and PET scans may be obtained to 
confirm staging or if clinically indicated.  
• Pregnancy test  
• Electrocardiogram (ECG)  
*NOTE:  MRIs done in this study may involve the use of contrast agent gadolinium, unless 
contraindicated.  
2.3 
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES 
Registration and status updates (e.g., when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration & Status Updates found here. 
2.3.1 Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently assigned to the study intervention or entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any serious adverse event 
(SAE). 

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2.3.2 Treatment Assignment and Randomization Procedures 
Cohorts 
Number 
Name 
Description 
1 
Lead-in Cohort 
Participants with histologically or cytologically confirmed 
advanced cervical cancer (FIGO (2018) stage IIIC-IVA) 
2 
Post- Lead-in Cohort 
Participants with histologically or cytologically confirmed 
advanced cervical cancer (FIGO (2018) stage IIB-IVA) 
Arms 
Number 
Name 
Description 
1 
Arm 1 
E7 TCR T cell Therapy 
Randomization and Arm Assignment 
Participants in Cohorts 1 and 2 will be directly assigned to Arm 1. 
2.4 
BASELINE EVALUATION 
Tests performed as part of screening may not need to be repeated if they were performed within 
the specified window at the discretion of the PI. 
2.4.1 Within 30 days prior to apheresis: 
• Complete physical examination, including weight and vital signs  
• Vein assessment (per apheresis clinic policy) 
• Chemistries: Chemistries Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 
(bicarbonate), Creatinine, Glucose, Urea nitrogen (BUN), Albumin, Calcium total, 
Magnesium total (Mg), Inorganic Phosphorus, Alkaline Phosphatase, ALT/GPT, 
AST/GOT, Total Bilirubin, Direct Bilirubin, LD, Total Protein, Total CK, Uric Acid 
• CBC with differential and platelet count  
• PT/PTT  
• Urinalysis 
2.4.2 Any time prior to starting cyclophosphamide: 
• Research tumor biopsy (optional) 
• Research blood draw 
2.4.3 Within 4 weeks prior to starting cyclophosphamide: 
• Clinical staging, which may include imaging (e.g., CT scan, MRI scan, PET scan) and/or 
exam under anesthesia. Scans from referring centers may be used if read by an NIH 
Clinical Center radiologist. 

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• Tumor measurements with documentation of the T and N stage and the overall disease 
stage. Scans from referring centers may be used if the NIH radiologist can obtain reliable 
tumor measurements. 
• Chest x-ray 
• ECG 
• Cardiac and/or pulmonary testing (e.g., cardiac stress test, echocardiogram, or pulmonary 
function tests) for participants at elevated risk such as those with COPD, diabetes, 
hyperlipidemia, hypertension, a history of smoking, or age >60. Participants with cardiac 
ischemia will not be treated. Participants with a clinically significant arrhythmia or LVEF 
<45% will be evaluated by a cardiologist. Participants with a FEV1/FVC<70% or FEV1< 
80% will be evaluated by a pulmonologist. These tests may be done at screening or at 
baseline and may be performed at outside institutions. If performed at screening, they do 
not need to be repeated at baseline as long as they are done within the appropriate 
timeframe.  
• TBNK  
• Thyroid panel 
2.4.4 Within 1 week prior to starting cyclophosphamide: 
• Complete physical examination, including weight and vital signs 
• Chemistries: Chemistries Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 
(bicarbonate), Creatinine, Glucose, Urea nitrogen (BUN), Albumin, Calcium total, 
Magnesium total (Mg), Inorganic Phosphorus, Alkaline Phosphatase, ALT/GPT, 
AST/GOT, Total Bilirubin, Direct Bilirubin, LD, Total Protein, Total CK, Uric Acid 
• CBC with differential and platelet count  
• PT/PTT, Fibrinogen and Triglycerides  
• Baseline oxygen saturation  
• Beta-HCG pregnancy test (serum or urine) for all women of child-bearing potential 
• ECOG assessment 
3 
STUDY IMPLEMENTATION 
3.1 
STUDY DESIGN 
This is a pilot study testing the feasibility of induction E7 TCR T cell therapy. The study schema 
is as follows: 

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3-week (+/- 4 days) check for clinical progression by clinical exam (see below) will be 
performed at the NIH.  
6-week (+/- 4 days) response and safety assessment will be performed at the NIH Clinical 
Center.  
The 3-week clinical check will include a physical exam, adverse event assessment and evaluation 
by gynecologic oncology to assess for possible hyper-progression.  
Tumor measurements at the 6-week response assessment will be performed as described in 
section 6.4.  
All participants will be referred for standard of care definitive treatment, regardless of response, 
following the 6-week safety check and response assessment.  
3.1.1 Leukapheresis 
The participant will undergo a 10-15 liter leukapheresis (generally, 12 liters will be processed to 
target a yield of 6-10 x109 lymphocytes) in the Department of Transfusion Medicine (DTM) 
Dowling Apheresis Clinic according to DTM standard operating procedures.  This procedure 
may occur on this protocol, or protocol 16C0061, if the participant chooses to co-enroll on that 
protocol.  The procedure requires dual venous access and takes approximately 3-4 hours to 
complete.  A central line will be placed if peripheral venous access is not sufficient. 
Leukapheresis material that is not required for clinical use will be retained and cryopreserved in 
10 vials at 100x106 cells per vial with remaining cells stored at 300x106 cells per vial for 
research and banked on protocol 16C0061 (Tissue Procurement Protocol) if the subject is co-
enrolled on that study. 
3.1.2 E7 TCR T cell Preparation 
After cells are obtained by apheresis (either on this protocol or protocol 16C0061 if the 
participant has co-enrolled on that protocol), further cell processing to generate E7 TCR cells 
will occur in the DTM according to standard operating procedures and the E7 TCR 
investigational new drug application.  If apheresis has been performed on protocol 16C0061 and 

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the participant consents and is eligible for treatment on this study, cells will be transferred to this 
study and all cell preparation will occur as part of this protocol.  Any unused cells from this 
protocol can be transferred to 16C0061 and banked for research if a participant is co-enrolled. E7 
TCR cells can be produced in approximately 11 to 15 days. Cell products may be cryopreserved 
during production to accommodate participant treatment schedules. Either freshly-collected cells 
or cryopreserved cells can be used to initiate the cell-preparation process.  Peripheral blood 
mononuclear cells (PBMC) will be isolated. Sufficient cells for three complete cell productions 
(2-3 vials at 3-4.5 x 109 cells/vial) may be retained in the DTM; the remaining cells may be 
frozen in 10 vials at 100 x 106 cells per vial with excess frozen at 300 x 106 cells/vial. Cells will 
be frozen in the DTM and then transferred to the Blood Processing Core (BPC) where they may 
be frozen and stored.  The contact for the Blood Processing Core (BPC) is  pager is 11964, tel # 
240 760 6180.  
Before infusion, the percentage of T cells expressing the E7 TCR will be determined by flow 
cytometry.  In addition to flow cytometry, further testing of the cells will take place prior to 
infusion to evaluate for microbial contamination, replication-competent retroviruses, and 
viability.  Details of this testing can be found in the appropriate DTM SOPs. Any remaining 
cryopreserved pretreatment PBMC collected on this protocol will be transferred from the 
Department of Transfusion Medicine to the Principal Investigator of this protocol for storage in 
the Blood Processing Core (BPC) and possible use in research and banked according to protocol 
16C0061 (Tissue Procurement Protocol) if subject co-enrolled on that study. 
3.1.3 Treatment Phase 
PBMC will be obtained by leukapheresis (approximately 2x109 to 1x1010 cells are obtained).  
PBMC will be cultured in the presence of anti-CD3 (OKT3) and aldesleukin in order to stimulate 
T-cell growth. Transduction is initiated by exposure of approximately 10x106 to 500x106 cells to 
supernatant containing the E7 TCR retroviral vector.  These transduced cells will be expanded 
and tested for their anti-tumor activity. Successful TCR gene transfer will be determined by 
FACS analysis for the TCR protein. Successful TCR gene transfer for each transduced peripheral 
blood lymphocyte (PBL) population will be defined as greater than 10% TCR positive cells.  
Participants will receive up to 3x1010 E7 TCR T cells (i.e. TCR+ cells). There is no lower limit 
of the cell dose as participants will have already received conditioning chemotherapy and it 
would not be in their interest to withhold a cell product, regardless of dose, as long as it meets 
release criteria. A central line catheter may be used for the intravenous infusion of E7 TCR T 
cells. 
Prior to receiving the engineered PBL cells, participants will receive a non-myeloablative, but 
lymphocyte depleting, preparative regimen consisting of cyclophosphamide and fludarabine, on 
days -6 to -2 before the intravenous infusion of in vitro tumor reactive TCR gene-transduced 
PBL plus IV high dose aldesleukin, as indicated in section 3.2. Participants will receive one 
course of treatment.  The start date of the course will be the start date of the chemotherapy; the 
end of treatment date will be at the  3-week check by clinical exam.   
3.1.4 Lead-in cohort 
The first two participants treated in the lead-in cohort will be staggered by 2 weeks in order to 
monitor for acute and sub-acute adverse events.    

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3.2 
 DRUG ADMINISTRATION 
Treatment schedule will be according to the following schedule (see Schedules 3.2.4).  Times are 
offered as examples and may be changed as long as a similar time relationship between 
administrations of the drugs is maintained. Study medication start times for drugs given once 
daily may be within 2 hours of the scheduled time (once it is established at the administration of 
the first medication).  All other medications may be given +/- one (1) hour of the scheduled time; 
the length of administration may be +/- 15 minutes.  Administration of diuretics, electrolyte 
monitoring and replacement, and hydration should all be performed as clinically indicated – the 
times noted below are offered only as examples. Chemotherapy infusions maybe slowed or 
delayed as medically indicated. Intravenous hydration administered during cyclophosphamide 
will be individualized for participant clinical factors. Participants at risk of adverse clinical 
consequences from volume overload (e.g., participants with history of pulmonary hypertension 
or cardiac dysfunction) may be considered for low-dose hydration rates or hemorrhagic cystitis 
prevention strategies that include mesna alone without intravenous hydration.  
3.2.1 Preparative Regimen  
The following will comprise a course of therapy for Day -6 through Day -2: 
Day -6 and -5:  
11 am:  Hydrate (if applicable). Begin hydration with 0.9% sodium chloride injection with or 
without 10 meq/L of potassium chloride at 90 ml/m2/hour (recommend starting at 
least 6 hours pre-cyclophosphamide and continue hydration until 24 hours after last 
cyclophosphamide infusion).  Furosemide 10-20 mg IV may be given once daily on 
cyclophosphamide treatment days to promote diuresis.  At any time during the 
preparative regimen, if the urine output <1.5 mL/kg/hour or if body weight >2 kg 
over pre-cyclophosphamide value, additional doses of furosemide 10-20 mg IV may 
be administered.  The hydration rate will be capped at 100 mL/hr. The rate of 
hydration and total time of hydration may be reduced or increased based on urine 
output and other clinical considerations per the clinical team. 
4 pm:  Ondansetron (0.15 mg/kg/dose [rounded to the nearest even mg dose between 8 mg 
and 16 mg based on participant weight] IV q 8 hours X 3 days), olanzapine (10 mg 
PO once daily for 5 days) and aprepitant (125 mg PO on the first day, 80 mg PO daily 
the following 2 days) will be utilized for prophylaxis for chemotherapy induced 
nausea and vomiting. Modifications to the antiemetic regimen may be made per 
clinical team discretion, but corticosteroids should be avoided. 
5 pm:  Cyclophosphamide 30 mg/kg/day X 2 days IV in 250 mL D5W with mesna 15 
mg/kg/day over 1 hour X 2 days. If the participant is obese (BMI > 35) drug dosage 
will be calculated using practical weight as described in Table 2.   
 
Begin mesna infusion at 1.5 mg/kg/hour intravenously diluted in a suitable diluent 
over 23 hours after each cyclophosphamide dose. If the participant is obese (BMI > 
35) drug dosage will be calculated using practical weight as described in Table 2.  
Day -6 to Day -2: 
Fludarabine 25 mg/m2/day IVPB daily over 15-30 minutes for 5 days.  

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If the participant is obese (BMI > 35) drug dosage will be calculated using practical weight as 
described in Table 2. (The fludarabine will be started approximately 1-2 hours after the 
cyclophosphamide and mesna on Days -6 and -5) 
3.2.2 Cell Infusion and Other Treatment Administration 
The E7 TCR cells will be delivered to the participant care unit by an authorized staff member.  
Prior to infusion, the cell product identity label is double-checked by two authorized staff (e.g., 
MD or RN), an identification of the product and documentation of administration are entered in 
the participant’s chart, as is done for blood banking protocols. The dose of E7 TCR T cells will 
be 3 x 1010 TCR+ T cells (unless fewer cells are generated) administered once. 
Day 0 (one to three days after the last dose of fludarabine): 
• E7 TCR T cells will be administered intravenously over 20 to 30 minutes via non-filtered 
tubing, gently agitating the bag during infusion to prevent cell clumping.   
• Aldesleukin as described in section 3.2.3 below.  
Day 0-4 (Day 0 is the day of cell infusion):  
• Fluconazole may be used at the discretion of the treating clinician  
• Valacyclovir or Acyclovir; see section 4.2.2 
Day 0-2 (Day 0 is the day of cell infusion): 
• Aldesleukin as described in section 3.2.3 below.  
Discharge: 
PJP prophylaxis may be started at or around the time of discharge. TMP/SMX may be 
administered at 160mg/800mg every other day or monthly inhaled pentamidine per treating 
clinician discretion. Refer to section 4.2.1. 
3.2.3 Aldesleukin 
Aldesleukin will be administered at a dose of 720,000 IU/kg (based on total body weight) as an 
intravenous bolus over a 15-minute period beginning within 24 hours after cell infusion and 
continuing for up to four days (maximum 6 doses). The start of aldesleukin treatment may be 
delayed up to 3 days after cell infusion if medically necessary. Doses will be preferentially 
administered every eight hours; however, up to 24 hours may elapse between doses depending 
on participant tolerance. Aldesleukin dosing will be stopped if toxicities are not sufficiently 
recovered with supportive measures within 24 hours of the last dose of aldesleukin.  Doses will 
be delayed or stopped if participants reach Grade 3 or 4 toxicity due to aldesleukin except for the 
reversible Grade 3 toxicities common to aldesleukin such as diarrhea, nausea, vomiting, 
hypotension, skin changes, anorexia, mucositis, dysphagia, or constitutional symptoms and 
laboratory changes as detailed in Appendix 3.  Toxicities will be managed as outlined in 
Appendix 2.  In addition, dosing may be held or stopped at the discretion of the treating 
investigator.  Because confusion is a possible side effect of aldesleukin administration, a Durable 
Power of Attorney may be signed by the participant to identify a surrogate to make decisions if a 
participant becomes unable to make decisions. 
3.2.4 Treatment Schedule Schema/Chart 

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Therapy 
Day 
-6 
-5 
-4 
-3 
-2 
-1 
0 
1 
2 
3 
4 
Cyclophosphamide 
30 mg/kg IV once daily x 2 days 
X 
X 
 
 
 
 
 
 
 
 
 
Ondansetron  
0.15 mg/kg IV every 8 hours x 3 days 
X 
X 
X 
 
 
 
 
 
 
 
 
Olanzapine  
10mg PO once daily x 5 days 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Aprepitant  
125 mg PO X1, 80 mg PO daily X2 
X 
X 
X 
 
 
 
 
 
 
 
 
Mesna  
1.5 mg/kg/hour 
X 
X 
 
 
 
 
 
 
 
 
 
Fludarabine 
25 mg/m IV once daily x 5 days 
X 
X 
X 
X 
X 
 
 
 
 
 
 
E7 TCR cells 
 
 
 
 
 
 
X 
 
 
 
 
Aldesleukin 
 
 
 
 
 
 
X 
X 
X 
 
 
3.3 
SAFETY PROTOCOL STOPPING RULES 
The study will be halted (immediately stop accrual and treatment) if any of the following occur:  
1. Death that occurs within 30 days of E7 TCR T cell injection (other than death related to 
progressive disease). 
2. Grade 3 or 4 toxicity that occurs within 30 days of E7 TCR T cell infusion and that does 
not resolve to Grade 2 or less within 10 days.  Note:  This applies to any event (s) that is 
not attributable to the preparative regimen, aldesleukin, underlying disease, or unrelated 
circumstances including standard of care therapy if administered within 30 days after cell 
infusion. 
3. Feasibility failure in 2 of the first 5 participants or in any 3 participants. 
The study will remain on hold until an appropriate evaluation of the cause is determined and a 
plan of correction, if necessary, is established.    
3.4 
STUDY CALENDAR 
Procedure 
Screening 
Baseline4 
Before treatment27 
Preparative regimen7 
Day 0 
During hospitalization8 
Follow-up Period 
3-week check by  
clinical exam1, 24 
6-week safety 
check  
and response 
assessment 11 
Annual  
Follow-up25 
Medical history 
X 
 
 
 
 
 
 
 
X 

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Procedure 
Screening 
Baseline4 
Before treatment27 
Preparative regimen7 
Day 0 
During hospitalization8 
Follow-up Period 
3-week check by  
clinical exam1, 24 
6-week safety 
check  
and response 
assessment 11 
Annual  
Follow-up25 
Physical exam 
X 
X 
 
 
X 
X23 
X 
X 
 
Vital signs 
X 
X 
 
 
X22 
X 
X 
X 
 
ECOG Performance Score 
 
X 
 
 
 
 
 
 
 
NIH Advance Directives 
Form2 
X 
 
 
 
 
 
 
 
 
Blood chemistries10   
X 
X 
X 
X 
 
X23 
 
X 
 
Complete blood count (CBC 
with diff.) 
X 
X 
X 
X 
 
X 
 
X 
 
Thyroid panel (TSH, FT3, 
FT4) 
X 
X 
 
 
 
 
 
X 
 
HLA typing/HPV genotype 
testing18 
X 
 
 
 
 
 
 
 
 
TBNK 
X 
X 
X 
 
 
X9 
 
X 
 
Urinalysis 
 
X 
 
X 
 
 
 
 
 
HBsAg, anti-HCV Antibody, 
and anti-HIV-1/2 Antibody19 
X 
 
 
 
 
 
 
 
 
Anti-HTLV-I/II, Anti-Hbc 
Antibody, West Nile Virus, 
HIV-1/HCV/HBV NAT, 
T.cruzi Antibody 20  
X 
 
 
 
 
 
 
 
 
Anti CMV antibody titer, 
HSV serology, and EBV 
panel 20 
X 
 
 
 
 
 
 
 
 
Pregnancy test in women of 
childbearing potential5 
X 
X 
 
 
 
 
 
 
 
Leukapheresis 
 
 
X16 
 
 
 
 
 
 
Biopsy  
 
X 
 
 
 
 
 
X26 
 
Correlative research studies  
X 
 
X 
 
X14 
X14 
X 
X 
 
E7 TCR assay17 
 
 
 
 
 
X 
X 
X 
X 
Cardiac evaluation12 
 
X 
 
 
 
 
 
 
 
Chest x-ray 
 
X 
 
 
 
 
 
 
 
ECG 
X 
X 
 
 
 
 
 
 
 
Chest CT and MRI or PET 21 
X 
X 
 
 
 
 
 
X 
 

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Procedure 
Screening 
Baseline4 
Before treatment27 
Preparative regimen7 
Day 0 
During hospitalization8 
Follow-up Period 
3-week check by  
clinical exam1, 24 
6-week safety 
check  
and response 
assessment 11 
Annual  
Follow-up25 
Pulmonary Function Tests3 
 
X 
 
 
 
 
 
 
 
Response evaluation 
 
 
 
 
 
 
 
X 
 
Adverse events 
 
 
X 
 
 
 
 
 
 
Infusion of transduced cells6 
 
 
 
 
X 
 
 
 
 
Additional apheresis or blood 
draw13,15 
 
 
 
 
 
 
X 
 
 
  
1. End of treatment visit will occur 3 weeks (21 days +/- 4 days) after the E7 TCR T cell 
infusion, or when the participant comes off treatment if before 21 days. If the participant 
cannot return to the Clinical Center for this visit, a request will be made to collect 
required clinical labs (specify as needed) from a local physician or laboratory.  If this is 
not possible, participants may be assessed by telephone for symptoms.   
2. As indicated in section 12.3, all subjects ≥ age 18 will be offered the opportunity to 
complete an NIH advance directives form.  This should be done preferably at baseline but 
can be done at any time during the study as long as the capacity to do so is retained.  The 
completion of the form is strongly recommended but is not required. 
3. For participants with a prolonged history of cigarette smoking, as clinically indicated in 
section 2.4.3. 
4. Exact timeline is indicated in section 2.4. 
5. For women of child-bearing potential as defined in section 2.1.1.7. 
6. See other treatments in Schedules, section 3.1.3 
7. On days -6 to -2 
8. Every 1 to 2 days while hospitalized 
9. Once total lymphocyte count is greater than 200/mm3, TBNK for peripheral blood CD4 
count will be drawn weekly (while the participant is hospitalized) 
10. Chemistries Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 (bicarbonate), 
Creatinine, Glucose, Urea nitrogen (BUN), Albumin, Calcium total, Magnesium total 
(Mg), Inorganic Phosphorus, Alkaline Phosphatase, ALT/GPT, AST/GOT, Total 
Bilirubin, Direct Bilirubin, LDH, Total Protein, Total CK, Uric Acid, PT/PTT, 
Fibrinogen and Triglycerides. After cell infusion, the following labs will only be 
collected if clinically indicated: Calcium total, Magnesium total (Mg), Phosphorus, LD, 
Total Protein, Total CK, Uric Acid, PT/PTT, Fibrinogen and Triglycerides.  

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11. 6-week response assessment (42 days+/- 4 days) after cell infusion. 
12. For participants who are greater than or equal to 60 years of age, or who have a history of 
ischemic heart disease, chest pain or clinically significant atrial and/or ventricular 
arrhythmias. Participants with a LVEF of less than or equal to 45% will not be eligible, as 
noted in section 2.4.3 
13. An approximately 5 liter apheresis may be performed at the 3-week check by clinical 
exam, if the participant is unable to undergo apheresis, approximately 96 mL of blood 
may be obtained.   Peripheral blood mononuclear cells will be cryopreserved so that 
immunologic testing may be performed and will be banked under protocol 16C0061 
(Tissue Procurement Protocol).  PBMC from apheresis may be stored in 10 vials at 
100x106 cells per vial with remaining cells stored at 300x106 cells per vial. 
14. See section 5.1.2. 
15. If the participant is unable to undergo apheresis, approximately 96 mL of blood may be 
obtained.  
16. This can occur at any time prior to treatment on protocol 16C0061 if the participant is co-
enrolled on that protocol. See section 3.1.1 for further details.    
17. Clinical assay performed by the NCI Flow Cytometry Laboratory in the Laboratory of 
Pathology. 
18.  See section 2.2. 
19. Within 3 months of enrollment or 7 days of cell product collection if results are from 
outside the NIH 
20.  Within 3 months of treatment, results not required for enrollment but required for 
treatment 
21. To confirm staging or if clinically indicated. (Within 4 weeks of enrollment, results not 
required for enrollment but required for treatment) 
22. After cell infusion (Day +1 to Day +7): Vital signs will be monitored hourly (+/- 15 
minutes) for four hours and then routinely (every 4-6 hours) unless otherwise clinically 
indicated 
23. As clinically indicated 
24. 21 days (+/- 4 days) after cell infusion. 
25. Participants will be contacted (either by phone or visit to NIH) every 1 year (+/- 1 
months) following completion of standard of care therapy for a total of 5 years to 
determine the dates and types of additional therapies (if any) that participants received 
after definitive treatment, the status of their disease and recent imaging studies. If 
participants have not had any imaging within 3 months of the annual follow-up, 
participants can have imaging performed at the NIH. Participants will also be contacted 
after completion of chemoradiation to have a tube of blood drawn and tested for 
persistence of E7 TCR T cells.   
26. Refer to section 5.1.3. 

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27. Within 4 weeks prior to treatment. 
3.5 
ON-STUDY EVALUATIONS 
Please see the study calendar in section 3.4 for details regarding on-study evaluations. 
3.5.1 Long-term Follow-Up 
Long-term follow-up of participants receiving gene transfer is required by the FDA and must 
continue even after the participant comes off the study.  Long-term follow-up will be done under 
a different protocol (20C0051) for which the participant will be co-enrolled. Refer to section 5.3. 
3.6 
COST AND COMPENSATION 
3.6.1 Costs 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that participants receive at the NIH Clinical Center.  If some tests and procedures performed 
outside the NIH Clinical Center, participants may have to pay for these costs if they are not 
covered by insurance company.  Medicines that are not part of the study treatment will not be 
provided or paid for by the NIH Clinical Center. 
3.6.2 Compensation 
No compensation is provided for participation in this study. 
3.6.3 Reimbursement 
This study offers subject reimbursement or payment for travel, lodging and/or meals while 
participating in the research. The amount, if any, is guided by NIH policies and guidelines. 
The NCI generally does not cover expenses during screening.  If a subject is scheduled for and 
begins treatment, the NCI will cover the cost for some of the expenses. Some of these costs may 
be paid directly by the NIH and some may be reimbursed to the subject.  The amount and form 
of these payments are determined by the NCI Travel and Lodging Reimbursement Policy. 
3.7 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
Prior to removal from study, effort must be made to have all subjects complete a safety visit 
approximately 21 days following the last dose of study therapy. 
3.7.1 Criteria for removal from protocol therapy 
• Completion of protocol therapy 
• Initiation of standard of care definitive therapy 
• Participant requests to be withdrawn from active therapy 
• Investigator discretion 
• Positive pregnancy test 
3.7.2 Off-Study Criteria 
• Completed study follow-up period 

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• Participant requests to be withdrawn from study 
• Death 
• Screen failure 
• Lost to follow-up 
• Inability to generate a cell product. A second attempt may be made to generate a cell 
product from the participant. If the second attempt fails, that participant will be removed 
from the study and replaced with another participant. 
• The investigators decide to end the study 
• The investigators decide it is in the participant’s best interest 
• Substantial participant non-compliance that prevents compliance with the study 
requirements. 
• Permanent loss of capacity to give consent 
3.7.3 Lost to Follow-Up 
A participant will be considered lost to follow-up if he or she fails to return for three (3) 
scheduled visits and is unable to be contacted by the study site staff.  
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site will attempt to contact the participant and reschedule the missed visit (i.e., 
ideally within 2-3 days of the missed visit) and counsel the participant on the importance 
of maintaining the assigned visit schedule and ascertain if the participant wishes to and/or 
should continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record or study file.  
• Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
4 
CONCOMITANT MEDICATIONS/MEASURES 
4.1 
PROHIBITED MEDICATIONS 
Current use of immunosuppressive medication, EXCEPT for the following: 
• Intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular 
injection); 
• Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent; 
or, 
• Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication) 

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4.2 
INFECTION PROPHYLAXIS 
Note: Other medications may be substituted or medications may be held at the discretion of the 
treating investigator. Below are guidelines, and suggested medications and schedule to be used; 
however, they can be altered by the treating physician as clinically indicated.    
4.2.1 Pneumocystis Jirovecii Pneumonia 
Participants may receive the fixed combination of trimethoprim and sulfamethoxazole [SMX] as 
double strength (DS) tab (DS tabs = TMP 160 mg/tab, and SMX 800 mg/tab) P.O. daily three 
times a week on non-consecutive days, beginning at or around the time of discharge from the 
hospital.  
Pentamidine may be substituted for TMP/SMX-DS in participants with sulfa allergies or per 
investigator discretion. It will be administered aerosolized at 300 mg per nebulizer within one 
week of chemotherapy start date. 
4.2.2 Herpes Virus Prophylaxis 
Participants will be given either acyclovir 800mg PO twice daily (preferred) or valacyclovir 
500mg PO twice daily (alternate) or, if unable to tolerate PO: acyclovir 250mg/m2 IV q 12 hr.  
Reversible renal insufficiency has been reported with IV but not oral acyclovir.  Neurologic 
toxicity including delirium, tremors, coma, acute psychiatric disturbances, and abnormal EEGs 
have been reported with higher doses of acyclovir.  Should this occur, a dosage adjustment will 
be made, or the drug will be discontinued.  Acyclovir will not be used concomitantly with other 
nucleoside analogs which interfere with DNA synthesis, e.g., ganciclovir.  In renal disease, the 
dose is adjusted as per product labeling. 
Prophylaxis for pneumocystis and herpes will continue for 6 months.  If the CD4 count is less 
than 200 at six months post-chemotherapy, prophylaxis will continue for at least six months and 
until the CD4 count is greater than 200 for two consecutive measures. If a participant misses less 
than 20% of their doses for either medication a protocol deviation does not need to be filed.  
4.2.3 Fungal Prophylaxis (Fluconazole) 
This will be decided by the treating clinician.  
4.2.4 Empiric Antibiotics  
Participants will start on broad-spectrum antibiotics as per current institutional guidelines for 
fever of 38.3°C once or two temperatures of 38.0°C or above at least one hour apart, AND an 
ANC < 500/mm3.  Infectious disease consultation may be obtained for participants with 
unexplained fever or infectious complications. 
4.3 
BLOOD PRODUCT SUPPORT  
Using daily CBC’s as a guide, the participant will receive platelets and packed red blood cells 
(PRBC’s) as needed.  As a general guideline, participants may be transfused for:  
• Hemoglobin < 8 gm/dL 
• Platelets < 10,000/mm3  
Note: Participants may be transfused at a higher platelet count as clinically indicated, such 
as: 

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o Increased risk for bleeding such as undergoing an invasive procedure or 
presence of metastatic lesion likely to bleed  
o fever greater than 38.5°C 
o sepsis 
All blood products will be irradiated.  Leukocyte filters will be utilized for all blood and platelet 
transfusions to decrease sensitization to transfused WBC’s and decrease the risk of CMV 
infection. 
4.4 
NEUTROPHIL RECOVERY 
Participants may receive Filgrastim for count recovery when clinically indicated. 
4.5 
OTHER CONCOMITANT MEDICATIONS TO CONTROL SIDE EFFECTS 
Concomitant medications to control side effects of therapy may be given. Meperidine (25-50 mg) 
will be given intravenously if severe chilling develops. Other supportive therapy will be given as 
required and may include acetaminophen (650 mg q4h), indomethacin (50-75 mg q8h) and 
ranitidine (150 mg g12h). If participants require steroid therapy they will be taken off treatment.  
Participants who require transfusions will receive irradiated blood products. Ondansetron 0.15 
mg/kg/dose IV every 8 hours may be administered for nausea and vomiting. Additional anti-
emetics may be administered as needed for nausea and vomiting uncontrolled by ondansetron.  
Antibiotic coverage for central venous catheters may be provided at the discretion of the 
investigator. 
5 
BIOSPECIMEN COLLECTION 
5.1 
CORRELATIVE STUDIES FOR RESEARCH/PHARMACOKINETIC STUDIES 
The amount of blood that may be drawn from adult participants for research purposes shall not 
exceed 10.5 mL/kg or 550mL; whichever is smaller, over any 8-week period.   
5.1.1 Pre-cell infusion evaluations 
• At baseline/screening 12 CPT tube and 2 SST tubes may be collected. One or more CPT 
tube(s) may be used to collect 4mL of plasma, which could then be frozen in 4mL vials. 
PBMC from the remainder of the CPT tubes may be frozen in aliquots of 10 x 106 
cells/vial. Serum from SST tubes may be aliquoted into four vials of 0.5-1mL each. All 
samples will be processed in the Blood Processing Core (BPC). Additional research 
blood may be collected and studied under protocol 16C0061 (Tissue Procurement 
Protocol). 
• At day -6 prior to cell infusion 6 CPT tubes and 1 SST tube may be collected. One or 
more CPT tube(s) may be used to collect 4mL of plasma, which could then be frozen in 
4mL vials. PBMC from the remainder of the CPT tubes may be frozen in aliquots of 10 x 
106 cells/vial. Serum from SST tubes may be aliquoted into four vials of 0.5-1mL each. 
All samples will be processed in the Blood Processing Core (BPC). 
5.1.2 Post cell infusion evaluations 
• 2 SST tube (4mL each) may be collected daily from serum starting on the day of 

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chemotherapy and continuing through the end of hospitalization. Serum will be processed 
in the Blood Processing Core (BPC) and may be aliquoted into four vials of 0.5-1 mL 
each. 
• Once total lymphocyte count is greater than 200/mm3, the following samples may be 
drawn and sent to the Blood Processing Core (BPC) on Monday, Wednesday, and Friday 
x 5 days, then weekly (while the participant is hospitalized). Send to the Blood 
Processing Core (BPC). Attention: NCIBloodcore@mail.nih.gov. Building 10, room 
5A08 pager is 11964, tel # 240 760 6180. 
o 6 CPT tubes (8mL each). One CPT tube daily may be used to collect 4mL of plasma, 
which could then be frozen in 4mL vials. PBMC from the remainder of the CPT tubes 
may be frozen in aliquots of 10 x 106 cells/vial 
• Following discharge, at each scheduled follow-up visit 6 CPT tubes and 1 SST tube may 
be collected. One or more CPT tube(s) may be used to collect 4mL of plasma, which 
could then be frozen in 4mL vials. PBMC from the remainder of the CPT tubes may be 
frozen in aliquots of 10 x 106 cells/vial. Serum from SST tubes may be aliquoted into 
four vials of 0.5-1 mL each. All samples will be processed in the Blood Processing Core 
(BPC).  
5.1.3 Tumor Biopsies (optional) 
• Biopsy of tumors are optional and will be performed at baseline and approximately 6 
weeks following T cell infusion. Biopsies may be performed in the clinic using either 
direct visualization or indirect visualization based on the preference of the physician 
performing the biopsy. In cases where the tumor is easily visualized, multiple biopsies 
may be collected but should not exceed 5 per tumor site. Local anesthetic with lidocaine 
may be used prior to each biopsy. In cases where the tumor is not accessible using either 
direct or indirect visualization in the clinic, the biopsy performed in the operating room 
under general anesthesia. Biopsies will only be performed if it does not interfere with the 
response assessment and the participant provides consent.  
• Specimens may be transported by the assigned research nurse to Dr. Christian Hinrichs’ 
lab for sample labeling. Contact: Nisha Nagarsheth, Bldg 10, room 4B-04, phone 772-
349-3229.  
• Following labeling, samples will be transported by an assigned lab member to the Blood 
Processing Core (BPC) where they will be frozen in optimal cutting temperature 
compound. Contact: Blood Processing Core (BPC) Attention: 
NCIBloodcore@mail.nih.gov, Building 10, room 5A08 pager is 11964, tel # 240 760 
6180. 
• Some of these samples will be archived and analyzed under another protocol 16C0061 
(Tissue Procurement Protocol) if the subject is also enrolled on that study.   
5.1.4 Immunological Testing 
• Apheresis may be performed prior to and approximately 3 weeks after the treatment.  
Apheresis product will be transferred to the Blood Processing Core (BPC) Attention: 
NCIBloodcore@mail.nih.gov.  Building 10, room 5A08 pager is 11964, tel # 240 760 

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6180. Cell product may be frozen in 10 vials at concentration 100 x 106 cells/mL and 
additional vials at 300 x 106 cells/mL. 
• At other time points, peripheral blood lymphocytes (PBL) and plasma may be obtained 
from whole blood by purification using centrifugation. These samples may be transferred 
directly to the Blood Processing Core (BPC) lab for processing. Plasma may be frozen in 
4mL vials. PBL may be frozen in aliquots of 10 x 106 cells/vial 
• Possible laboratory research studies on tumor biopsies are as follows: Expression of p16, 
CD3, CD4, CD8, MHC I, and MHC II by immunohistochemistry; flow cytometry to 
determine the frequency of E7 TCR T cells in the samples; generation and 
characterization of TIL cells; generation and characterization of tumor cell lines. IHC 
quantification may be performed and include scoring of the intensity and frequency of 
staining. Flow cytometry data may be analyzed with FlowJo software.  
• Possible laboratory research studies on PBMC and PBL are as follows:  Specific 
cytolysis determined by impedance-based assay, frequency of effector cells as 
determined by ELISPOT, quantity of cytokine production as determined by coculture 
assay with cytokine quantification, cytokine production by intracellular flow cytometry, 
phenotypic analysis by flow cytometry. Immunological assays may be standardized by 
the inclusion of 1) pre-infusion PBMC and 2) an aliquot of the T cells cryopreserved at 
the time of infusion.  
• Possible laboratory research on serum or plasma are as follows: HPV DNA 
quantification, cytokine quantification 
• The planned methods for performing the laboratory studies above are as described in 
Stevanovic, et al, Journal of Clinical Oncology, 2015 and Draper, et al, Clinical Cancer 
Research, 2015. [12, 14] 
• The laboratory studies are considered exploratory. Statistical analysis may be performed 
in consultation with a biostatistician.  
• Specimens collected in the course of this research project may be banked and used in the 
future to investigate new scientific questions related to this study and protocol 16C0061 
(Tissue Procurement Protocol). 
• Genomic studies will not be pre-planned and will be conducted under protocol 16C0061 
(Tissue Procurement Protocol).    
5.2 
SUMMARY OF SAMPLE COLLECTION 
Test/ 
assay 
Volume blood 
(approx) 
Type of 
tube 
Collection point  
(+/- 48hrs) 
Location of 
specimen analysis 
Plasma/ 
PBMC 
48-96 mL 
CPT 
<4 weeks prior to cell 
infusion, day-6  
Clinical 
Pharmacology 
Blood Processing 
Core (BPC), Bldg 
10 room 5A08.  
 

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Test/ 
assay 
Volume blood 
(approx) 
Type of 
tube 
Collection point  
(+/- 48hrs) 
Location of 
specimen analysis 
Serum 
8-16 mL 
SST 
<4 weeks prior to cell 
infusion, day-6 
Clinical 
Pharmacology 
Blood Processing 
Core (BPC), Bldg 
10 room 5A08.  
 
Plasma/ 
PBMC 
48 mL 
CPT 
Post cell infusion day 1, 
3, every Mon/Wed/Fri x 5 
days, weekly until 
discharge and follow-up 
visits 
Clinical 
Pharmacology 
Blood Processing 
Core (BPC), Bldg 
10 room 5A08.  
 
Serum 
Variable, based on 
length of 
hospitalization and 
duration of follow-up 
SST 
Daily at the start of 
chemo until discharge 
from hospital, follow-up 
visits 
Clinical 
Pharmacology 
Blood Processing 
Core (BPC), Bldg 
10 room 5A08.  
 
Biopsy 
(optional)  
N/A 
N/A 
Prior to starting 
chemotherapy and 
approximately 6 weeks 
following T cell infusion 
Processed in Hinrichs 
Lab, then transported 
to  
Clinical 
Pharmacology 
Blood Processing 
Core (BPC), Bldg 
10 room 5A08.  
 
5.3 
GENE THERAPY-SPECIFIC FOLLOW-UP  
Persistence of TCR transduced cells will be assessed by quantitative PCR and/or flow cytometry 
at follow-up visits 1, 3, 6 and 12 months after cell infusion, or until TCR-expressing cells are no 
longer detectable.  If any participant shows an increasing population of TCR gene transduced T 
cells at month six or later (by FACS staining or qPCR), the previously archived samples will be 
subjected to techniques to identify predominant clonal populations of transduced cells that would 
suggest transformation. These cells will be obtained from the CPTs drawn for research at follow 
up visits or under the long-term gene therapy follow up protocol if the participant is off study. 
Participants’ blood samples will be obtained and undergo analysis for detection of replication 
competent retroviruses (RCR) by PCR prior to cell infusion and at 3, 6, and 12 months post cell 
administration.  Blood samples will be archived annually thereafter if all previous testing has 
been negative with a brief clinical history.  These cells will be obtained from the CPTs drawn for 
research at follow up visits or under the separate long-term gene therapy follow up protocol 
(20C0051) if the participant is off study. 

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5.4 
SAMPLE STORAGE, TRACKING AND DISPOSITION 
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management System. 
Should a CRIS screen not be available, the CRIS downtime procedures will be followed. 
Samples will not be sent outside NIH without appropriate approvals and/or agreements, if 
required.  
5.4.1 Samples Managed by Dr. Figg’s Blood Processing Core (BPC) 
5.4.1.1 Blood Collection 
Please e-mail NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples (the 
Friday before is preferred). 
For sample pickup, page 102-11964. 
For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 
240-760-6190 (main clinical pharmacology lab number). 
For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov 
The samples will be processed, barcoded, and stored in Dr. Figg’s lab until requested by the 
investigator. 
5.4.1.2 Sample Data Collection 
All samples sent to the Blood Processing Core (BPC) will be barcoded, with data entered and 
stored in Labmatrix utilized by the BPC. This is a secure program, with access to Labmatrix 
limited to defined Figg lab personnel, who are issued individual user accounts. Installation of 
Labmatrix is limited to computers specified by Dr. Figg. These computers all have a password 
restricted login screen.  
Labmatrix creates a unique barcode ID for every sample and sample box, which cannot be traced 
back to participants without Labmatrix access. The data recorded for each sample includes the 
participant ID, name, trial name/protocol number, time drawn, cycle time point, dose, material 
type, as well as box and freezer location. Participant demographics associated with the clinical 
center participant number are provided in the system. For each sample, there are notes associated 
with the processing method (delay in sample processing, storage conditions on the ward, etc.). 
5.4.2 Hinrichs Laboratory 
Samples transferred to the Hinrichs laboratory will be barcoded and tracked with Labmatrix. 
Laboratory research data will be stored on the NCI secure server in the Hinrichs laboratory 
folder with secure access by laboratory personnel only. Access to personally identifiable 
information (PII) is limited to the PI and study personnel who interact directly with the 
participant and their samples. 
5.4.3 Protocol Completion/Sample Destruction  
Barcoded samples are stored in barcoded boxes in a locked freezer at either -20 or -80°C 
according to stability requirements.  These freezers are located onsite in the BPC and offsite at 
NCI Frederick Central Repository Services in Frederick, MD. Visitors to the laboratory are 
required to be accompanied by laboratory staff at all times.  

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Access to stored clinical samples is restricted. Samples will be stored until requested by a 
researcher named on the protocol. All requests are monitored and tracked in LabMatrix. All 
researchers are required to sign a form stating that the samples are only to be used for research 
purposes associated with this trial (as per the IRB approved protocol) and that any unused 
samples must be returned to the BPC. It is the responsibility of the NCI Principal Investigator to 
ensure that the samples requested are being used in a manner consistent with IRB approval. 
Following completion of this study, samples will remain in storage as detailed above. Access to 
these samples will only be granted following IRB approval of an additional protocol, granting 
the rights to use the material.  
If, at any time, a participant withdraws from the study and does not wish for their existing 
samples to be utilized, the individual must provide a written request. Following receipt of this 
request, the samples will be destroyed (or returned to the participant, if so requested).. The PI 
will record any loss or unanticipated destruction of samples as a deviation. Reporting will be per 
the requirements of section 7.2. 
Sample barcodes are linked to participant demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use of the 
Labmatrix. It is critical that the sample remains linked to participant information such as race, 
age, dates of diagnosis and death, and histological information about the tumor, in order to 
correlate genotype with these variables. 
5.5 
SAMPLES FOR GENETIC/GENOMIC ANALYSIS 
Genomic studies will be conducted under protocol 16C0061 (Tissue Procurement Protocol) if 
participant is co-enrolled. 
6 
DATA COLLECTION AND EVALUATION  
6.1 
DATA COLLECTION 
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system, C3D and Labmatrix, and ensuring data accuracy, consistency and timeliness. 
The principal investigator, associate investigators/research nurses and/or a contracted data 
manager will assist with the data management efforts. All data obtained during the conduct of the 
protocol will be kept in secure network drives or in approved alternative sites that comply with 
NIH security standards. Primary and final analyzed data will have identifiers so that research 
data can be attributed to an individual human subject participant. 
The key for assignment of participant code identification numbers with the personal identifiers 
will be stored in a secure database. This key will not be shared with other investigators. 
Investigators conducting the individual sample testing will only have access to coded 
identification numbers and coded participant information (i.e., treatment regimens, treatment 
responses, diagnoses, pathology information). 
End of study procedures: Data will be stored according to HHS, FDA regulations and NIH 
Intramural Records Retention Schedule as applicable.  
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 

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requirements in section 7.2.1. 
6.1.1 Adverse Event (AE) Recording 
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event.  
Document AEs from the first study intervention, Study Day -6, through Day 21. Beyond 21 days 
after the last intervention, only adverse events which are serious and related to the study 
intervention need to be recorded.  
6.1.2 Reporting of Laboratory Events 
An abnormal laboratory value will be recorded in the database as an AE only if the laboratory 
abnormality is characterized by any of the following: 
• 
Results in discontinuation from the study 
• 
Is associated with clinical signs or symptoms  
• 
Requires treatment or any other therapeutic intervention 
• 
Is associated with death or another serious adverse event, including hospitalization.  
• 
Is judged by the Investigator to be of significant clinical impact 
• 
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the 
participant’s outcome. 
• 
Grade 1 AEs will not be recorded  
 
6.2 
DATA SHARING PLANS 
6.2.1 Human Data Sharing Plan 
What data will be shared? 
I will share human data generated in this research for future research as follows: 
• Coded and linked data in an NIH-funded or approved public repository.   
• Coded and linked data in BTRIS (automatic for activities in the Clinical Center) 
• Identified or coded and linked data with approved outside collaborators under appropriate 
agreements. 
How and where will the data be shared?  
Data will be shared through: 
• An NIH-funded or approved public repository: Clinicaltrials.gov  
• BTRIS (automatic for activities in the Clinical Center) 
• Approved outside collaborators under appropriate individual agreements. 
• Publication and/or public presentations. 
When will the data be shared?  

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• Before publication. 
• At the time of publication or shortly thereafter. 
6.3 
GENOMIC DATA SHARING PLAN 
The GDS Policy does not apply to this protocol because there are no genomic tests done on this 
study (i.e., any genomic studies would be done on a separate protocol for participants who are 
co-enrolled). 
6.4 
RESPONSE CRITERIA 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) for participants with solid tumors [27]. Changes in the largest diameter 
(unidimensional measurement) of the tumor lesions and the shortest diameter in the case of 
malignant lymph nodes are used in the RECIST criteria. Imaging modalities used in this study 
will be consistent with current standard of care according to NCCN guidelines. Scans will be 
obtained at 4-week intervals as outlines in section 3.1.1 
6.4.1 Disease Parameters 
Measurable disease:  Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as:  
• By chest x-ray: >20 mm;  
• By CT scan:  
o Scan slice thickness 5 mm or under: as >10 mm 
o Scan slice thickness >5 mm: double the slice thickness  
• With calipers on clinical exam: >10 mm.   
All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph 
node must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will 
be measured and followed. 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable. 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same participant, these are preferred for selection as target lesions. 

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Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline.  Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected.  A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up.  
6.4.2 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical lesions:  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed using calipers 
(e.g., skin nodules).  In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
Conventional CT and MRI:  This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  
MRI is also acceptable in certain situations (e.g., for body scans).   
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement.  Furthermore, the availability of 
MRI is variable globally.  As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease.  
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence.  It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases.  Ideally, the same type of scanner should be used and the 

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image acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
PET-CT:  At present, the low dose or attenuation correction CT portion of a combined PET-CT 
is not always of optimal diagnostic CT quality for use with RECIST measurements.  However, if 
the site can document that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be 
used for RECIST measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time.  Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not routinely or serially 
performed.   
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next.  If new lesions are identified by ultrasound in the course of the study, confirmation by CT 
or MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used instead 
of CT in selected instances. 
Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor evaluation is 
not advised.  However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence following 
complete response (CR) or surgical resection is an endpoint. 
Tumor markers:  Tumor markers alone cannot be used to assess response.  If markers are initially 
above the upper normal limit, they must normalize for a participant to be considered in complete 
clinical response.  Specific guidelines for both CA-125 response (in recurrent ovarian cancer) 
and PSA response (in recurrent prostate cancer) have been published.[28-30]  In addition, the 
Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be 
integrated with objective tumor assessment for use in first-line trials in ovarian cancer.[31] 
Cytology, Histology:  These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
FDG-PET:  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 

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the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively 
described in the protocol and supported by disease-specific medical literature for the 
indication.  However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
6.4.3 PERCIST Criteria Summary 
Note:  Participants that do not have measurable disease by RECIST v1.1 may have their disease 
measured using PERCIST [32-34]. If participants have disease measurable by both criteria, 
response will be monitored using RECIST v1.1. 
Response to Treatment 
The PERCIST categories for response to treatment 
The PERCIST categories for response to treatment 
Complete metabolic response (CMR) 
Complete resolution of FDG uptake in all 
lesions 
Partial metabolic response (PMR) 
 
≥ 30% Reduction of the SULpeak and an 
absolute drop of 0.8 SULpeak units 
Progressive metabolic disease (PMD) 
 
 
≥ 30% Increase in the SULpeak of the FDG 
uptake and an absolute increase of 0.8 
SULpeak, or appearance of FDG-avid new 
lesions 
Stable metabolic response (SMD) 
Does not qualify for CMR, PMR, or PMD 
 
1. Complete Metabolic Response: a target lesion must show complete resolution 
of FDGuptake, with FDG uptake less than the mean SUL of the liver and 
indistinguishable from that of the surrounding background. 
a. This requires data for all other lesions to return to background levels and that no 
new FDG-avid lesions in a pattern typical of cancer appear.  

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b. When no FDG-avid tumor is visible, the mean SULpeak of the anatomic location 
situated as close as possible to the site of the original tumor should be measured.  
c. A normal structure with high FDG uptake, such as a bowel loop that occupies the 
site of the original target lesion, should be avoided in the measurement of results 
of the follow-up study.  
d. A complete metabolic response according to PERCIST 1.0 does not require 
the SULpeak to decrease to zero. 
2. Partial metabolic response: a decrease of greater than or equal to 30% and of at least 
0.8 SUL units must be shown between the most intense evaluable lesion at baseline and 
the most intense lesion at follow-up (not necessarily the same lesion).  
a. Also requires the following:  
i. a decrease in SULpeak of greater than or equal to 0.8 SUL units in the 
target lesion 
ii. no new FDG-avid lesions in a pattern typical of cancer 
iii. no identifiable increase in size greater than 30% in the target lesion 
iv. no SULpeak or identifiable increase in size greater than 30% in a nontarget 
lesion.  
3. Stable metabolic disease: an increase or decrease in SULpeak of less than 30% is 
required.  
4. Progressive Metabolic Disease: Lesions must show an increase of greater than or equal 
to 30% and an increase of at least 0.8 SUL units in a target lesion or development of a 
new lesion or more than one new lesions.  
a. This can include new FDG-avid lesions in a pattern typical of cancer, an increase 
in SULpeak or an identifiable anatomic increase in size greater than or equal to 
30% in target lesions, or unequivocal progression in nontarget lesions. 
*The choice between partial metabolic response (PMR) and stable metabolic disease (SMD) 
depends on the difference between the percentage of change in SUL and absolute SUL. If the 
decrease from baseline to follow-up is sufficient, the response is PMR. If the decrease is less 
than 30% or 0.8 SUL units, the response is SMD 
Required Baseline Parameters for PET 
• Measurement of the “hottest” single tumor and background area on images, usually of the 
liver, is required at baseline. (if diseased liver, can use descending thoracic aorta) 
• A single target lesion at each time point is selected as the primary parameter on the basis 
of the concept that the most metabolically active tumor focus corresponds to the most 
aggressive portion of the tumor, which is the most clinically important area.  
• With PERCIST, standardized uptake value corrected for lean body mass (SUL) are used 
and the maximum over 1cc volumes of interest (SULpeak) is chosen instead of the widely 
used single-pixel maximum standardized uptake value (SUVmax).  This fixed-volume 
approach is used to minimize the effect of differences in voxel sizes, reducing variability 

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and bias.  
  Target Lesion at Baseline 
• The SULpeak is measured in the single hottest tumor.  
• For a tumor to be measurable at baseline, the SULpeak must be greater than or equal to one 
and a half times the mean SUL in the 3-cm diameter spherical VOI plus two times its 
standard deviation to have a minimum threshold for evaluation.  
• A minimal level of tumor uptake at baseline is proposed to ensure that a decline 
in FDG uptake with therapy can be measured in the dynamic range of the imager (ie, that 
it remains higher than background uptake), to decrease the likelihood that a change is due 
to chance, and to minimize overestimation of response or progression. 
• When the SULpeak of the tumor at baseline is lower than this threshold, the tumor is 
considered not measurable with PERCIST 1.0 
Follow-up imaging 
• Known areas of iatrogenic or benign FDG uptake should not be selected as the target 
lesion, even when such a focus has the highest SULpeak value.  
• PERCIST requires the reader to select the hottest tumor at each time point, and the target 
lesion selected at baseline may not the hottest tumor at follow-up.  
• To be assessable, differences between baseline and follow-up SUL in the liver must 
be (a) less than or equal to 20% of the larger of the two liver measurements and (b) less 
than or equal to 0.3 SUL units.  
• The imaging conditions that allow for comparison are as follows: (a) The difference 
between the injection-to-imaging time of the baseline study and to that of the follow-up 
study should, though not required, to be less than or equal to 15 minutes. (b) The 
injection- to-imaging start time for both baseline and follow-up imaging should, though 
not required, to be greater than or equal to 50 minutes and less than or equal to 70 
minutes.  
Objective Response 
• PERCIST encourages recording of the percentage of change in tumor metabolism as a 
continuous variable with notation of the number of weeks since treatment was begun. The 
percentage of change in target lesion(s) is computed as: 
 100 · (FTLSULpeak – BTLSULpeak)/BTLSULpeak 
o FTLSULpeak is the SULpeak of the follow-up target lesion  
o BTLSULpeak is the SULpeak of the baseline target lesion. 
6.4.4 RECIST Criteria Summary 
6.4.4.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 

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Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum of diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm.  (Note:  the appearance of one or more new lesions is also 
considered progressions). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum of diameters while on study. 
6.4.4.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis). 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
participant to be considered in complete clinical response. 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally trump 
target lesion status.  It must be representative of overall disease status change, not a single lesion 
increase.     
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
6.4.4.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The participant's best response assignment 
will depend on the achievement of both measurement and confirmation criteria. 
For Participants with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-
CR/Non-PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not 
evaluated 
No 
PR 

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PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a 
new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression. 
Note: Participants with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease 
progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
6.4.5 Duration of Response 
Duration of overall response:  The duration of overall response is measured from the time cell 
infusion until the first date that progressive disease is objectively documented (taking as 
reference for progressive disease the smallest measurements recorded since the treatment 
started). 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  
6.5 
TOXICITY CRITERIA 
The following adverse event management guidelines are intended to ensure the safety of each 

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participant while on the study.  The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 
5.0.  A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm).  
6.6 
FEASIBILITY ASSESSMENT 
Feasibility will be assessed by three criteria. Failure by any one criterion will be scored as a 
feasibility failure. 
1. Delivery of the E7 TCR T cell induction therapy without an increase in tumor T or N 
stage (for example an increase from T1 to T2) between baseline and the last response 
assessment before referral for definitive treatment (with an absolute increase in tumor 
size of at least 5 mm). This criterion will be assessed by determining the T and N stage at 
baseline and at the 6-week response assessment. An increase in either T stage or N stage 
will be scored as a feasibility failure. Participants that develop hyper-progression at the 3-
week safety check will also be considered a feasibility failure. 
2. Initiation of definitive therapy without a delay in treatment related to toxicity of the 
induction therapy. This criterion will be assessed by review of the medical records from 
the treating center and by communication with the clinical team delivering the definitive 
therapy. If there is a delay, the toxicity type and grade that was the cause will be 
recorded. The duration of the delay that resulted from the toxicity will be recorded. Any 
delay related to the toxicity of the induction therapy will be scored as a feasibility failure. 
Furthermore, participants that require dose reduction in chemoradiation that is definitely 
due to the induction therapy will be scored as a feasibility failure.  
3. If any participant starts the conditioning regimen chemotherapy but does not receive cells 
for any protocol-related reason (e.g., toxicity of the conditioning regimen, manufacturing 
failure, tumor hyper-progression), it will be considered a feasibility failure.  
7 
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN 
7.1 
DEFINITIONS  
Please refer to definitions provided in Policy 801: Reporting Research Events found here. 
7.2 
OHSRP OFFICE OF COMPLIANCE AND TRAINING 
7.2.1 Expedited Reporting 
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found here. Note: Only IND Safety Reports that 
meet the definition of an unanticipated problem will need to be reported per these policies. 
7.2.2 IRB Requirements for PI Reporting at Continuing Review 
Please refer to the reporting requirements in Policy 801: Reporting Research Events found here.  
7.3 
NCI CLINICAL DIRECTOR REPORTING  
Problems expeditiously reported to the OHSRP in iRIS will also be reported to the NCI Clinical 

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Director.  A separate submission is not necessary as reports in iRIS will be available to the 
Clinical Director. 
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email to the Clinical Director unless they are due to 
progressive disease.   
To report these deaths, please send an email describing the circumstances of the death to Dr. 
Dahut at NCICCRQA@mail.nih.gov within one business day of learning of the death. 
7.4 
INSTITUTIONAL BIOSAFETY COMMITTEE (IBC) REPORTING CRITERIA 
7.4.1 Serious Adverse Event Reports to IBC 
The Principal Investigator (or delegate) will notify IBC of any unexpected fatal or life-
threatening experience associated with the use of E7 TCR T cells as soon as possible but in no 
event later than 7 calendar days of initial receipt of the information.  Serious adverse events that 
are unexpected and associated with the use of the E7 TCR T cells but are not fatal or life-
threatening, must be reported to the NIH IBC as soon as possible, but not later than 15 calendar 
days after the investigator’s initial receipt of the information.  Adverse events may be reported 
by using the FDA Form 3500a. 
7.4.2 Annual Reports to IBC 
Within 60 days after the one-year anniversary of the date on which the IBC approved the initial 
protocol, and after each subsequent anniversary until the trial is completed, the Principal 
Investigator (or delegate) shall submit the information described below.  Alternatively, the IRB 
continuing review report can be sent to the IBC in lieu of a separate report.  Please include the 
IBC protocol number on the report. 
7.4.2.1 Clinical Trial Information  
A brief summary of the status of the trial in progress or completed during the previous year. The 
summary is required to include the following information:  
• the title and purpose of the trial  
• clinical site 
• the Principal Investigator 
• clinical protocol identifiers;  
• participant population (such as disease indication and general age group, e.g., adult or 
pediatric);  
• the total number of participants planned for inclusion in the trial; the number entered into 
the trial to date whose participation in the trial was completed; and the number who 
dropped out of the trial with a brief description of the reasons  
• the status of the trial, e.g., open to accrual of subjects, closed but data collection ongoing, 
or fully completed,  
• if the trial has been completed, a brief description of any study results.  

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7.4.2.2 Progress Report and Data Analysis  
Information obtained during the previous year's clinical and non-clinical investigations, 
including:  
• a narrative or tabular summary showing the most frequent and most serious adverse 
experiences by body system 
• a summary of all serious adverse events submitted during the past year 
• a summary of serious adverse events that were expected or considered to have causes not 
associated with the use of the gene transfer product such as disease progression or 
concurrent medications 
• if any deaths have occurred, the number of participants who died during participation in 
the investigation and causes of death 
• a brief description of any information obtained that is pertinent to an understanding of the 
gene transfer product’s actions, including, for example, information about dose-response, 
information from controlled trials, and information about bioavailability.  
7.5 
NIH REQUIRED DATA AND SAFETY MONITORING PLAN 
7.5.1 Principal Investigator/Research Team  
The clinical research team will meet weekly on a regular basis when participants are being 
actively treated on the trial to discuss each participant. Decisions about dose level enrollment and 
dose escalation if applicable will be made based on the toxicity data from prior participants.  
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Events meeting requirements for expedited reporting as described in 
section 7.2.1 will be submitted within the appropriate timelines.   
The principal investigator will review adverse event and response data on each participant to 
ensure safety and data accuracy. The principal investigator will personally conduct or supervise 
the investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.  
7.5.2 Safety Monitoring Committee (SMC) 
This protocol will be periodically reviewed by an intramural Safety Monitoring Committee. 
Initial review will occur as soon as possible after the annual NIH Intramural IRB continuing 
review date. Subsequently, each protocol will be reviewed as close to annually as the quarterly 
meeting schedule permits or more frequently as may be required by the SMC based on the risks 
presented in the study. For initial and subsequent reviews, protocols will not be reviewed if there 
is no accrual within the review period.  
The SMC review will focus on unexpected protocol-specific safety issues that are identified 
during the conduct of the clinical trial. 
Written outcome letters will be generated in response to the monitoring activities and submitted 
to the Principal investigator and Clinical Director or Deputy Clinical Director, CCR, NCI. 

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8 
SPONSOR PROTOCOL/SAFETY REPORTING 
8.1 
DEFINITIONS 
8.1.1 Adverse Event  
Any untoward medical occurrence in a participant or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product (ICH E6 (R2)) 
8.1.2 Serious Adverse Event (SAE) 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
• 
Death, 
• 
A life-threatening adverse event (see section 8.1.3) 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
o A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery 
arranged prior to the start of the study), a planned hospitalization for pre-existing 
condition, or a procedure required by the protocol, without a serious deterioration in 
health, is not considered a serious adverse event. 
o A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for participant convenience) is not considered a serious adverse event.  
o Emergency room visits or stays in observation units that do not result in admission to 
the hospital would not be considered a serious adverse event. The reason for seeking 
medical care should be evaluated for meeting one of the other serious criteria. 
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect. 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the participant or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. 
8.1.3 Life-threatening  
An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of 
either the investigator or sponsor, its occurrence places the participant or subject at immediate 
risk of death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death. (21CFR312.32) 

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8.1.4 Severity 
The severity of each Adverse Event will be assessed utilizing the CTCAE version 5.0. 
8.1.5 Relationship to Study Product 
All AEs will have their relationship to study product assessed using the terms:  related or not 
related.   
• Related – There is a reasonable possibility that the study product caused the adverse 
event. Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the adverse event. 
• Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event. 
8.2 
ASSESSMENT OF SAFETY EVENTS 
AE information collected will include event description, date of onset, assessment of severity 
and relationship to study product and alternate etiology (if not related to study product), date of 
resolution of the event, seriousness and outcome. The assessment of severity and relationship to 
the study product will be done only by those with the training and authority to make a diagnosis 
and listed on the Form FDA 1572 as the site principal investigator or sub-investigator.  AEs 
occurring during the collection and reporting period will be documented appropriately regardless 
of relationship.  AEs will be followed through resolution. 
SAEs will be: 
• 
Assessed for severity and relationship to study product and alternate etiology (if not 
related to study product) by a licensed study physician listed on the Form FDA 1572 as 
the site principal investigator or sub-investigator. 
• 
Recorded on the appropriate SAE report form, the medical record and captured in the 
clinical database. 
• 
Followed through resolution by a licensed study physician listed on the Form FDA 1572 
as the site principal investigator or sub-investigator. 
For timeframe of recording adverse events, please refer to section 6.1. All serious adverse events 
recorded from the time of first investigational product administration must be reported to the 
sponsor with the exception of any listed in section 8.4.  
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS 
Any AE that meets protocol-defined serious criteria or meets the definition of Adverse Event of 
Special Interest that require expedited reporting must be submitted immediately (within 24 hours 
of awareness) to OSRO Safety using the CCR SAE report form. Any exceptions to the expedited 
reporting requirements are found in section 8.4. 
All SAE reporting must include the elements described in section 8.2. 
SAE reports will be submitted to the Center for Cancer Research (CCR) at: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  CCR SAE report form 
and instructions can be found at: 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=157942842  

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Following the assessment of the SAE by OSRO, other supporting documentation of the event 
may be requested by the OSRO Safety and should be provided as soon as possible. 
8.4 
WAIVER OF EXPEDITED REPORTING TO CCR  
As death due to disease progression is part of the study objectives (relapse free survival), and 
captured as an endpoint in this study, it will not be reported in expedited manner to the sponsor. 
However, if there is evidence suggesting a causal relationship between the study drug and the 
event, report the event in an expedited manner according to section 8.3. 
8.4.1 Specific Toxicities 
Hematological toxicities as outlined below will not be included in expedited reporting to CCR 
because these are expected toxicities from the conditioning regimen (commercial product): 
 
CTCAE System 
Organ Class 
Adverse 
Event 
Grade 
Prolongation of 
Hospitalization 
Expected 
Frequency Attribution 
Investigations 
Neutrophil 
count 
decreased 
1-3 
Expected 
100% 
Commercial Product 
(Cyclophosphamide and 
fludarabine) 
Investigations 
Neutrophil 
count 
decreased 
4, if < 14 
days 
Expected 
100% 
Commercial Product 
(Cyclophosphamide and 
fludarabine) 
Infection 
Febrile 
Neutropenia 
3-4 
Expected 
60% 
Commercial Product 
(Cyclophosphamide and 
fludarabine in 
combination with 
aldesleukin) 
Blood and 
lymphatic system 
disorders 
Anemia 
1-3 
Expected 
100% 
Commercial Product 
(Cyclophosphamide and 
fludarabine) 
Investigations 
Platelet count 
decreased 
1-3 
Expected 
100% 
Commercial Product 
(Cyclophosphamide and 
fludarabine) 
Investigations 
Platelet count 
decreased 
4, if < 14 
days 
Expected 
100% 
Commercial Product 
(Cyclophosphamide and 
fludarabine) 
Investigations 
White blood 
cell decreased 
1-4 
Expected 
100% 
Commercial Product 
(Cyclophosphamide and 
fludarabine) 

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CTCAE System 
Organ Class 
Adverse 
Event 
Grade 
Prolongation of 
Hospitalization 
Expected 
Frequency Attribution 
Investigations 
Lymphocyte 
count 
decreased 
1-4 
Expected 
100% 
Commercial Product 
(Cyclophosphamide and 
fludarabine) 
Investigations 
CD4 
lymphocytes 
decreased 
1-4 
Expected 
100% 
Commercial Product 
(Cyclophosphamide and 
fludarabine) 
 
For participants that start standard of care treatment prior to 21 days from cell infusion, we will 
only record and report adverse events and serious adverse events that are possibly related to E7 
TCR T cells.  
The PI will submit a summary table of all grade 3-5 events, whether or not considered related to 
the product, every 6 months. The report shall include the number of participants treated in the 
timeframe, the number of events per AE term per grade which occurred in the 6-month 
timeframe and in total since the start of the study, attribution, and type/category of serious.  
Reports will be submitted to the Center for Cancer Research (CCR) at 
OSROSafety@mail.nih.gov. 
The Sponsor might request case summaries for those events if, upon review, the Sponsor 
determines that an aggregate safety report is required (21CFR312.32(c)(1)(iv)). 
8.5 
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS 
Reporting will be per the collaborative agreement with Kite Pharma (CRADA #03022). 
8.6 
REPORTING PREGNANCY  
8.6.1 Maternal exposure 
If a participant becomes pregnant during the course of the study, the study treatment should be 
discontinued immediately, and the pregnancy reported to the Sponsor no later than 24 hours of 
when the Investigator becomes aware of it. The Investigator should notify the Sponsor no later 
than 24 hours of when the outcome of the Pregnancy become known, 
Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects 
and spontaneous miscarriages that meet serious criteria (section 8.1.2) should be reported as 
SAEs.  
The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth, or congenital abnormality) should be followed up and documented. 
8.7 
REGULATORY REPORTING FOR STUDIES CONDUCTED UNDER CCR-SPONSORED IND 
Following notification from the investigator, CCR, the IND sponsor, will report any suspected 
adverse reaction that is both serious and unexpected.  CCR will report an AE as a suspected 

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adverse reaction only if there is evidence to suggest a causal relationship between the study 
product and the adverse event.  CCR will notify FDA and all participating investigators (i.e., all 
investigators to whom the sponsor is providing drug under its INDs or under any investigator’s 
IND) in an IND safety report of potential serious risks from clinical trials or any other source, as 
soon as possible, in accordance to 21 CFR Part 312.32.  
All serious events will be reported to the FDA at least annually in a summary format. 
8.8 
SPONSOR PROTOCOL NON-ADHERENCE REPORTING 
Protocol non-adherence is defined as any noncompliance with the clinical trial protocol, GCP, or 
protocol-specific procedural requirements on the part of the participant, the Investigator, or the 
study site staff inclusive of site personnel performing procedures or providing services in support 
of the clinical trial. 
It is the responsibility of the study Staff to document any protocol non-adherence identified by 
the Staff or the site Monitor on the OSRO Site Protocol Non-Adherence Log.  The protocol-
specific, cumulative non-adherence log should be maintained in the site essential documents file 
and submitted to OSRO via OSROMonitoring@mail.NIH.gov on the first business day of each 
month over the duration of the study. In addition, any non-adherence to the protocol should be 
documented in the participant’s source records and reported to the local IRB per their guidelines. 
OSRO required protocol non-adherence reporting is consistent with E6(R2) GCP: Integrated 
Addendum to ICH E6(R1): 4.5 Compliance with Protocol; 5.18.3 (a), and 5.20 Noncompliance; 
and ICH E3 16.2.2 Protocol deviations. 
9 
CLINICAL MONITORING  
Clinical site monitoring is conducted to ensure that the rights of the participants are protected, 
that the study is implemented per the approved protocol, Good Clinical Practice and standard 
operating procedures, and that the quality and integrity of study data and data collection methods 
are maintained.  Monitoring for this study will be performed by NCI CCR Office of Sponsor and 
Regulatory Oversight (OSRO) Monitoring based on OSRO standards, FDA Guidance E6(R2) 
Good Clinical Practice: Integrated Addendum to ICH E6(R1) March 2018, and applicable 
regulatory requirements. 
Details of clinical site monitoring will be documented in a Clinical Monitoring Plan (CMP) 
developed by OSRO. CMPs will be protocol-specific, risk-based and tailored to address human 
subject protections and integrity of the study data. The intensity and frequency of monitoring 
will be based on several factors, including study type, phase, risk, complexity, expected 
enrollment rate, and any unique attributes of the study and the site. OSRO Monitoring visits and 
related activities will be conducted throughout the life cycle of each protocol, with the first 
activity being before study start to conduct a Site Assessment Visit (SAV) (as warranted), 
followed by a Site Initiation Visit (SIV), Interim Monitoring Visit(s) (IMVs), and a study Close-
Out Visit (COV). 
Some monitoring activities may be performed remotely, while others will take place at the study 
site(s).  Monitoring visit reports will describe visit activities, observations, findings of protocol 
non-adherence and associated action items or follow-up required for resolution of findings.  
Monitoring reports will be distributed to the study PI, NCI CCR QA, coordinating center (if 
applicable) and the OSRO regulatory file. 

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If protocol non-adherence is identified by the Monitor (i.e., any noncompliance with the clinical 
trial protocol, GCP, or protocol-specific procedural requirements on the part of the participant, 
the Investigator, or the site Staff) the Monitor will note the observation, review with site Staff 
and if unresolved, request that the Staff document the non-adherence on the protocol-specific 
OSRO Site Protocol Non-Adherence Log (see Section 8.8).   
10 STATISTICAL CONSIDERATIONS 
10.1 STATISTICAL HYPOTHESES 
10.1.1 Primary efficacy endpoints:  
The primary objective of this protocol is to determine the feasibility of induction E7 TCR T cell 
therapy for FIGO (2018) stage IIB-IVA, HPV16+ cervical cancer. 
The endpoint to be measured is the fraction of subjects for whom E7 TCR induction therapy is 
feasible as defined in section 6.6.  
10.1.2 Secondary efficacy endpoints: 
The secondary endpoints will be to assess the relapse-free survival at 2 years and 5 years 
following definitive standard of care therapy, to evaluate the safety of E7 induction therapy, to 
determine the percentage of E7 TCR T cells following completion of chemoradiation and to 
assess objective response rate following E7 induction therapy.   
10.2 SAMPLE SIZE DETERMINATION 
This study evaluates the fraction of participants who can receive induction therapy with E7 TCR 
cells without failing the feasibility criteria in section 6.6. For a given participant, this will be 
considered a success. It would be desirable if the fraction of participants who are able to achieve 
success were consistent with 80-85%. The trial will first enroll 5 participants who are FIGO 
(2018) stage IIIC-IVA to assess feasibility in a small number of high-risk participants.  If after 
these first 5 participants have been treated, the number of participants with a success is not at 
least 3 (3/5=60%), the trial will stop since the one sided 90% upper confidence bound on 2/5 is 
75.3%, indicating inconsistency with a desirable 80% success rate or greater.  If at least 3 have 
success, these 5 participants will be included in this pilot trial of 15 evaluable participants who 
undergo the E7 TCR cell administration. If in these 15 there are 12 or more who can be 
considered a success, the probability of this occurring is 9.1% if the true probability of success is 
60%, 17.0% if the true probability of success is 65%, 30% if the true probability of success is 
70%, 65% if the true probability of success is 80%, and 82% if the true probability of success is 
85%. Thus, if 12/15 (80%) or more of participants who undergo the E7 TCR T cell 
administration achieve a success, this would be more consistent with 80-85% or more probability 
of this being the case than with 65% or less probability of this being the case, and thus would be 
considered an acceptable fraction.  
It is anticipated that up to one participant per month may enroll onto this trial. Thus, accrual is 
expected to be completed in approximately 1.5 years. To allow for a small number of inevaluable 
participants, up to 18 participants may be treated. A maximum of 5 participants evaluable for 
feasibility will be treated in the lead-in cohort (cohort 1). A maximum of 10 participants 
evaluable for feasibility will be treated in the post-lead-in cohort (cohort 2). The accrual ceiling 
will be set at 180 participants to allow for up to 90% rate of screen failure. 

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10.3 POPULATIONS FOR ANALYSIS 
All subjects who start chemotherapy conditioning regimen under this protocol will be included in 
the analyses.  
10.3.1 Feasibility Analysis 
All participants who start conditioning chemotherapy and who can be evaluated for the three 
feasibility criteria in section 6.6 will be evaluable for feasibility. 
10.3.2 Toxicity Analysis 
All participants will be evaluable for toxicity from the time of their treatment with E7 TCR T 
cells. 
10.3.3 Response Analysis 
Participants who receive E7 TCR T cell therapy and either experience clinical progression at the 
3-week clinical check or are evaluated at the 6-week response assessment will be evaluable for 
response. Response will be classified according to the definitions below.    
10.4 STATISTICAL ANALYSES 
10.4.1 General approach 
The fraction who achieve a success will be determined and reported. 
10.4.2 Analysis of the primary efficacy endpoints 
The fraction who achieve a success among those who start conditioning chemotherapy and who 
can be evaluated for the three feasibility criteria in section 6.6, with 95% confidence intervals on 
the fraction reported as well. 
10.4.3 Analysis of the secondary efficacy endpoints 
The 2 year and 5 year RFS will be estimated from a Kaplan-Meier curve of RFS. 
To evaluate the toxicity of induction E7 TCR T cell therapy for FIGO (2018) stage IIB-IVA, 
HPV16+ cervical cancer, the types and grades of toxicity obtained will be report and findings 
described.  
The objective response rate (PR+CR) following E7 TCR T cell induction therapy will be 
estimated and reported along with a 95% confidence interval.  
10.4.4 Safety analysis 
Adverse events will be recorded and reported as defined in Section 6.1.1. 
10.4.5 Baseline Descriptive Statistics 
Demographic and clinical characteristics of all participants will be reported. 
10.4.6 Planned interim analyses 
An early interim look at the fraction with success after 5 participants with FIGO (2018) stage 
IIIC-IVA have been treated will be conducted.  
10.4.7 Subgroup analyses 

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None will be performed. 
10.4.8 Tabulation of individual participant data 
None will be provided 
10.4.9 Exploratory analyses 
The exploratory objectives are: 
• To perform laboratory research to begin to understand treatment response and to develop 
biomarkers that predict response.  
• To determine the percentage of participants able to receive standard chemoradiation 
without requiring dose-escalation due to hematologic toxicities.  
Statistical tests performed will be considered exploratory with results presented without formal 
adjustment but interpreted in the context of the number of tests performed. 
11 COLLABORATIVE AGREEMENTS 
11.1 COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT (CRADA)   
Coded, linked samples may be provided to Kite Pharma for assistance in performing the research 
studies described in section 5.1. The code key will not be provided to collaborators.  Kite Pharma 
is collaborating in the development of the E7 TCR. A CRADA between NCI and Kite Pharma is 
in place (CRADA # 03022). Kite Pharma will be providing funding for this study.  
12 HUMAN SUBJECTS PROTECTIONS  
12.1 RATIONALE FOR SUBJECT SELECTION 
The participants to be entered in this protocol have advanced HPV-associated cervical cancer 
and are more likely to have persistent or recurrent disease after standard therapy. 
Only female participants are affected by this condition and, therefore, eligible for the study. 
Subjects from all racial/ethnic groups are eligible for this study if they meet the eligibility 
criteria.  To date, there is no information that suggests that differences in drug metabolism or 
disease response would be expected in one group compared to another.  Efforts will be made to 
extend accrual to a representative population, but in this preliminary study, a balance must be 
struck between participant safety considerations and limitations on the number of individuals 
exposed to potentially toxic and/or ineffective treatments, on the one hand, and the need to 
explore sex and ethnic aspects of clinical research on the other hand.  If differences in outcome 
that correlate to gender or to ethnic identity are noted, accrual may be expanded, or a follow-up 
study may be written to investigate those differences more fully. 
12.2 PARTICIPATION OF CHILDREN 
The use of the non-myeloablative regimen in this protocol entails serious discomforts and 
hazards for the participant, such that fatal complications are possible.  It is therefore only 
appropriate to carry out this experimental procedure in the context of life-threatening metastatic 
cancer.  Since the efficacy of this experimental procedure is unknown, it does not seem 
reasonable to expose children to this risk without further evidence of benefit.  Should results of 
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standard forms of therapy, future research can be conducted in the pediatric population to 
evaluate potential benefit in that participant population. 
12.3 RISK/BENEFIT ASSESSMENT 
12.3.1 Known Potential Risks 
Over 400 participants have been treated in the Surgery Branch, NCI with Tumor-Infiltrating 
Lymphocytes (TIL).  Early toxicities related specifically to the infusion of the cells (those which 
are seen immediately following cell infusion and prior to aldesleukin administration) are 
generally mild and include fevers, chills, headache, and malaise. Toxicities which occur 
following administration of aldesleukin but are thought to be related to the cells include immune 
mediated events such as vitiligo, transient uveitis, hearing loss and vestibular dysfunction. The 
use of the non-myeloablative regimen prior to cell administration increases the toxicity of this 
treatment as profound myelosuppression occurs in all participants. In 93 participants treated with 
TIL using the non-myeloablative chemotherapy regimen with or without total body irradiation, 
there was one treatment related death (NMA + 200 cGy TBI) due to an unexpected but 
preexisting diverticular abscess. In the 101 participants treated in subsequent randomized trial 2 
treatment related deaths occurred, both due to the TBI component of the treatment regimen.   
The major discomforts of the research are those of nausea and vomiting, mucositis, anorexia, 
diarrhea, fever and malaise.  Side effects of common drugs used in this regimen include: 
• Cyclophosphamide: Marrow suppression, nausea, mucositis, rash, hemorrhagic cystitis, 
myocardial damage, alopecia, infertility, nausea and vomiting, SIADH.   
• Fludarabine: Myelosuppression, fever and chills, nausea and vomiting, malaise, fatigue, 
anorexia, weakness, neurologic toxicity, and interstitial pneumonitis.  Serious 
opportunistic infections have occurred in CLL participants treated with fludarabine. 
• Antimicrobials in general: Allergic reactions, renal impairment, nausea, vomiting, 
hepatic damage, marrow suppression, photosensitivity.  
• High-dose aldesleukin administration: A listing of these side effects in 525 participants 
who received 1,039 treatment courses are listed in Appendix 3. 
12.3.1.1 Biopsy 
The risks associated with biopsies are pain and bleeding at the biopsy site. To minimize pain, 
local anesthesia will be used. Rarely, there is a risk of infection at the sampling site. 
12.3.1.2 Blood Sampling 
Side effects of blood draws include pain and bruising, lightheadedness, and rarely, fainting. 
12.3.1.3 Leukapheresis 
There may be some tingling in the face, mouth and fingers due to the medicine used to keep the 
blood from clotting during the procedure. The nurses may give a calcium-containing antacid to 
take away this tingling. Rarely, people may experience lightheadedness or dizziness. Rare 
complications of this procedure are lowered blood pressure, lightheadedness, dizziness, nausea, 
possible problems with the cell separator machine which would not allow the red cells and 
plasma to be returned and bleeding or bruising where the needles are put in your arms. 

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12.3.1.4 Intravenous Catheter 
The risks associated with placing some catheters include pain, bleeding, infection and collapsed 
lung. The long-term risks of the catheter include infection and clotting of your veins. It may be 
necessary to remove the catheter.  
12.3.1.5 CT scan, PET, MRI and Ultrasound  
Although rare, the intravenous (IV) contrast material involved in some CT, PET and MRI scans 
causes medical problems or allergic reactions in some people. Most reactions are mild and result 
in hives or itchiness. In rare instances, an allergic reaction can be serious and potentially life 
threatening. Participants will be asked if they have had prior reaction to contrast material during 
medical tests. There are no anticipated risks for the ultrasound procedure.  
12.3.1.6 Risks related to Radiation Exposure 
This research study involves exposure to radiation from chest x-ray, CT scans, PET scans, and 
CT-guided biopsies. The amount of radiation exposure that may be received from these 
procedures is equal to approximately 9.3 rem. A rem is a unit of absorbed radiation.  
Every day, people are exposed to low levels of radiation that come from the sun and the 
environment around them. The average person in the United States receives a radiation exposure 
of 0.3 rem per year from these sources. This type of radiation is called “background radiation.”  
This study will expose participants to more radiation than they get from everyday background 
radiation. No one knows for sure whether exposure to these low amounts of radiation is harmful 
to your body.  
The chest X-ray, PET and CT scans in this study may expose participants to the roughly the 
same amount of radiation as 31 years worth of background radiation. Being exposed to too much 
radiation can cause harmful side effects such as an increase in the risk of cancer. The risk 
depends on how much radiation they are exposed to. Please be aware that about 40 out of 100 
people (40%) will get cancer during their lifetime, and 20 out of 100 (20%) will die from cancer. 
The risk of getting cancer from the radiation exposure in this study is 0.9 out of 100 (0.9%) and 
of getting a fatal cancer is 0.4 out of 100 (0.4%). 
12.3.2 Known Potential Benefits 
The experimental treatment has a chance to provide potential clinical benefit by shrinking of the 
tumor or lessening of symptoms, such as pain, that are caused by the cancer. With no 
known additional risks related to the previously produced vector for participants who have 
received cells with vectors made the potential benefit outweighs the potential risks. 
12.3.3 Assessment of Potential Risks and Benefits 
The standard approach to the administration of high-dose aldesleukin in all studies is to continue 
dosing until Grade 3 or 4 events occur. The most commonly seen Grade 4 events are pulmonary 
and renal impairment, and mental status changes. These toxicities may sometimes require 
intubation for protection of the participant’s airway. It is important to note that although these 
participants require significant supportive measures during this period, all toxicities are 
reversible, and the overwhelming majority of participants have suffered no long-term sequelae 
following this treatment regimen. However, fatal complications are possible, and it is therefore 
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Toxicities seen on protocols using this non-myeloablative regimen and aldesleukin that occur 
during the follow up period are rare but have included EBV lymphoma following prolonged 
lymphopenia, herpes zoster infection, and sensory neuropathy likely related to fludarabine.  
12.4 CONSENT PROCESS AND DOCUMENTATION 
The informed consent document will be provided to the participant  for review prior to 
consenting. A designated study investigator will carefully explain the procedures and tests 
involved in this study, and the associated risks, discomforts and benefits. In order to minimize 
potential coercion, as much time as is needed to review the document will be given, including an 
opportunity to discuss it with friends, family members and/or other advisors, and to ask questions 
of any designated study investigator. A signed informed consent document will be obtained prior 
to entry onto the study. 
The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other NIH approved remote platforms) per discretion of the 
designated study investigator and with the agreement of the participant.  Whether in person or 
remote, the privacy of the subject will be maintained. Consenting investigators (and participant, 
when in person) will be located in a private area (e.g., clinic consult room). When consent is 
conducted remotely, the participant will be informed of the private nature of the discussion and 
will be encouraged to relocate to a more private setting if needed.  
*Please note that consent for treatment (consent labeled Treatment - Affected Patient) must be 
obtained by a designated appropriately licensed study investigator (e.g., MD, NP, PA, DO). 
However, study investigators not falling into this category (e.g. RNs) who are designated as able 
to obtain consent, may do so for non-treatment procedures such as screening. 
     
13 REGULATORY AND OPERATIONAL CONSIDERATIONS  
13.1 STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants, 
investigators, funding agency, the Investigational New Drug (IND) sponsor and regulatory 
authorities.  If the study is prematurely terminated or suspended, the Principal Investigator (PI) 
will promptly inform study participants, the Institutional Review Board (IRB), and sponsor and 
will provide the reason(s) for the termination or suspension.  Study participants will be 
contacted, as applicable, and be informed of changes to study visit schedule. 
 Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants 
• Demonstration of efficacy that would warrant stopping    
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Determination that the primary endpoint has been met 

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• Determination of futility 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and as applicable, Food and Drug Administration (FDA). 
13.2 QUALITY ASSURANCE AND QUALITY CONTROL 
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  An individualized quality management 
plan will be developed to describe a site’s quality management. 
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution. 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the 
clinical trial is conducted and data are generated and biological specimens are collected, 
documented (recorded), and reported in compliance with the protocol, International Conference 
on Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements 
(e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)).  
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local 
and regulatory authorities. 
13.3 CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be 
required to have such conflicts managed in a way that is appropriate to their participation in the 
design and conduct of this trial.  The study leadership in conjunction with the National Cancer 
Institute has established policies and procedures for all study group members to disclose all 
conflicts of interest and will establish a mechanism for the management of all reported dualities 
of interest. 
13.4 CONFIDENTIALITY AND PRIVACY 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s). This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be 
held in strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical 

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records (office, clinic, or hospital) and pharmacy records for the participants in this study. The 
clinical study site will permit access to such records. 
The study participant’s contact information will be securely stored at the clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor 
requirements. 
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at the National Cancer Institute (NCI). This will not 
include the participant’s contact or identifying information. Rather, individual participants and 
their research data will be identified by a unique study identification number. The study data 
entry and study management systems used by the clinical site(s) and by NCI research staff will 
be secured and password protected. At the end of the study, all study databases will be archived 
at the NCI. 
To further protect the privacy of study participants, a Certificate of Confidentiality has been 
issued by the National Institutes of Health (NIH).  This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any 
civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or 
local level. By protecting researchers and institutions from being compelled to disclose 
information that would identify research participants, Certificates of Confidentiality help achieve 
the research objectives and promote participation in studies by helping assure confidentiality and 
privacy to participants. 
14 PHARMACEUTICAL INFORMATION 
14.1 ALDESLEUKIN 
14.1.1 Source/Acquisition and Accountability 
Aldesleukin (interleukin-2) will be provided by the NIH Clinical Pharmacy Department from 
commercial sources. 
14.1.2 Formulation/Reconstitution 
Aldesleukin, NSC #373364, is provided as single-use vials containing 22 million IU (~1.3mg) 
IL-2 as a sterile, white to off-white lyophilized cake plus 50mg mannitol and 0.18 mg sodium 
dodecyl sulfate, buffered with approximately 0.17 mg monobasic and 0.89 mg dibasic sodium 
phosphate to a pH of 7.5 (range 7.2 to 7.8).  The vial is reconstituted with 1.2 mL of Sterile 
Water for Injection, USP, and the resultant concentration is 18 million IU/mL or 1.1 mg/mL.  
Diluent should be directed against the side of the vial to avoid excess foaming.  Swirl contents 
gently until completely dissolved.  Do not shake.  Since vials contain no preservative, 
reconstituted solution should be used within 24 hours. 
14.1.3 Storage 
Intact vials are stored in the refrigerator (2 to 8°C) protected from light.  Each vial bears an 
expiration date. 
14.1.4 Dilution/Stability 

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Reconstituted aldesleukin should be further diluted with 50 mL of 5% Human Serum Albumin 
(HSA).  The HSA should be added to the diluent prior to the addition of IL-2.  Dilutions of the 
reconstituted solution over a 1000-fold range (i.e., 1 mg/mL to 1 mcg/mL) are acceptable in 
either glass bottles or polyvinyl chloride bags.  Aldesleukin is chemically stable for 48 hours at 
refrigerated and room temperatures, 2 to 30°C. 
14.1.5 Administration  
The dosage will be calculated based on total body weight.  The final dilution of aldesleukin will 
be infused over 15 minutes.  Aldesleukin will be administered as an inpatient. 
14.1.6 Toxicities 
Expected toxicities of aldesleukin are listed in the product label and in Appendix 2.  Grade 3 
toxicities common to aldesleukin include diarrhea, nausea, vomiting, hypotension, skin changes, 
anorexia, mucositis, dysphagia, or constitutional symptoms and laboratory changes as detailed in 
Appendix 1.  Additional Grade 3 and 4 toxicities seen with aldesleukin are detailed in Appendix 
2.   
14.2 FLUDARABINE 
(Please refer to package insert for complete product information.) 
14.2.1 Description 
Fludarabine phosphate is a synthetic purine nucleoside that differs from physiologic nucleosides 
in that the sugar moiety is arabinose instead of ribose or deoxyribose.  Fludarabine is a purine 
antagonist antimetabolite. 
14.2.2 Source/Acquisition and Accountability 
Fludarabine will be purchased by the NIH Clinical Pharmacy Department from commercial 
sources.  Fludarabine is supplied in a 50 mg vial as a fludarabine phosphate powder in the form 
of a white, lyophilized solid cake. 
14.2.3 Formulation/Reconstitution 
Fludarabine Phosphate Injection, USP is supplied both as a 50 mg vial in the form of a white, 
lyophilized solid cake and as a 50 mg per 2 mL vial containing a clear, sterile solution (25 
mg/mL). Both formulations contain 25 mg of mannitol and sodium hydroxide for pH adjustment. 
Following reconstitution of the lyophilized vial with 2 mL of sterile water for injection to a 
concentration of 25 mg/mL, the solution has a pH of 7.7.  Fludarabine Phosphate Injection 
available as a sterile solution has a pH of 6.8.  
14.2.4 Stability 
Following reconstitution, fludarabine is stable for at least 16 days at room temperature. Since no 
preservative is present, the manufacturer recommends that fludarabine be used within 8 hours of 
reconstitution of the lyophilized product or within 8 hours of vial entry for the fludarabine 
solution. Expiration dating of prepared fludarabine doses will follow institutional guidelines.  
Specialized references should be consulted for specific compatibility information.   
14.2.5 Storage 
Intact vials should be stored refrigerated (2 to 8°C). 

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14.2.6 Administration 
Fludarabine is administered as an IV infusion in 100 mL 0.9% sodium chloride, USP or 5% 
Dextrose in Water, USP over approximately 30 minutes.  The doses will be based on body 
surface area (BSA).  If participant is obese (BMI >35), drug dosage will be calculated using 
practical weight as described in Table 2.  
Table 2.  Modification of Dose Calculations* in participants whose BMI is greater than 35 
1. BMI Determination: 
BMI = weight (kg) / [height (m)]2 
2. Calculation of ideal body weight 
Male = 50kg + 2.3 (number of inches over 60 inches) 
 
Example: ideal body weight of 5’10” male 
 
 
50 + 2.3 (10) = 73 kg 
Female = 45.5kg + 2.3 (number of inches over 60 inches) 
 
Example: ideal body weight of a 5’3” female 
 
 
45.5 + 2.3 (3) = 57kg 
3. Calculation of “practical weight” 
Calculate the average of the actual and the ideal body weights.  This is the 
practical weight to be used in calculating the doses of chemotherapy and 
associated agents designated in the protocol.   
14.2.7 Toxicities 
At doses of 25 mg/m2/day for 5 days, the primary side effect is myelosuppression; however, 
thrombocytopenia is responsible for most cases of severe and life-threatening hematologic 
toxicity.  Serious opportunistic infections have occurred in CLL participants treated with 
fludarabine.  Hemolytic anemia has been reported after 1 or more courses of fludarabine with or 
without a prior history of a positive Coomb’s test; fatal hemolytic anemia has been reported.  In 
addition, bone marrow fibrosis has been observed after fludarabine therapy.  Other common 
adverse effects and potentially fatal central nervous system toxicity in the form of progressive 
encephalopathy, blindness, and coma is only rarely observed at the currently administered doses 
of fludarabine.  More common neurologic side effects at the current doses of fludarabine include 
weakness, pain, malaise, fatigue, paresthesia, visual or hearing disturbances, and sleep disorders.  
Adverse respiratory effects of fludarabine include, cough, dyspnea, allergic or idiopathic 
interstitial pneumonitis.  Tumor lysis syndrome has been rarely observed in fludarabine 
treatment of CLL.  Treatment on previous adoptive cell therapy protocols in the Surgery Branch 
have caused persistently low (below 200) CD4 counts, and 1 participant developed 
polyneuropathy manifested by vision blindness, and motor and sensory defects. 
14.3 CYCLOPHOSPHAMIDE  
(Refer to FDA-approved package insert for complete product information.) 

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14.3.1 Description:   
Cyclophosphamide is a nitrogen mustard-derivative alkylating agent.  Following conversion to 
active metabolites in the liver, cyclophosphamide functions as an alkylating agent; the drug also 
possesses potent immunosuppressive activity.  The serum half-life after IV administration ranges 
from 3 to 12 hours; the drug and/or its metabolites can be detected in the serum for up to 72 
hours after administration. 
14.3.2 Source/Acquisition and Accountability 
Cyclophosphamide will be obtained from commercially available sources by the Clinical Center 
Pharmacy Department. 
14.3.3 Stability 
Following reconstitution as directed with sterile water for injection, cyclophosphamide is stable 
for 24 hours at room temperature or 6 days when kept at 2 to 8°C. 
14.3.4 Administration 
It will be diluted in 250 mL D5W and infused over 1 hour.  The dose will be based on the 
participant’s body weight.  If participant is obese (BMI>35) drug dosage will be calculated using 
practical weight as described in Table 2. 
14.3.5 Toxicities 
Hematologic toxicity occurring with cyclophosphamide usually includes leukopenia and 
thrombocytopenia.  Anorexia, nausea and vomiting, rash and alopecia occur, especially after 
high-dose cyclophosphamide; diarrhea, hemorrhagic colitis, infertility, and mucosal and oral 
ulceration have been reported.  Sterile hemorrhagic cystitis occurs in about 20% of participants; 
severity can range from microscopic hematuria to extensive cystitis with bladder fibrosis.  
Although the incidence of hemorrhagic cystitis associated with cyclophosphamide appears to be 
lower than that associated with ifosfamide, mesna (sodium 2-mercaptoethanesulfonate) has been 
used prophylactically as an uroprotective agent in participants receiving cyclophosphamide.  
Prophylactic mesna is not effective in preventing hemorrhagic cystitis in all participants.  
Participants who receive high dose cyclophosphamide may develop interstitial pulmonary 
fibrosis, which can be fatal.  Hyperuricemia due to rapid cellular destruction may occur, 
particularly in participants with hematologic malignancy.  Hyperuricemia may be minimized by 
adequate hydration, alkalinization of the urine, and/or administration of allopurinol.  If 
allopurinol is administered, participants should be watched closely for cyclophosphamide 
toxicity (due to allopurinol induction of hepatic microsomal enzymes).  At high doses, 
cyclophosphamide can result in a syndrome of inappropriate antidiuretic hormone secretion; 
hyponatremia with progressive weight gain without edema occurs.  At high doses, 
cyclophosphamide can result in cardiotoxicity.  Deaths have occurred from diffuse hemorrhagic 
myocardial necrosis and from a syndrome of acute myopericarditis; in such cases, congestive 
heart failure may occur within a few days of the first dose.  Other consequences of 
cyclophosphamide cardiotoxicity include arrhythmias, potentially irreversible cardiomyopathy, 
and pericarditis.  Other reported adverse effects of cyclophosphamide include headache, 
dizziness, and myxedema; faintness, facial flushing, and diaphoresis have occurred following IV 
administration.  Mesna (sodium 2-mercaptoethanesulphonate; given by IV injection) is a 
synthetic sulfhydryl compound that can chemically interact with urotoxic metabolites of 

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cyclophosphamide (acrolein and 4-hydroxycyclophosphamide) to decrease the incidence and 
severity of hemorrhagic cystitis. 
14.4 CELL PREPARATION (E7 TCR TRANSDUCED PBL) (IND # 19564) 
The procedure for the expanding the human PBL and the Certificate of Analysis (CoA) are 
similar to those approved by the Food and Drug Administration and used at the NCI in ongoing 
protocols. The PBL will be transduced with retroviral supernatant containing the E7 TCR. The 
risks of retroviral transduction of human PBL are discussed in section 1.2.4. 
14.4.1 Retroviral Vector Containing the E7 TCR gene 
The retroviral vector supernatant (PG13-MSGV1-E7-TCR) encoding a T cell receptor directed 
against HPV16 E711-19) was prepared and preserved following cGMP conditions in the Surgery 
Branch Vector Production Facility (SBVPF).  The E7 TCR vector was produced by the Surgery 
Branch Vector Production Facility. The backbone is the MSGV1 retrovirus that has been used in 
prior gene therapy clinical trials. It was produced using a PG13-based packaging line. 
The retroviral vector E7 TCR consists of 7,310 bps including the 5’LTR from the murine stem 
cell virus (promoter), packaging signal including the splicing donor (SD) and splicing acceptor 
sites, alpha and beta chain genes of the E7 TCR.  The alpha and beta chains are linked by a P2A 
peptide.  The vector was codon optimized for expression by human cells with constant region 
exchanged for murine counterparts with an added disulfide bond and hydrophobic substitutions 
in the alpha chain constant region transmembrane domain.     
The physical titer will be determined by transduction of PBL with serial dilutions of the vector.  
TCR expression on the cell surface will be measured using FACS following staining with an 
anti-mouse constant region antibody.  The titer will be measured as transducing units per 
milliliter.  Portions of the supernatant will be stored at -80°C at Surgery Branch, NCI, American 
Type Culture Collection (ATCC), Rockville, MD, and the NIH Clinical Center Department of 
Transfusion Medicine.  These storage facilities are equipped with around-the-clock temperature 
monitoring.  Upon request, supernatant will be delivered on dry ice to be used in ex vivo 
transduction of participant PBL.  There will be no re-use of the same unit of supernatant for 
different participants.  Retroviral titer has been shown to be stable after immediate thawing and 
immediate administration (coating the tissue culture wells previously coated with Retronectin).  
Handling of the vector should follow the guidelines of Biosafety Level-2 (BSL-2). The specific 
guidelines for Biosafety Level-2 (BSL-2) can be viewed at 
http://www.cdc.gov/biosafety/publications/bmbl5/BMBL5_sect_IV.pdf. 
14.5 HPV16 GENOTYPING ASSAY (NSR DEVICE) 
In order to be eligible for the study, participants are required to have HPV16-associated, high-
grade cervical intraepithelial neoplasia. HPV16 Genotyping assay testing is not FDA approved 
for this purpose; however, it is being used in this study as a diagnostic device. Validation assays 
to support the use of the assay have been submitted to the IND. All documentation is in the IND 
files.  
According to 21 CFR 812.3(m), a significant risk device presents a potential for serious risk to 
the health, safety and welfare of a subject and meets the significant risk criteria listed in the table 
below along with the sponsor’s conclusions with regard to the applicability of these criteria to 

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the current study. The device has been assessed by the sponsor as non-significant risk per the 
below.  
 
Applicable to 
current study 
Justification 
Is an implant 
No 
The HPV16 genotyping assay test is not 
introduced into the subject  
Is used in supporting or 
sustaining human life 
No 
The device is diagnostic  
Is of substantial importance 
in diagnosing, mitigating or 
treating disease or preventing 
impairment of human health 
No 
While the device is diagnostic, we do not 
believe it presents a potential for serious risk 
to the health and welfare of the subject. The 
assessment of HPV16 positivity is only used 
to determine eligibility for the study and is 
assessed to help to increase the possibility that 
all persons enrolling on the study might 
derive benefit from therapy. Persons that are 
deemed ineligible to enroll on the basis of this 
test are eligible for studies within GMB that 
are not reliant on this test.   
Otherwise poses a risk 
No 
Testing will be performed on archival 
samples or on fresh tissue that is collected at 
screening for confirmation of diagnosis.  
 
 
 

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cells with beta2-microglobulin loss over the course of metastatic melanoma. Int J 
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Jin BY, Campbell TE, Draper LM, Stevanovic S, Weissbrich B, Yu Z, Restifo NP, 
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Scholler J, Brady TL, Binder-Scholl G, Hwang WT, Plesa G, Hege KM, Vogel AN, 
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Bear AS, Morgan RA, Cornetta K, June CH, Binder-Scholl G, Dudley ME, Feldman SA, 
Rosenberg SA, Shurtleff SA, Rooney CM et al: Replication-competent retroviruses in 
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Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, Eisenberger MA, 
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30. 
Bubley GJ, Carducci M, Dahut W, Dawson N, Daliani D, Eisenberger M, Figg WD, 
Freidlin B, Halabi S, Hudes G et al: Eligibility and response guidelines for phase II 
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Vergote I, Rustin GJ, Eisenhauer EA, Kristensen GB, Pujade-Lauraine E, Parmar MK, 
Friedlander M, Jakobsen A, Vermorken JB: Re: new guidelines to evaluate the 
response to treatment in solid tumors [ovarian cancer]. Gynecologic Cancer 
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Wahl RL, Jacene H, Kasamon Y, Lodge MA: From RECIST to PERCIST: Evolving 
Considerations for PET response criteria in solid tumors. J Nucl Med 2009, 50 Suppl 
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O JH, Wahl RL: PERCIST in Perspective. Nucl Med Mol Imaging 2018, 52(1):1-4. 
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Response Criteria in Solid Tumors 1.0. Radiology 2016, 280(2):576-584. 
 
 
 

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16 APPENDICES 
16.1 APPENDIX 1: PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
2 
In bed <50% of the time. 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities. Up and about 
more than 50% of waking hours. 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any 
self-care. Totally confined to bed 
or chair. 
5 
Dead. 
 
 
 
 

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16.3 APPENDIX 2: ADVERSE EVENTS OCCURRING IN ≥ 10% OF PARTICIPANTS TREATED WITH 
ALDESLEUKIN (N=525) 
 
Body System  
% Participants  
 
Body System  
   
 % 
Participants 
Body as a Whole  
 
 
 
Metabolic and Nutritional Disorders 
Chills   
 
 
52  
 
Bilirubinemia   
 
 
40 
Fever   
 
 
29  
 
Creatinine increase  
 
 
33 
Malaise  
 
 
27  
 
Peripheral edema  
 
 
28 
Asthenia  
 
 
23 
 
 SGOT increase  
 
 
23 
Infection  
 
 
13  
 
Weight gain   
 
 
16 
Pain   
 
 
12  
 
Edema  
 
 
 
15 
Abdominal pain  
 
11  
 
Acidosis  
 
 
 
12 
Abdomen enlarged  
 
10  
 
Hypomagnesemia  
 
 
12 
Cardiovascular  
 
 
 
Hypocalcemia  
 
 
11 
Hypotension   
 
71  
 
Alkaline phosphatase incr 
 
10 
Tachycardia   
 
23 
 
Nervous 
Vasodilation   
 
13  
 
Confusion  
 
 
 
34 
Supraventricular  
 
12  
 
Somnolence   
 
 
22 
tachycardia 
Cardiovascular disordera  
11  
 
Anxiety  
 
 
 
12 
Arrhythmia  
 
 
10  
 
Dizziness  
 
 
 
11 
Digestive  
 
 
 
 
Respiratory 
Diarrhea  
 
 
67  
 
Dyspnea  
 
 
 
43 
Vomiting  
 
 
50  
 
Lung disorderb  
 
 
24 
Nausea  
 
 
35  
 
Respiratory disorderc   
 
11 
Stomatitis  
 
 
22  
 
Cough increase  
 
 
11 
Anorexia  
 
 
20  
 
Rhinitis  
 
 
 
10 
Nausea and vomiting   
19  
 
Skin and Appendages 
Hemic and Lymphatic  
 
 
Rash   
 
 
 
42 
Thrombocytopenia  
 
37 
 
 Pruritus  
 
 
 
24 
Anemia  
 
 
29  
 
Exfoliative dermatitis  
 
18 
Leukopenia 
 
 
16  
 
Urogenital 

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Oliguria  
 
 
 
63 
 
a Cardiovascular disorder: fluctuations in blood pressure, asymptomatic ECG changes, CHF. 
b Lung disorder: physical findings associated with pulmonary congestion, rales, rhonchi. 
c Respiratory disorder: ARDS, CXR infiltrates, unspecified pulmonary changes. 
1Source: Proleukin® Prescribing Information – June 2007 
 
 

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16.4 APPENDIX 3: EXPECTED IL-2 TOXICITIES AND THEIR MANAGEMENT 
 
Toxicity 
Grade 
Supportive Medications 
Stop Cycle* 
Stop 
Treatment** 
Chills 
3 
IV Meperidine 25-50mg IV 
q1hr, prn 
No  
No 
Fever 
3 
Acetaminophen 650mg po 
q4hr; Indomethacin 50-75mg 
po q8h 
No 
No 
Pruritus 
3 
Hydroxyzine HCl 10-20mg po 
q6h, prn; Diphenhydramine 
HCl 25-50mg po q4h prn 
No  
No 
Nausea/Vomiting/A
norexia 
3 
Ondansetron 10mg IV q8hr 
prn, Granisetron 0.01 mg/kg 
IV qday prn, Droperidol 1mg 
IV a4-6h prn; Prochlorperazine 
25mg PR prn or 10mg IV q6hr 
prn 
No 
No 
Diarrhea 
3 
Loperamide 2mg po q3h prn; 
Diphenoxylate HCl 2.5mg and 
Atropine sulfate 25mcg po q3h 
prn; Codeine sulfate 30-60mg 
po q4h prn 
If uncontrolled 
after 24h despite 
all supportive 
measures 
No 
Malaise 
3 or 4 
Bedrest 
If other toxicities 
occur 
simultaneously 
No 
Hyperbilirubinemia 
3 or 4 
Observation 
If other toxicities 
occur 
simultaneously 
No 
Anemia 
3 or 4  
Transfusion with PRBCs 
If uncontrolled 
despite all 
supportive 
measures 
No 
Thrombocytopenia 
3 or 4  
Transfusion with platelets 
If uncontrolled 
despite all 
supportive 
measures 
No 

Abbreviated Title:  E7 Induction Cervical Cancer 
 
75 
Version Date:  11/4/2020 
 
Toxicity 
Grade 
Supportive Medications 
Stop Cycle* 
Stop 
Treatment** 
Edema/Weight gain 
3 
Diuretics prn 
No  
No 
Hypotension 
3 
Fluid resuscitation, 
Vasopressor support 
If uncontrolled 
despite all 
supportive 
measures 
No 
Dyspnea 
3 or 4  
Oxygen or ventilator support 
If requires 
ventilator 
support 
No 
Oliguria 
3 or 4  
Fluid boluses or dopamine at 
renal doses 
If uncontrolled 
despite all 
supportive 
measures 
No 
Increased Creatinine 
3 or 4 
Observation 
Yes (Grade 4) 
No 
Renal Failure 
3 or 4  
Dialysis/CVVH 
Yes 
Yes 
Pleural Effusion 
3 
Thoracentesis 
If uncontrolled 
despite all 
supportive 
measures 
No 
Bowel Perforation 
3 
Surgical intervention 
Yes 
Yes 
Confusion 
3 
Observation 
Yes 
No 
Somnolence 
3 or 4  
Intubation for airway 
protection 
Yes 
Yes 
Arrhythmia 
3 
Correction of fluid and 
electrolyte imbalances; 
chemical conversion or 
electrical conversion therapy 
If uncontrolled 
despite all 
supportive 
measures 
No 
Elevated Troponin 
Levels 
3 or 4  
Observation 
Yes 
If changes in 
LV function 
have not 
improved to 
baseline by 
next dose 

Abbreviated Title:  E7 Induction Cervical Cancer 
 
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Toxicity 
Grade 
Supportive Medications 
Stop Cycle* 
Stop 
Treatment** 
Myocardial 
Infarction 
4 
Supportive care 
Yes 
Yes 
Elevated 
Transaminases 
3 or 4 
Observation 
For Grade 4 
without liver 
metastases 
If changes 
have not 
improved to 
baseline by 
next dose 
Hyperbilirubinemia 
3 or 4  
Observation 
For Grade 4 
without liver 
metastases 
If changes 
have not 
improved to 
baseline by 
next dose 
Electrolyte 
Imbalances 
3 or 4 
Electrolyte replacement 
If uncontrolled 
despite all 
supportive 
measures 
No 
Neutropenia 
4 
Observation 
No 
No 
*Unless the toxicity is not reversed within 12 hours. 
**Unless the toxicity is not reversed to Grade 2 or less by next treatment. 
 
 

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Abbreviated Title: 
Version Date: 
 
 
16.5 APPENDIX 4: INTERLEUKIN-2 TOXICITIES OBSERVED IN PARTICIPANTS TREATED AT THE 
NIH