Phase I Study of Human Chimeric Antigen Receptor Modified T Cells in Patients With Mesothelin Expressing Cancers
Phase: PHASE1
Conditions: Lung Adenocarcinoma, Ovarian Cancer, Peritoneal Carcinoma, Fallopian Tube Cancer, Mesotheliomas Pleural, Mesothelioma Peritoneum
Sponsor: University of Pennsylvania



huCART-meso in Mesothelin Expressing Cancers 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ........................................................................................................ 6 
STUDY SUMMARY ................................................................................................................. 8 
Figure 1-1:  STUDY SCHEMA (COHORTS 1-5*) ....................................................................... 12 
Figure 1-2:  Study Schema (Cohort 6) ................................................................................... 13 
Figure 1-3:  Study Schema (Cohort 7) ................................................................................... 14 
1 
INTRODUCTION ........................................................................................................... 15 
1.1 
Background .............................................................................................................................. 15 
1.1.1 
Mesothelin ................................................................................................................. 15 
1.1.2 
Lung Adenocarcinoma, Epithelial Ovarian Cancer, and Mesothelioma ..................... 16 
1.1.3 
Adoptive immunotherapy .......................................................................................... 18 
1.1.4 
Lymphodepletion ....................................................................................................... 19 
1.1.5 
Local versus systemic administration of CAR T cells .................................................. 20 
1.2 
Investigational Agent ............................................................................................................... 20 
1.3 
Preclinical data ........................................................................................................................ 21 
1.4 
Clinical data to date ................................................................................................................. 21 
1.5 
Toxicities associated with CART cells ...................................................................................... 21 
1.6 
Trial Rationale .......................................................................................................................... 21 
1.7 
Potential Risks and Benefits .................................................................................................... 21 
1.7.1 
huCART-meso Cells ..................................................................................................... 21 
1.7.2 
Mesothelin Expression ............................................................................................... 24 
1.7.3 
Research Procedures .................................................................................................. 24 
1.7.4 
Potential Benefits ....................................................................................................... 25 
1.8 
Justification of Route and Dose Regimen ................................................................................ 25 
2 
STUDY OBJECTIVES ...................................................................................................... 27 
2.1 
Primary Objectives .................................................................................................................. 27 
2.2 
Secondary Objectives .............................................................................................................. 27 
3 
STUDY DESIGN ............................................................................................................ 28 
3.1 
General Design ........................................................................................................................ 28 
3.2 
Cohort Assignment .................................................................................................................. 29 
3.3 
Study Endpoint Analysis .......................................................................................................... 30 
4 
SUBJECT SELECTION AND WITHDRAWAL ..................................................................... 30 
4.1 
Inclusion Criteria ...................................................................................................................... 30 
4.2 
Exclusion Criteria ..................................................................................................................... 32 
4.3 
Reproductive Risks .................................................................................................................. 33 
4.4 
Subject Recruitment ................................................................................................................ 33 
4.5 
Subject Withdrawal / Discontinuation .................................................................................... 34 
4.5.1 
Reasons for Subject Discontinuation ......................................................................... 34 
4.5.2 
Data Collection and Follow-up ................................................................................... 34 
4.5.3 
Replacement of Subjects ............................................................................................ 35 

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5 
INVESTIGATIONAL PRODUCTS ..................................................................................... 35 
5.1 
Description .............................................................................................................................. 35 
5.1.1 
huCART-meso cells ..................................................................................................... 35 
5.1.2 
Cyclophosphamide ..................................................................................................... 35 
5.1.3 
Fludarabine ................................................................................................................. 36 
5.2 
Treatment Regimen ................................................................................................................. 36 
5.3 
Preparation and Administration of Investigational Product(s) ............................................... 37 
5.3.1 
huCART-meso cells ..................................................................................................... 37 
5.3.2 
Cyclophosphamide (Applicable Cohorts) ................................................................... 40 
5.3.3 
Fludarabine (Cohort 7) ............................................................................................... 40 
5.4 
Dose-Limiting Toxicity (DLT) and Cohort Progression ............................................................. 41 
5.5 
Subject Compliance Monitoring .............................................................................................. 42 
5.6 
Prior and Concomitant Therapy .............................................................................................. 42 
6 
STUDY PROCEDURES ................................................................................................... 44 
6.1 
Screening ................................................................................................................................. 44 
6.2 
Leukapheresis .......................................................................................................................... 45 
6.3 
Pre-infusion safety visit (Week -2 to -1) .................................................................................. 46 
6.4 
Lymphodepleting Chemotherapy Administration ................................................................... 47 
6.5 
huCART-meso product administration (Day 0) ....................................................................... 49 
6.6 
Post-Infusion Inpatient Observation (Cohorts 5-7 only) ......................................................... 50 
6.7 
Post-infusion Visits (Cohorts 1-5)* .......................................................................................... 50 
6.7.1 
Safety Follow-up Visits ............................................................................................... 50 
6.7.2 
Day 28 (+/- 5 days): Safety and Tumor Staging .......................................................... 50 
6.7.3 
Month 2 (+/- 5 days): Safety ....................................................................................... 50 
6.7.4 
Month 3 (+/- 5 days): Safety and Tumor Staging ....................................................... 50 
6.7.5 
Month 6 (+/- 5 days): Safety and Tumor Staging ....................................................... 51 
6.7.6 
Quarterly Evaluations for up to 2 Years Post-Infusion ............................................... 51 
6.8 
Post-Infusion Visits (Cohort 6 only) ......................................................................................... 51 
6.8.1 
Safety Follow-up Visits (Post Infusion #1) .................................................................. 51 
6.8.2 
Additional huCART-meso Infusion(s).......................................................................... 51 
6.8.3 
Post-Infusion Safety Follow-up (Infusions #2 and #3) ................................................ 52 
6.8.4 
Month 3 (+/- 5 days): Safety and Tumor Staging ....................................................... 53 
6.8.5 
Month 6 (+/- 5 days): Safety and Tumor Staging ....................................................... 54 
6.8.6 
Quarterly Evaluations for up to 2 Years Post-Infusion ............................................... 54 
6.9 
Post-Infusion Visits (Cohort 7) ................................................................................................. 54 
6.9.1 
Safety Follow-up Visits (Post Infusion #1) .................................................................. 54 
6.9.2 
Additional huCART-meso Infusion(s).......................................................................... 54 
6.9.3 
Post-Infusion Safety Follow-up (Infusions #2 and #3) ................................................ 56 
6.9.4 
Month 3 (+/- 5 days): Safety and Tumor Staging ....................................................... 57 
6.9.5 
Month 6 (+/- 5 days): Safety and Tumor Staging ....................................................... 57 
6.9.6 
Quarterly Evaluations for up to 2 Years Post-Infusion ............................................... 57 
6.10 Long-term Follow-up Protocol ................................................................................................ 57 
7 
ASSESSMENTS ............................................................................................................. 57 
7.1 
Disease Assessments ............................................................................................................... 57 
7.2 
Research Correlative Studies Assessment ............................................................................... 58 
7.2.1 
Collection of Research Samples ................................................................................. 58 
7.2.2 
Planned Correlative Studies ....................................................................................... 59 

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8 
STATISTICAL PLAN ....................................................................................................... 60 
8.1 
General Design Issues .............................................................................................................. 60 
8.2 
Sample Size Determination ..................................................................................................... 60 
8.3 
Subject Population(s) for Analysis ........................................................................................... 60 
8.4 
Analysis of Primary Endpoints ................................................................................................. 61 
8.5 
Analysis of Secondary Endpoints ............................................................................................. 61 
8.6 
Analysis of Correlative Endpoints ............................................................................................ 61 
9 
SAFETY AND ADVERSE EVENTS .................................................................................... 62 
9.1 
Definitions ............................................................................................................................... 62 
9.1.1 
Adverse Event ............................................................................................................. 62 
9.1.2 
Serious Adverse Event ................................................................................................ 62 
9.1.3 
Unexpected adverse events ....................................................................................... 62 
9.1.4 
Related adverse events .............................................................................................. 63 
9.1.5 
Unanticipated Adverse Device Effect (UADE) ............................................................ 63 
9.1.6 
Protocol-defined Adverse Event ................................................................................ 63 
9.1.7 
Adverse Event Reporting Period ................................................................................ 64 
9.1.8 
Preexisting Condition/General Physical Examination Findings .................................. 64 
9.1.9 
Abnormal Laboratory Values ...................................................................................... 64 
9.2 
Recording of Adverse Events ................................................................................................... 64 
9.2.1 
Cytokine Release Syndrome Grading System ............................................................. 66 
9.2.2 
ASTCT Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) 
Consensus Grading (Lee et al. 2019) .......................................................................... 67 
9.3 
Reporting of Serious Adverse Events ...................................................................................... 68 
9.3.1 
Investigator Reporting:  Local Regulatory Review Committees ................................. 69 
9.3.2 
Pregnancies ................................................................................................................ 69 
9.4 
Toxicity Management, Stopping Rules and Study Termination .............................................. 69 
9.4.1 
Criteria for stopping or pausing the study ................................................................. 69 
9.4.2 
General Toxicity Management Considerations .......................................................... 70 
9.5 
Protocol Exceptions and Deviations ........................................................................................ 76 
9.6 
Data and Safety Monitoring Board .......................................................................................... 77 
10 
DATA HANDLING AND RECORDKEEPING ...................................................................... 78 
10.1 Confidentiality ......................................................................................................................... 78 
10.2 Source Documents .................................................................................................................. 78 
10.3 Data Management ................................................................................................................... 79 
10.4 Sharing of Study Data .............................................................................................................. 79 
10.5 Future Use of Research Data/Specimens ................................................................................ 79 
10.6 Records Retention ................................................................................................................... 79 
11 
STUDY MONITORING, AUDITING, AND INSPECTING ..................................................... 80 
11.1 Study Monitoring Plan ............................................................................................................. 80 
11.2 Auditing and Inspecting ........................................................................................................... 80 
12 
ETHICAL CONSIDERATIONS .......................................................................................... 80 
13 
STUDY FINANCES......................................................................................................... 81 
13.1 Funding Source ........................................................................................................................ 81 
13.2 Conflict of Interest ................................................................................................................... 81 
13.3 Subject Stipends or Payments ................................................................................................. 81 

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13.4 Study Discontinuation ............................................................................................................. 81 
14 
PUBLICATION PLAN ..................................................................................................... 81 
15 
REFERENCES ................................................................................................................ 82 
16 
APPENDIX 1:  SCHEDULE OF EVENTS (Cohorts 1-5*) ..................................................... 90 
17 
APPENDIX 2:  SCHEDULE OF EVENTS (Cohort 6) ............................................................ 95 
18 
APPENDIX 3:  SCHEDULE OF EVENTS (Cohort 7) ........................................................... 102 
19 
APPENDIX 4:  NEW YORK HEART ASSOCIATION (NYHA) FUNCTIONAL 
CLASSIFICATION ......................................................................................................... 109 
20 
APPENDIX 5:  IMMUNE EFFECTOR CELL-ASSOCIATED ENCEPHALOPATHY (ICE) 
SCORE ........................................................................................................................ 110 
 

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LIST OF ABBREVIATIONS 
AE, adverse event 
CAR, chimeric antigen receptor 
CCI, Center for Cellular Immunotherapies 
CD137, 4-1BB costimulatory molecule 
CFR, Code of Federal Regulations 
CRF, case report form 
CRM, Continual Reassessment Method  
CRS, Cytokine Release Syndrome 
CTCAE, common terminology criteria for adverse events 
CTL, cytotoxic T lymphocyte 
CTX, cyclophosphamide 
CVPF, Clinical Cell and Vaccine Production Facility at the University of Pennsylvania 
DLT, dose-limiting toxicity 
DSMB, Data and Safety Monitoring Board  
EOC, epithelial ovarian cancer 
FDA, Food and Drug Administration 
GCP, Good Clinical Practices 
GMP, Good Manufacturing Practices 
HACA, human anti-CAR antibody 
HAMA, human anti-mouse antibody 
IBC, Institutional Biosafety Committee 
IP, intrapleural administration 
i.p., intraperitoneal administration 
IRB, Institutional Review Board 
irRC, immune related response criteria 
MABEL, Minimum Anticipated Biological Effect Level 
MAS, Macrophage Activation Syndrome 
MPM, malignant pleural mesothelioma 
MPM, MyPennMedicine (UPenn patient portal) 
OBD, optimal biologic dose 
PBMC, peripheral blood mononuclear cells 
PDA, pancreatic ductal adenocarcinoma 
PDAE, protocol-defined adverse event 
PDSAE, protocol-defined serious adverse event 
PDCS, Product Development and Correlative Sciences laboratory 
ROA, route of administration 
SAE, serious adverse event 
SS1, mesothelin specific scFv 
TCR, T cell receptor 
TCSL, Translational and Correlative Studies Laboratory 

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UADE, Unanticipated Adverse Device Effect 
UPenn, University of Pennsylvania 
 

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STUDY SUMMARY 
Title 
Phase I study of human CAR modified T cells in patients with mesothelin expressing 
cancers 
Short Title 
huCART-meso in mesothelin expressing cancers  
Protocol Number 
UPCC# 02916; IRB# 826085; 
 
Phase 
Phase 1 -  Safety and Proof of Concept 
Methodology 
Phase I study to establish safety and feasibility of both intravenous administration 
and local delivery of lentiviral transduced huCART-meso cells with or without 
lymphodepletion.   
Study Duration 
This protocol will require approximately 6-8 years. Each subject will be followed for 
up to 2 years post study treatment on this study. Subject will then be asked to 
enroll; into a separate long-term follow-up study and followed for up to 15 years 
post-infusion.   
Study Center(s) 
University of Pennsylvania 
Number of Subjects 
Up to 27 evaluable subjects. Evaluable subjects are those who receive the target 
dose of huCART-meso cells as per their cohort assignment. 
Study Design 
This is a Phase I study evaluating the safety and feasibility of both intravenous 
administration and local delivery of lentiviral transduced huCART-meso cells with 
and without lymphodepleting chemotherapy. 
• 
Cohort 1 (N = 3-6): will receive a single dose of 1-3x107 huCART-meso 
cells/m2 on day 0 without any conditioning chemotherapeutic regimen.   
• 
Cohort 2 (N = 3-6): will receive a single dose of 1-3x107 huCART-meso 
cells/m2 on day 0, following a flat dose of 1 gram/m2 of cyclophosphamide 
administered 2-4 days prior to huCART-meso cells (day -4 to day -2).   
• 
Cohort 3 (N=3-6): will receive a single dose of 1-3x108 /m2 lentiviral 
transduced huCART-meso cells on day 0 without any conditioning 
chemotherapeutic regimen.  Cohort 3 permanently closed with Protocol 
V5.  
• 
Cohort 4 subjects (N=3-6) will receive a single dose of  1-3x108 /m2 lentiviral 
transduced huCART-meso cells on day 0, following a flat dose of 1 gram/m2 
of cyclophosphamide administered 2-4 days prior to huCART-meso cells 
(day -4 to day -2). Cohort 4 permanently closed with Protocol V5.  
• 
Cohort 5 (N = up to 6): will receive a single dose of 1-3x107 huCART-meso 
cells/m2 day 0 by intrapleural infusion (IP) through an indwelling pleural 
catheter without any conditioning chemotherapeutic regimen. The safety 
of this dose level has been established by Cohorts 1 and 2.  
• 
Cohort 6 (N = up to 6): will receive a dose of 1-3x107huCART-meso cells/m2 
via IV infusion on Day 0, following a flat dose of 1 gram/m2 of 
cyclophosphamide administered 2-4 days prior to huCART-meso cells (~Day 
-4 to -2).  This initial infusion may be followed by up to two additional IV 
infusions of huCART-meso cells at the same dose level, given between 21-
42 days apart, if the subject meets eligibility to receive additional infusions 
(See Section 6.8.2).  Cyclophosphamide will not be repeated prior to 
subsequent doses of huCART-meso cells. Cohort 6 was activated with 
Protocol V6. Enrollment into Cohort 6 will occur in parallel with Cohort 5. 

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• 
Cohort 7 (N = up to 6): will receive a single dose of 1-3x107 huCART-meso 
cells/m2 via intraperitoneal (i.p.) administration, following lymphodepleting 
chemotherapy with cyclophosphamide 300 mg/m2/day and fludarabine 30 
mg/m2/day given over 3 days by intravenous infusion.  Lymphodepleting 
chemotherapy will be scheduled such that the last day of chemotherapy is 
3 days (+/- 1 day) prior to the 1st infusion of huCART-meso cells.  This initial 
i.p. infusion may be followed by up to two additional infusions of huCART-
meso cells via intravenous (IV) administration at the same dose level, given 
between 21-42 days apart.  The subject must meet eligibility to receive 
additional infusions (See Section 6.9.2).  Lymphodepleting chemotherapy 
will not be repeated prior to additional infusions of huCART-meso cells. 
Infusion #1 for the first three subjects in Cohort 7 will be staggered by at 
least 21 days to allow for the assessment of DLTs. Enrollment into Cohort 7 
will occur in parallel with Cohort 5 and Cohort 6. 
 
The Maximum Tolerated Dose (MTD) is defined as the dose at which 0-1 DLT occurs 
in 6 evaluable subjects tested within the dose range of this study.  As of Protocol 
Amendment V5, the maximum tolerated dose has been established as 1-3x107 
huCART-meso cells/m2. 
 
Adverse events will be collected and evaluated during the protocol specified 
adverse event reporting period outlined in Section 9.1. 
Objectives 
Primary objective: 
Determine the safety and feasibility of intravenous administration and local 
delivery of lentiviral transduced huCART-meso cells, with and without 
lymphodepleting chemotherapy in the target population.   
 
Secondary objectives: 
Clinical objectives:  
1. Assess the clinical anti-tumor effect by standard criteria (RECIST [modified 
RECIST for mesothelioma] and immune-related response criteria [where 
feasible]) for each tumor type. 
2. Assess progression-free survival (PFS) and overall survival (OS). 
 
Correlative objectives: 
1. Evaluate huCART-meso cells engraftment and persistence in peripheral 
blood and body fluid. 
2. Determine the bioactivity of huCART-meso cells in peripheral blood and 
body fluid. 
3. Evaluate the development of anti-CART immune responses favoring 
rejection of huCART-meso cells (where scientifically relevant). 
4. Evaluate the development of secondary cellular and humoral anti-tumor 
responses as a consequence of epitope spreading. 
5. Where tumor material or body fluids can be obtained: 
a. Measure trafficking of huCART-meso  
b. Evaluate mesothelin expression on tumor cells to assess for 
antigen-escape 
c. Evaluate genetic editing (if feasible) 

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d. Analyze tumor microenvironment and cell interactions (if feasible) 
Study Population and 
Main Inclusion 
Criteria 
Patients 18 years of age and older diagnosed with one of the following 
malignancies that have progressed after at least one prior regimen of standard 
therapy: 
• 
Persistent or recurrent serous epithelial ovarian cancer or primary 
peritoneal carcinoma or fallopian tube carcinoma  
• 
Metastatic or recurrent lung adenocarcinoma- Recruitment of NSCLC 
patients suspended with Protocol Amendment V10 
• 
Malignant pleural or peritoneal epithelial mesothelioma. 
Investigational 
Agent(s), Dose, Route, 
Regimen 
Investigational Agent(s): 
• 
huCART-meso cells: autologous T cells lentivirally transduced with chimeric 
anti-mesothelin immunoreceptor M5 scFv fused to the 4-1BB and CD3ζ 
signaling domains. 
• 
Cyclophosphamide and fludarabine: cytotoxic chemotherapy agents used 
for lymphodepletion prior to huCART-meso cell administration in targeted 
cohorts. 
 
Dose: 
• 
huCART-meso:  
o 1-3x107 huCARTmeso cells/m2 (Cohort 1-2, 5-7)  
 
In the event of 2 DLTs at this dose level, we will dose de-
escalate by 10-fold. 
o 1-3x108 huCART-meso cells/m2 (Cohort 3 and 4).  Cohorts 3 and 4 
permanently closed with Protocol V5. 
• 
Cyclophosphamide:  
o Cohort 2 and Cohort 6: Flat dose of 1 gram/m2  
o Cohort 7: 300 mg/m2/day given over 3 days 
• 
Fludarabine: 
o Cohort 7: 30 mg/m2/day given over 3 days 
 
Route of Administration: 
• 
huCART-meso:  
o Intravenous (Cohorts 1, 2, 6, and 7; Cohorts 3 and 4 permanently 
closed with Protocol V5)  
o Intrapleural (Cohort 5) 
o Intraperitoneal (Cohort 7) 
• 
Cyclophosphamide: intravenous (Cohorts 2, 6 and 7; Cohort 4 permanently 
closed with Protocol V5) 
• 
Fludarabine:  Intravenous (Cohort 7 only) 
 
Regimen: 
• 
huCART-meso cells:  
o Cohorts 1, 2 and 5: Single dose on Day 0  
o Cohort 6:  The initial IV infusion may be followed by up to two 
additional IV infusions of huCART-meso cells at the same dose 
level, between 21-42 days apart. 

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o Cohort 7:  Intraperitoneal (i.p) infusion followed by up to two 
additional infusions of huCART-meso cells given via IV 
administration at the same dose level, given between 21-42 days 
apart. 
• 
Cyclophosphamide: single dose administered 2-4 days (~Day -4 to -2) prior 
to huCART-meso cells (Cohort 2), and Cohort 6 (prior to first infusion only); 
Cohort 4 permanently closed with Protocol V5. 
• 
Cyclophosphamide and Fludarabine (Cohort 7 only): given over 3 days; 
scheduled so that the last dose of chemotherapy falls 3 days (+/- 1 day) 
prior to CAR T-cell infusion (Day 0).    
Duration of 
administration- 
huCART-meso cells 
Based on the total volume to be infused and the recommended infusion rate of 10-
20 ml per minute. 
Reference Therapy 
None 
Statistical 
Methodology 
This is a phase I safety and feasibility study. The statistical analysis will be primarily 
descriptive in keeping with the exploratory nature of the study. Descriptive 
statistics will be applied to determine the relative persistence and trafficking to 
blood (and optionally tumor) of the huCART-meso cells. Data regarding the number 
of CAR T cells in blood, and the tracking of soluble biomarker levels will be 
presented graphically. Correlations with radiographic and other standard measures 
of tumor burden will be determined. We will compute 95% confidence intervals for 
proportions and means. 
 
Adverse events will be collected and evaluated for all subjects during the protocol 
specified adverse event reporting period outlined in Section 9.1. AEs will be graded 
for severity using the National Cancer Institute (NCI) – Common Terminology 
Criteria (v4.03). All adverse events will be described and exact 95% confidence 
intervals will be produced for adverse event rates, both overall and within major 
categories. The data will be monitored on an ongoing basis for evidence of 
excessive toxicity. Results will be tabulated and summarized. 
 
Rates of clinical responses will be summarized in exact 95% confidence intervals. 
Distributions of progression-free and overall survival and duration of clinical 
response will be presented graphically using Kaplan-Meier curves. The two-year 
survival rates will be presented. 
 

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FIGURE 1-1:  STUDY SCHEMA (COHORTS 1-5*) 
 
*Cohort 3 and 4 permanently closed with Protocol V5 

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FIGURE 1-2:  STUDY SCHEMA (COHORT 6) 
 
 
 
 

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FIGURE 1-3:  STUDY SCHEMA (COHORT 7) 
 
 
 

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1 
INTRODUCTION 
1.1 
Background 
1.1.1 
Mesothelin 
Mesothelin was originally identified by Pastan and colleagues as a tumor associated antigen due to its 
limited expression by normal tissues and overexpression on tumors (Chang et al., 1992; Chang and Pastan, 
1996). The mesothelin gene encodes a precursor 71-kDa protein that is processed to yield the 40-kDa 
protein, mesothelin, which is anchored at the cell membrane by a glycosylphosphatidyl inositol (GPI) 
linkage and an amino-terminal 31-kDa shed fragment, called megakaryocyte potentiating factor (MPF). 
Both fragments contain N-glycosylation sites. A soluble splice variant of the 40-kDa carboxyl-terminal 
fragment called “soluble mesothelin/MPF-related” has been found in the sera of patients with 
PDA(Johnston et al., 2009). Mesothelin is currently being explored both as a therapeutic target as well as 
a bio-marker for disease activity and therapeutic response (Argani et al., 2001). 
 
Mesothelin is a differentiation antigen that is also present on normal tissues. Using the mouse anti-human 
mesothelin antibody K1 that was developed by the Pastan group, strong K1 reactivity has been 
demonstrated within mesothelial cells that line the peritoneal, pleural, and pericardial cavities, although 
at lower levels than usually seen for malignant tissues(Chang et al., 1992). Weak K1 reactivity has been 
detected within the Fallopian tube epithelium, tracheal basal epithelium and tonsils epithelium. However, 
K1 reactivity has not been detected in the majority of normal tissues including the liver, kidneys, spleen, 
bone marrow, lymph nodes, thymus, cardiac muscle, tongue, skeletal muscle, skin, cerebral cortex, 
cerebellum, spinal cord, peripheral nerve, pituitary, adrenal, salivary gland, mammary gland, thyroid, 
parathyroid, testis, prostate, epididymis, cervical epithelium, lung parenchyma, esophagus, small-bowel 
epithelium, colon epithelium, bladder epithelium, gall-bladder epithelium(Chang et al., 1992). Of note, K1 
antibody has lower affinity and it stains frozen tissues but not formalin fixed tissue, probably due to the 
destruction of the epitope upon tissue fixation (Pastan and Hassan, 2014). Mesothelin has also been found 
on all layers of the cornea(Jirsova et al., 2010). 
 
Epithelial MPM universally expresses mesothelin while sarcomatoid MPM does not express mesothelin 
(Chang and Pastan, 1996), suggesting that anti-mesothelin targeted therapies will not be successful in this 
histologic subtype.   
 
Mesothelin is also expressed on a large number of lung cancers, however, in most cases, expression is 
low.  Approximately 25% of lung adenocarcinomas express mesothelin strongly on >25% of cells. 
Interestingly, this population of high mesothelin expressors is enriched in the Kras-positive patients 
(Kachala et al., 2014; Thomas et al., 2015).   
 
Most serous epithelial ovarian carcinomas, and the related primary peritoneal carcinomas, express 
mesothelin (Chang et al., 1992). Mesothelin is a target of a natural immune response in ovarian cancer(Ho 
et al., 2005), and has been proposed to be a target for cancer immunotherapy(Hassan et al., 2004). The 
presence of mesothelin-specific CTLs in patients with pancreatic cancer correlates with overall survival 
(Thomas et al., 2004). In addition, Pastan and coworkers have used soluble antibody fragments of an anti-
mesothelin antibody conjugated to immunotoxins to treat cancer patients with mesothelin-positive 
tumors. This approach has demonstrated adequate safety and some clinical activity in pancreatic cancer 
(Hassan et al., 2007a; Hassan et al., 2007b). In ovarian cancer, this therapeutic strategy produced one 
minor response by RECIST criteria and stable disease in a second patient who also had complete resolution 

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of their ascites. Fallopian tube carcinoma is a rare type of carcinoma that is similar to epithelial ovarian 
cancer from the clinical and histological perspective. The standard of care also follows the principles 
applied to the epithelial ovarian cancer patients (Pectasides et al., 2006). Weak expression of mesothelin 
was detected on this tumor type using the mouse anti-human mesothelin antibody K1 (Chang et al., 1992). 
Additional supportive preclinical data for targeting mesothelin has been published (Stromnes et al., 2015).  
1.1.2 
Lung Adenocarcinoma, Epithelial Ovarian Cancer, and Mesothelioma 
Subjects with one of these three cancers have been chosen as the study population here because of the 
frequent expression of the target antigen mesothelin in these three types of malignancies. Each 
malignancy, including the current conventional and immunotherapeutic approaches for treating it, is 
discussed below.  
1.1.2.1 
Lung Adenocarcinoma 
Lung cancer is the leading cause of cancer related mortality in the United States. NSCLC (non-small cell 
lung cancer) accounts for approximately 85% of all lung cancers and encompasses different histologies 
including squamous cell carcinoma, large cell carcinoma, and adenocarcinoma (Siegel et al., 2015). Most 
NSCLC patients present with loco-regionally advanced or metastatic disease where response rates and 
median overall survival remain dismal. Platinum-based chemotherapy is the mainstay of treatment for 
NSCLC in both adjuvant and metastatic disease. Over the last few years, we have made improvements in 
overall survival of patients with metastatic disease due to the availability of immune therapies and 
targeted therapies based on patients’ individual molecular profile(Borghaei et al., 2015; Mok et al., 2009; 
Sandler et al., 2006; Topalian et al., 2012). Anti-PD1 antibodies have been approved in Japan and USA, 
based on potent activity in a variety of tumors. In 2015, pembrolizumab (anti-PD1 Keytruda made by 
Merck) was FDA approved for non-small cell lung cancer and nivolumab (anti-PD1 Opdivo made by Bristol-
Myers Squibb) was approved for non-small cell lung cancer and metastatic renal cell carcinoma. 
Combination of checkpoint inhibitor therapies such as nivolumab (fully human IgG4 anti-PD-1) with or 
without ipilimumab (anti-CTLA-4) for treatment of recurrent small cell lung cancer (NCT1928394) has been 
shown to be tolerable and to induce durable responses (2015 ASCO Abstract# 7503). We have also 
witnessed the advent of maintenance strategies and antiangiogenesis approaches that have improved 
patient outcomes (Patel et al., 2009).  However, despite these advances in treatment, overall survival of 
patients with metastatic NSCLC remains poor at 12 to 18 months, and there are virtually no long term 
survivors.  
 
Even after response to first line therapy, patients eventually develop progressive disease and require 
additional treatment. The management of patients with advanced NSCLC who have relapsed after their 
initial treatment is a difficult problem. The approach depends upon the initial systemic therapy 
administered and upon whether symptoms relate to widely disseminated metastatic disease or whether 
symptoms are related to involvement of a single location. Treatment in this setting is largely palliative in 
this refractory population and there is a major, immediate need for new therapies that have the potential 
for long term remission, disease control and can improve quality of life and overall survival. 
 
The Sponsor has decided to suspend enrollment of NSCLC patients into Cohort 5 as of Amendment 10. 
This decision was based on the following considerations: 
• 
Limited recruitment of this disease population to date; only 1 evaluable subject infused to date. 
• 
No current plans to further develop this investigational product in this disease population. 
• 
Logistical challenges of re-introducing pre-screening/mesothelin expression testing back into the 
study for one targeted disease population within Cohort 5 only. 

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1.1.2.2 
Ovarian Cancer 
Ovarian cancer is the 5th most common cancer in women and, in the United States in 2015, 21,290 women 
were diagnosed with ovarian cancer and 14,180 women died of the disease (2015).  Despite efforts 
studying different cytotoxic and targeted agents to treat ovarian cancer, no major improvement in cure 
rates has been seen (Huang et al., 2008). Surgery and platinum-based therapies are the current standard 
of care for ovarian cancer management. Thus, new approaches to ovarian cancer treatment are desired. 
As ovarian tumors have previously been shown to be immunogenic (Zhang et al., 2003) 
immunotherapeutic strategies, including vaccines, adoptive cell transfer, and immunomodulatory drugs, 
have recently been presented as possible methods of combating ovarian cancer (Coukos et al., 2016).  
 
In an early cell transfer trial by Fujita et al., administration of autologous tumor infiltrating lymphocytes 
(TILs) to ovarian cancer patients in the adjuvant setting (after surgical resection and subsequent cisplatin-
chemotherapy) resulted in a prolonged disease-free survival and increased the 3-year survival rate, 
supporting the notion that T cell transfer can actively inhibit ovarian tumor growth (Fujita et al., 1995). 
Moreover, administration of TILs (alone or in combination with cisplatin-containing chemotherapy) after 
a single dose of cyclophosphamide was shown to induce objective cancer regressions in some patients 
with existent chemotherapy-naïve or recurrent ovarian cancer as well (Chang and Pastan, 1996). The 
mechanism of tumor eradication appeared to be cell-mediated as suggested by the increased CD8+ T cell 
percentages, activation of cellular immunity and enhanced natural killer activity detected in the blood 
from treated patients (Johnston et al., 2009). 
1.1.2.3 
Malignant Mesothelioma 
Malignant mesothelioma is the most serious effect of exposure to asbestos. It is an aggressive cancer 
affecting the membrane lining of the lungs or peritoneum. There are three major types of mesothelioma 
depending on the organ affected: pleural mesothelioma, peritoneal mesothelioma, and pericardial 
mesothelioma.  
 
Peritoneal mesothelioma is a primary malignancy of the mesothelial surface of the peritoneum and 
represents about 20% of the mesothelioma cases. It is a locally progressive tumor that encases the 
abdominal organs and often is diagnosed at a late stage due to nonspecific patient symptoms. While up 
front responses with cisplatin and pemetrexed only have about a 25% response rate with overall survival 
around one year, centers of excellence employing a multimodality approach of cytoreductive surgery with 
hyperthermic intraperitoneal chemotherapy have demonstrated 5-year survival rates of 39-63%. 
However, peritoneal mesothelioma remains incurable and novel therapeutic options are needed.   
 
Malignant pleural mesothelioma (MPM) is a primary neoplasm of the mesothelial lining of the pleura 
space.  MPM is usually staged using the IMIG/AJCC staging system.  At the time of diagnosis, stage II 
disease is most common (50%), stages I (18%) and III (28%) are less frequent, and stage IV disease is very 
infrequent (4%).  Thus, in most cases, MPM is a diffuse but locoregional disease at the time of diagnosis. 
The tumor grows in a locally-invasive fashion, often invading thoracic structures such as chest wall, 
pericardium, myocardium, and great vessels.  Distant, blood-borne metastases occur very late in the 
disease (Sterman et al., 1999).   
 
Traditional MPM therapy has included three modalities that have been used individually or in 
combination: surgery, irradiation, and chemotherapy.  Unfortunately, to date, none of these modalities 
has proven curative.  Surgical resection allows the removal of gross tumor but cannot provide 
microscopically-negative margins.  Radiation is limited by the large tumor volume and the radiation 

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intolerance of adjacent intrathoracic organs.  The most effective combination chemotherapy, pemetrexed 
(Alimta)/cisplatin, has yielded overall response rates of up to 40%, but with improvements in overall 
median survival of only 3.5 months(Vogelzang et al., 2003).  Because of these shortcomings, several 
clinical trials utilizing aggressive surgical approaches (i.e. extrapleural pneumonectomy) coupled with 
radiation treatment and pre- or post-operative chemotherapy have been conducted in good performance 
status patients.  Peri-operative morbidity from this multimodality therapy has been significant, and there 
remains a peri-operative mortality rate of 5%, even in the most experienced centers.   
 
After cisplatin/pemetrexed, there is no well-accepted second-line chemotherapy (for review, see(Ceresoli 
et al., 2009), but based on activity in front-line patients, most centers use either vinorelbine or 
gemcitabine, either alone or in combination with a platinum agent if disease progression has occurred 
shortly after first line therapy.  There is surprisingly little data about the patient response to second-line 
therapy; however, in the best study published to date(Zucali et al., 2008), the activity and toxicity of 
combination gemcitabine/vinorelbine in pemetrexed-pretreated MPM patients was assessed.  Thirty 
consecutive patients who had been pretreated with pemetrexed were given gemcitabine (1000 mg/m2) 
and vinorelbine (25 mg/m2) intravenously on Days 1 and 8 every three weeks.  Most patients were PS 0 
or 1 (83%).  Only three patients had a partial response (10%); there were no complete responses.  The 
median time to progression was 2.8 months (range 0.8 - 25 months).  Progression-free survival at three 
months was 45% (95% CI, 26.4 - 64.3%).  The median survival rate was 10.9 months (range 0.8 - 25.3 
months).  Novel therapeutic approaches are clearly needed in this disease. 
1.1.3 
Adoptive immunotherapy 
Breaking tolerance to self-antigens is a major obstacle in the application of immunotherapy to solid 
malignancies. Vaccine strategies aimed at harnessing endogenous anti-tumor T cells are limited by the T 
cell receptor (TCR) repertoire which can be deleted within the thymus as part of central tolerance or 
rendered non-functional by post-thymic mechanisms of peripheral tolerance. One approach designed to 
overcome these obstacles is adoptive immunotherapy, a term used to describe the transfer of immune 
cells for the treatment of cancer or infectious disease (June, 2007). With adoptive immunotherapy, 
therapeutically effective T cells can be engineered to recognize tumors.  
 
Penn has continued to pioneer new adoptive immunotherapeutic strategies such as producing genetically 
engineered T cells referred to as chimeric antigen receptors (CARs). The significant advancement with 
such therapies is that CARs combine the effector functions of T lymphocytes with the ability of antibodies 
to recognize distinct surface antigens in a non-MHC restricted manner. As a result, CARs can be used to 
redirect T cells to recognize an intact membrane protein independent of antigen processing.   
 
The in vivo persistence, expansion, and functional capacity of adoptively transferred engineered T cells is 
dependent on two discrete signals mediated by cell surface receptors. The primary “activation” signal is 
produced by ligation of the TCR with an MHC-peptide complex. The second “costimulatory” signal is 
generated by ligation of a costimulatory molecule on the T cell surface with its cognate ligand on the 
surface of an antigen presenting cell.  
 
We and others have observed that 4-1BB, a T cell co-stimulatory receptor induced by TCR activation, is 
critical for long-term proliferation of CD8 cells whereas CD28 is essential for sustained CD4 cell 
proliferation(Maus et al., 2002). Consistent with this finding, we have found that “bipartite receptors” 
comprised of TCRζ and either CD28 or 4-1BB signaling modules substantially improve the function and 
proliferation of T cells in vivo. (Kalos et al. 2011)(Porter et al. 2011) (Grupp et al. 2013a) (Maude et al. 

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2014) (Porter et al. 2015)(Milone et al. 2009). In previous studies, we found that adoptive 
immunotherapeutics, such as CART19 administered intravenously, can persist for more than 5 years in 
some patients with advanced, chemotherapy-resistant leukemia.   
 
Based on this broad experience, we pursued a similar approach in developing a CAR specific for mesothelin 
protein (Carpenito et al., 2009). Here, we have used the same type of lentiviral transduction system and 
the same type of CAR construct, comprised of a mesothelioma specific scFv fused to the 4-1BB and CD3z 
signaling domains, to generate CART-meso cells. The main difference between the anti-CD19 CAR and 
anti-mesothelin CAR constructs rely on the origin of the scFv portion of the construct which is specific to 
the target protein.   
1.1.4 
Lymphodepletion  
Adoptive immunotherapy strategies may be able to capitalize on homeostatic T cell proliferation 
(Dummer et al., 2002), a recent finding that naive T cells begin to proliferate and differentiate into 
memory-like T cells when total numbers of naive T cells are reduced below a certain threshold(Goldrath 
and Bevan, 1999; Surh and Sprent, 2000). Lymphodepletion eliminates regulatory T-cells and other 
competing elements of the immune system that act as “cytokine sinks”, enhancing the availability of 
cytokines such as IL-7 and IL-15 (Klebanoff et al., 2005). This hypothesis has been tested clinically in 
patients with metastatic melanoma refractory of conventional treatments (Dudley et al., 2002). The 
patients received a lymphodepleting conditioning regimen consisting of cyclophosphamide (60 mg/kg x 2 
days) and fludarabine (25 mg/m2 x 5 days) prior to adoptive transfer of T cells. Patients with myeloma, 
NHL, and CLL have been treated with infusions of ex-vivo co-stimulated and expanded autologous T cells 
after lymphodepleting chemotherapy, and observed improved engraftment (Laport et al., 2003) (Kalos et 
al., 2011; Porter et al., 2011; Rapoport et al., 2005) (Porter et al., 2015).  
 
Based on the reported data as well as the data collected from our recently closed study (UPenn UPCC# 
31213, NCT02159716) that tested the safety of an earlier generation mesothelin directed CART cells in a 
similar patient population  indicated that preconditioning using intravenous cyclophosphamide (1.5 g/m2) 
was safe and enhanced CART expansion in peripheral blood. Neutropenia was observed in all subjects 
with a subset being febrile at 10-14 day post-infusion which interfered with obtaining the protocol 
recommended tumor biopsy in that timeframe.  These data informed our perspective on lymphodepletion 
in this study, and we initially proposed to lower the cyclophosphamide dose to 1 g/m2 which we believed 
would limit toxicity in the target patient populations.  
 
However, preconditioning with cyclophosphamide and fludarabine in combination (Cohort 7 only) with 
adoptively transferred lymphocytes for the treatment of neoplasia induces modulation of several 
cytokines and homeostatic proliferation of the transferred lymphocytes, promotes homing of those 
lymphocytes to secondary lymphoid organs, and contributes to in vivo T cell persistence.  This provides a 
rationale for combining adoptive immunotherapy with chemotherapy.(Bracci et al., 2007; Moschella et 
al., 2011) The main goal of using both cyclophosphamide and fludarabine is to achieve lymphodepletion 
that may enhance engraftment of adoptive T cells, while minimizing complications from 
neutropenia/myelosuppression. Therefore, provided the previously published data as well as the 
preliminary data from early cohorts in this study, we hypothesize the use of cyclophosphamide and 
fludarabine in preparation for local administration will improve the engraftment of the huCART-meso cells 
without increasing the risk to subjects.  

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1.1.5 
Local versus systemic administration of CAR T cells  
The route of CART administration is an area of interest (Katz et al., 2016; Tilley et al., 2014) due to the 
finding that trafficking of CART cells to solid tumors is limited (Moon et al., 2011). A recent paper published 
by the Memorial Sloan Kettering Cancer Center indicates that intrapleural (IP) delivery of anti-mesothelin 
redirected CAR T cells in mice is superior to systemic delivery (de Biasi et al., 2014). This publication was 
followed by opening of a clinical trial testing the safety of anti-mesothelin redirected CAR T cells 
(iCasp9M28z T cells) with or without cyclophosphamide preconditioning (1.5 g/m2) in patients with 
malignant pleural disease from mesothelioma, lung cancer, or breast cancer by intrapleural 
administration (NCT02414269). Other studies are also testing the merits of local/intratumoral route of 
administration (NCT02498912, NCT01818323) of CAR T cells in solid tumors.  
 
In addition, based on our prior experience with mesothelin-directed CAR T cell therapies, we hypothesize 
that local delivery of the maximum tolerated dose (MTD) of huCART-meso cells (established via IV infusion 
in early cohorts on this study, 1-3x107 huCART-meso cells/m2) may reduce the risk to subjects by mitigating 
the potential for off-tumor, on-target toxicities such as those previously discussed.  Brown et al., based 
on in silico modeling of CAR T cell delivery to peripheral organs, maintains that the typical CAR T cell dose 
administered intravenously in solid tumor clinical trials (approximately 108 cells) is likely insufficient to 
promote an appreciable anti-tumor effect (Brown et al, 2019; doi: http://dx.doi.org/10.1101/759167). 
Therefore, local administration allows for delivery of the huCART-meso cells directly to the tumor, 
minimizing their peripheral distribution, reducing the potential for off-tumor, on-target toxicity, and 
maximizing the number of CAR T cells that extravasate into the tumor microenvironment.  Therefore, local 
administration of huCART-meso cells may increase the overall therapeutic index of this investigational 
product.  
 
Thus, we propose to test the safety and feasibility of local administration, test the CART escape and 
persistence into the blood, and directly compare to the same parameters following IV administration of 
the same dose.  
 
Finally, in an effort to further balance both toxicity and efficacy, the Cohort 7 will permit repeat IV 
infusions of huCART-meso cells every 21-42 days (at the clinical discretion of the physician-investigator) 
after the initial local dose.  We hypothesize that repeat IV infusions will bolster the anti-tumor effect of 
persistent huCART-meso cells which may lead to improved clinical outcomes while mitigating risk of 
toxicities observed at higher IV doses.  
1.2 
Investigational Agent 
The investigational agent in this protocol is huCART-meso cells, which are autologous T cells transduced 
with chimeric antigen receptor (CAR) composed of anti-mesothelin M5 scFv fused to 4-1BB and TCRzeta 
signaling domains.  huCART-meso cells will be manufactured using the lentiviral transduction platform, 
the same as multiple other investigational cellular products tested at UPENN. The same technology that 
is used to transduce CART19 cells will be used to transduce huCART-meso cells (lentiviral transduction). 
The M5 scFv with specificity for mesothelin is newly derived from a human scFv library by Novartis Inc. 
The scFv is expected to redirect specificity of the transduced T cells to mesothelin expressing cells. The 
intracellular signaling domain of the CAR molecule is comprised of the TCRζ  and 4-1BB signaling modules 
previously tested in clinical studies (Grupp and June, 2010; Hassan et al., 2010a; June et al., 2009; Kreitman 
et al., 2009; Romeo and Seed, 1991), both entirely of the native human sequences. The CAR receptors are 
“universal” in that they bind antigen in an MHC-independent fashion, thus, one receptor construct can be 
used to treat a population of patients with mesothelin antigen-positive tumors. 

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Clinical grade engineered T cells will be manufactured at the UPENN Clinical Cell and Vaccine Production 
Facility (CVPF).  Please refer to the current version of the huCART-meso Investigator’s Brochure for 
additional details.  
1.3 
Preclinical data  
Please refer to the current version of the huCART-meso Investigator’s Brochure for additional details. 
1.4 
Clinical data to date 
Please refer to the current version of the huCART-meso Investigator’s Brochure for additional details. 
1.5 
Toxicities associated with CART cells 
Please refer to the current version of the huCART-meso Investigator’s Brochure for complete details.    
1.6 
Trial Rationale 
Immunotherapy is a novel and promising approach for the treatment of solid tumors; immunotherapy 
with CART cells in particular has the potential advantage of targeted therapies that can invoke a rapid 
tumor response, and the advantage of long-lived responses that are the hallmark of engagement of the 
adaptive immune system such as memory T cells.  
 
This Phase I study poses the hypothesis that targeting the mesothelin antigen that is widely and frequently 
expressed in multiple tumor types, particularly epithelial ovarian cancer and mesothelioma will be safe, 
feasible, and result in anti-tumor responses. Furthermore, this study addresses the questions of whether 
a human construct persists better in vivo than a murine based CAR construct, whether lymphodepletion 
is necessary for engraftment and persistence of huCART-meso directed T cells in patients with solid 
tumors, and whether intrapleural (IP) and intraperitoneal (i.p.) administration has benefits compared to 
IV administration.  
 
As of Protocol Amendment V5, the maximum tolerated dose has been established as 1-3x107 huCART-
meso cells/m2. While the safety of this dose level has been established using IV administration, there was 
a lack of clear clinical efficacy at this dose level in Cohorts 1 and 2.  Therefore we believe that exploration 
of a different dosing regimen is warranted.  In pre-clinical studies, we have seen both safety and increased 
efficacy of multiple CAR T cell doses.  Therefore, we plan to explore the safety and feasibility of 
administering up to three (3) infusions of huCART-meso cells at the MTD (given a minimum of 21 days 
apart) in Cohort 6 (intravenous administration) and Cohort 7 (intraperitoneal administration on Day 0, 
followed by repeat IV administration).  As a secondary objective, we will also evaluate the anti-tumor 
response of this regimen.     
1.7 
Potential Risks and Benefits 
This protocol is designed to determine the safety and feasibility of both intravenous administration and 
local delivery of permanently modified CAR T cells that target mesothelin, with or without 
lymphodepletion.   
1.7.1 
huCART-meso Cells 
Please refer to the current version of the huCART-meso Investigator’s Brochure for complete details.   

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1.7.1.1 
Intrapleural Administration of CAR T cells (Cohort 5)  
It is anticipated that subjects with pleural effusion will already have a catheter in place.  However, in the 
event a catheter must be placed for IP administration, the risks associated with this include infection, 
bleeding, local pain at insertion site, pneumothorax, subcutaneous emphysema, and post drainage pain.  
There is also a risk associated with the moderate sedation used at the time of catheter placement which 
includes over sedation, nausea, vomiting, respiratory compromise, irregular heart rhythm, and low blood 
pressure.   The subject will be closely monitored by a licensed provider per institutional standard practice.  
The timing of placement and subsequent removal of the catheter will be per clinical discretion.  
 
The risks associated with pleural instillation are the same as those associated with IV administration.  
However, there is also a higher risk of pleuritis given the direct administration into the pleural cavity.  
1.7.1.2 
Intraperitoneal Access and Administration of CAR T cells (Cohort 7)   
Some subjects may already have a catheter in place; however, in the event a catheter must be placed for 
Intraperitoneal (i.p.) Instillation, placement of the catheter will be performed by Interventional Radiology 
(IR) or other appropriately licensed provider.  Location (IR or bedside) of the paracentesis procedure will 
depend on the ascites volume (moderate/large amount of ascites, i.e. at least 3 cm pocket is required for 
bedside placement).  The timing of placement and subsequent removal of the catheter will be per clinical 
discretion. 
 
Percutaneous techniques will be utilized in this protocol. Percutaneous insertion with radiologic guidance 
has the advantage of minimally invasive and correct catheter positioning in the lower abdomen. Safely 
accessing the intra-abdominal space for an individual patient may or may not require administration of a 
small volume of saline or contrast.  
 
Risks associated with the procedure include, but are not limited to, pain or discomfort at the needle 
insertion site, bleeding at the site, internal bleeding, injury to a blood vessel, organ puncture, and infection 
which may result in an infection of the blood stream. The development of any infection may result in the 
need for intravenous antibiotics. X-ray contrast material may be used at the time of catheter insertion. 
Risks associated with the X-ray contrast material include an allergic reaction.  
 
Moderate sedation may be used during the catheter placement. Risks of the medications used for the 
moderate sedation include aspiration (inhaling food or liquid into the lungs), respiratory depression, over-
sedation, nausea, vomiting, respiratory compromise, irregular heart rhythm, and low blood pressure. In 
addition to the potential risks associated with the procedure, the X-ray contrast material, and the 
moderate sedation, there may be other unpredictable risks including death. 
 
Subjects will be asked to sign a standard hospital consent form for this procedure. The subject will be 
closely monitored during/after the procedure by a licensed provider per institutional standard practice. 
 
The risk of peritoneal inflammation with IP administration is anticipated to be higher than that of IV 
administration given the direct administration into the peritoneal cavity. 
1.7.1.3 
Cyclophosphamide  
In over 10% patients, cyclophosphamide has dermatologic reactions (alopecia beginning 3-6 weeks) and 
may cause sterility; thrombocytopenia and anemia are less common than leukopenia and neutropenia 
with an onset at 7 days, nadir at 10-14 days, and recovery at 21 days. Nausea and vomiting occur more 

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frequently with large doses, usually beginning 6-10 hours after administration; subjects will be offered 
antiemetic prophylaxis and therapy. Acute hemorrhagic cystitis, believed to be a result of chemical 
irritation of the bladder by acrolein, a cyclophosphamide metabolite, occurs in 7% to 12% of patients and 
has been reported in up to 40% of patients in some series. Patients will be encouraged to drink plenty of 
fluids during and after therapy (most adults will require at least 2 L/day), and void frequently. With large 
IV doses, IV hydration is usually recommended. The use of mesna and/or continuous bladder irrigation is 
rarely needed for doses <2 g/m2.  Less frequent reactions (1-10%) such as facial flushing, headache, and 
skin rush may occur. Nasal congestion occurs when IV doses are administered too rapidly (large doses via 
30-60 minute infusion); patients experience runny eyes, rhinorrhea, sinus congestion, and sneezing during 
or immediately after the infusion. If needed, a decongestant or decongestant/antihistamine (e.g., 
pseudoephedrine or pseudoephedrine/triprolidine) can be used to prevent or relieve these symptoms. 
 
The above describes the risks of cyclophosphamide when given as part of routine care.  We expect similar 
side effects when administered as part of this study.   
1.7.1.4 
Fludarabine   
Fludarabine may induce myelosuppression, including anemia, thrombocytopenia, neutropenia, and 
lymphopenia.  Severe, often reversible, myelosuppression may occur, although this typically occurs 
following cumulative dosing of fludarabine (administered for 3 consecutive days every 28 days).  In this 
study, patients will receive one 3-day administration of fludarabine.  Autoimmune hematologic 
phenomena, including hemolytic anemia or immune thrombocytopenia may occur following 1 or more 
cycles of fludarabine.  Patients undergoing treatment with fludarabine will be evaluated and monitored 
closely for cytopenias and/or hemolysis.  Nausea and vomiting may occur with fludarabine, and subjects 
will be offered antiemetic prophylaxis and therapy.   
 
The above describes the risks of cyclophosphamide and fludarabine when given as part of routine care.  
We expect similar side effects when administered as part of this study.   
1.7.1.5 
Fludarabine in Combination with Cyclophosphamide 
• 
Common: Lowered neutrophils/granulocytes that may lead to infection. Lowered platelets may 
lead to an increase in bruising or bleeding, Lowered red blood cells. Lowered lymphocytes may 
lead to infection, fatigue, nausea, vomiting, time away from work, hair loss, or Herpes zoster 
infection of the skin.  
• 
Less Likely: Allergic reaction, severe allergic reaction that causes fever, aches and pains in the 
joints, skin rash, and swollen lymph glands, stuffy or runny nose, sneezing, sore throat, abnormal 
fast heartbeat, excessive sweating, flushing, itching, rash, swelling of the lips, eyes, tongue, and 
throat which can be severe, hives, diarrhea, high blood sugar, low blood potassium, dizziness, 
convulsion or seizure, abdominal pain, pain such as back, joint, and/or muscle pain, headache, 
wheezing, cough, shortness of breath, inflammation of the lung which may cause difficulty 
breathing and difficulty getting oxygen, infertility or sterility, or irregular menstrual periods. Some 
women may not resume their periods, SIADH (syndrome of inappropriate antidiuretic hormone), 
increased production of tears associated with the administration of cyclophosphamide, metallic 
taste, cystitis and hematuria.  
• 
Rare But Serious: hemolytic anemia. Changes in vision or changes in degree of alertness both of 
which can be severe or fatal, rash which may become severe, potentially life-threatening 
condition affecting less than 10% of the skin in which cell death causes the outer skin layer to 
separate from the middle layer, life-threatening condition affecting greater than 30% of the skin 

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in which cell death causes the outer layer of skin to separate from the middle layer, severe lung 
dysfunction resulting in the ability to breathe which can be life-threatening, allergic reactions to 
blood transfusions, Tumor Lysis Syndrome - a rapid decline in the number of tumor cells that can 
lead to kidney failure and/or chemical imbalances that may have a serious effect on other organs 
such as heart. If this were to occur, subjects will receive close monitoring and blood tests, as well 
as appropriate medical treatment. It is possible that secondary malignancies including 
myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) may also be experienced. 
1.7.2 
Mesothelin Expression  
Mesothelin IHC testing was required as part of eligibility screening for subjects enrolled prior to the 
implementation of Protocol Amendment V9. The risk of a failed mesothelin immunohistochemistry test 
(false-positive) resulting in huCART-meso infusion in a patient with no mesothelin expression on his/her 
tumor is the same as the risks listed above, with the exception of TLS and CRS which are not expected due 
to the lack of tumor antigen expression.  
 
Mesothelin IHC testing was subsequently eliminated as an eligibility parameter with Protocol Amendment 
V9.  Eliminating IHC testing as an enrollment activity is based on the heterogeneity of mesothelin 
expression on accessible tumors, and the limited, and likely non-representative, amount of tissue being 
analyzed by IHC. This heterogeneity may bias diagnostic conclusions based on mesothelin-negative IHC 
results, since other areas of the tumor may in fact express mesothelin at study-qualifying levels. 
Therefore, IHC analysis is being removed in favor of the more sensitive, specific, and reliable GeoMx Digital 
Spatial Profiling analysis for both the presence of mesothelin on tumor tissue as well as CAR T cell 
localization to tumor. Furthermore, since a primary objective of the study is to evaluate the safety of 
huCART-meso cells, removing IHC testing neither impacts the safety endpoint nor adds additional risk to 
subjects. However, by eliminating IHC testing as an enrollment activity, it is anticipated to improve subject 
eligibility. Finally, the risk mitigation strategies employed on the study (e.g.: eliminating the first pass of 
huCART-meso cells through the lungs by implementing local delivery, inpatient monitoring post-infusion, 
an acute awareness of complications based on prior experience, etc.) are designed to mitigate on-target, 
off-tumor adverse reactions such as ARDS.  
1.7.3 
Research Procedures 
Additional risks for the participating subjects are related to procedures including the following:  
Potential risks of the apheresis procedure include nausea, vomiting, fainting or dizziness, seizures, skin 
rash, hives, flushing, blood loss, and infection. Tingling of the lips, muscle cramping and, very rarely, 
changes in heart rhythm can occur. These can be prevented or made milder by giving calcium 
supplements, either by mouth or in the vein, also called intravenous (IV).  
 
Very rarely, (less than 1 in 1,000 procedures), clotting may occur in the apheresis machine or in a patient 
and is potentially life-threatening. To reduce the risk of clotting, a drug called ACD (acid-citrate-dextrose) 
will be used. This drug may increase the risk of bleeding and may cause temporary tingling of the lips and 
limbs, muscle cramping, seizures, or changes in the heart rhythm.  
 
After the apheresis procedure the patient may experience temporary discomfort, including irritation, 
swelling or bruising at the place where the needle was inserted into the vein to collect the blood. 
Apheresis can also occasionally cause hives, numbness and tingling, or swelling of the feet and ankles. 

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1.7.3.2 
Blood Draws 
Risks associated with blood draws include bruising, swelling, black and blue marks, fainting and/or 
infection at the site.  Rarely, patients may experience anemia from having blood drawn frequently.  
1.7.3.3 
Tumor Biopsy 
Risks may differ depending on the type of biopsy performed; however, common side effects may include: 
pain, discomfort, soreness, bleeding, and bruising.   
 
Given that the patient populations recruited for this protocol have limited therapeutic options, we believe 
that the above risks are acceptable.   
1.7.4 
Potential Benefits   
It is possible that the anti-mesothelin CAR T cells will exert an anti-tumor effect; in two preliminary studies 
(UPCC#17510 and 21211) performed at UPENN testing RNA CART-meso cells, 2 subjects had an objective 
anti-tumor response out of 14 total subjects. CART 19 cells infused in patients with ALL, CLL, lymphoma 
and multiple myeloma have been shown to exert sustained clinical responses (Brentjens et al., 2013; 
Garfall et al., 2015; Grupp et al., 2013b; Kalos et al., 2011; Maude et al., 2014; Porter et al., 2011), 
(Brentjens et al., 2013). Additionally, safety and efficacy of CAR T cells redirected against BCMA are tested 
in patients with multiple myeloma at UPENN and the preliminary results indicate that this cellular therapy 
is tolerable and induce durable responses (unpublished data). 
1.8 
Justification of Route and Dose Regimen 
Route of Administration (ROA).  
• 
Intravenous: Autologous huCART-meso cells will be administered intravenously (IV) as a single 
dose infusion. This route of administration is the most likely to result in distribution of huCART-
meso to all sites of tumor. Intravenous infusion is being evaluated in Cohorts 1-4 and 6. Cohorts 
3 and 4 were permanently closed with Protocol V5 due to toxicity.  
• 
Intrapleural (IP): Cohort 5 will evaluate autologous huCART-meso cells administered intrapleurally 
(IP) in patients with malignant effusions in the pleural space (i.e. MPM, and ovarian cancer with 
cytologically confirmed malignant pleural effusion), where the tumor is uniquely accessible and 
directed administration of therapeutic agents, such as CART cells, is possible. The method of IP 
instillation for targeted therapeutic delivery has been employed previously at the University of 
Pennsylvania in patients with malignant mesothelioma (Sterman et al., 2016; Sterman et al., 2005; 
Sterman et al., 1998) and elsewhere in ovarian cancer patients (Hasenburg et al., 2001). In these 
studies, no toxicities were associated directly with the IP route of administration.  
Note: As of protocol Amendment 10, recruitment of NSCLC patients into Cohort 5 is suspended 
due to limited enrollment of this disease population to date.  There are also no plans to 
further develop this investigational product in this disease population. 
• 
Intraperitoneal (i.p.): Cohort 7 will evaluate autologous huCART-meso cells administered via 
intraperitoneal instillation.  This cohort will target subjects with ovarian cancer and peritoneal 
mesothelioma.  Local administration will allow for delivery of the huCART-meso cells directly to 
the tumor, minimizing their peripheral distribution, reducing the potential for off-tumor, on-
target toxicity, minimizing the first-pass effect in the lungs, and maximizing the number of CAR T 
cells that extravasate into the tumor microenvironment.  There, it is anticipated that local 
intraperitoneal administration may increase the overall therapeutic index of this investigational 
product.  

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o The method of localized instillation for targeted therapeutic delivery has been employed 
previously at the University of Pennsylvania in patients with malignant mesothelioma 
who had pleural administration of agent (Sterman et al., 2016; Sterman et al., 2005; 
Sterman et al., 1998) and elsewhere in ovarian cancer patients (Hasenburg et al., 2001). 
In one patient with pancreatic adenocarcinoma with peritoneal carcinomatosis and no 
other treatment options available, anti-mesothelin CAR T cells were safely delivered by 
intraperitoneal administration on a compassionate-use basis at UPenn with the 
expectation that delivery of T cells via an i.p. route of administration may provide 
significant clinical benefit (UPCC#21211; IRB#814373).   
• 
Repeat IV Administration (Cohorts 6 and 7): In an effort to further balance both toxicity and 
efficacy, repeat administration of huCART-meso cells will be performed via IV infusion after the 
initial dose (approximately every 21-42 days, as per the physician-investigator’s clinical 
discretion).  We hypothesize that additional IV infusions may maintain the therapeutic index of 
previously administered cells in the tumor microenvironment, which may have become exhausted 
or hypofunctional. There is strong pre-clinical data supporting this hypothesis in a mouse model 
of pancreatic cancer (Stromnes et al., 2015), and we anticipate that repeat infusions may bolster 
the anti-tumor potential of huCART-meso cells in this setting.   
 
Dose Rationale for huCART-meso Product.  The decision for a starting dose for biologics is guided based 
on 1) FDA Guidance for Industry: S6 Preclinical Safety Evaluation of Biotechnology-derived 
Pharmaceuticals; 2) Joint taskforce report from the BioIndustry Association (BIA) and the Association of 
the British Pharmaceutical Industry (ABPI); 3) the available literature on phase I trials to date conducted 
with CAR T cells, and 4) accumulating experience on phase I trials targeting mesothelin using the CAR 
technology.  
 
For biologics, the goal is to start at or below the minimum anticipated biological effect level (MABEL) and 
the conventional dose escalation for cell based therapies is half log10 increments. Since toxicity usually 
arises from exaggerated pharmacological effects with biologics, sometimes combined with a narrow 
therapeutic range and/or a steep dose-response relationship from the no observed adverse effect level 
(NOAEL) to toxicity, the pharmacologically active dose is often a more sensitive indicator of potential 
toxicity for biotechnology-derived pharmaceuticals. There are various ways of estimating MABEL. One 
way is to model the occupancy of the target with different doses; another is to test effects on human 
tissues ex vivo (readily applied if the target is carried by the human lymphocyte in peripheral blood); the 
third is to use data from a carefully qualified animal model. Finally, a literature review of the effects of 
other relevant molecules is important.  
 
In an in vivo study using the NOD/SCID/γc-/- mouse tumor xenograft performed by our group at UPenn 
with a similar CAR of different specificity, the pharmacologically effective dose (PED) of the CAR T cells 
was 1x107 CAR T cells/mouse. At this dose, some of the mice developed xenogeneic graft versus host 
disease. The maximum tolerated dose (MTD) in the mouse model was 50x107cells/mouse.  The NOAEL 
was ~1x106 CAR T cells per mouse. The NOD/SCID/γc-/- is the best available model for evaluating 
preclinical efficacy of CAR T cells for mesothelin-expressing tumors; however, the mouse tumor xenograft 
model is a non-relevant species for determination of some aspects of toxicology for this particular CAR T 
cell, because the anti-mesothelin scFv SS1 component does not bind to normal mouse mesothelial tissue, 
and therefore, the mouse will under-predict toxicity. However, the lack of an immune response to the 
CAR T cells in the mouse tumor model will tend to over-predict other effects, because humans will make 
responses that limit the persistence of vector- modified T cells(Kershaw et al., 2006; Lamers et al., 2006). 

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If mice are considered 2000-fold smaller than humans, the estimated values of NOAEL and PED are 2x109 
cells and 2x1010 cells, respectively. These estimated values suggest that 109 meso-CAR T cells per subject 
might be safe. 
 
In the clinical studies of meso RNA CAR T cells opened at UPENN, flat doses of 108 and 109 total 
cells/infusion for multiple infusions have been administered to 14 subjects with either pleural 
mesothelioma or pancreatic cancer (NCT01355965, NCT01897415). In all cases, the efficacy of 
electroporation and CAR expression was over 85% cells on a flow based assay.  In several cases, mild 
cytokine release syndromes have been observed upon multiple exposures to the higher dose T cell 
product. One subject developed an anaphylactic reaction after the 3rd infusion due to development of 
HAMA; however, 101 infusions have been given to date to 14 subjects and no other SAE related to 
investigational product has been reported suggesting that doses up to 109 cells are safe.   
 
The follow up study at UPENN has been the one testing the safety of lentivirally transduced autologous T 
cells targeting mesothelin (CART-meso cells) using the same CAR construct as the RNA based studies, 
namely one using the mouse SS1 derived scFv (NCT02159716). Our group treated 15 subjects 
(mesothelioma, serous ovarian cancer and pancreatic cancer) with one infusion of either 3x107 or 3x108 
CART-meso cells/m2 with or without lymphodepleting chemotherapy. The safety profile of this study has 
been favorable. The majority of the related AEs are Grades 1‐2 (79.5%). The majority of Grade 3‐4 related 
AEs were for one pancreatic cancer patient (20 of 24, 83.3%) and they met the DLT criteria. The study was 
completed with infusion of 15 subjects without any other DLT.   
 
In the reported literature, CAR T cells have been tested at up to 5x1010 cells (Kershaw et al., 2006). 
However, considering all the information presented herein, we have chosen to start our study with a low 
dose of 1-3x107 huCART-meso cells/m2 per subject, with an acceptable dose range to allow for small 
variations in manufacturing and transduction.   As part of this study, 6 subjects have been safely treated 
at dose level of 1-3x107 huCART-meso cells/m2 with and without lymphodepleting chemotherapy (3 
subjects in Cohort 1; 3 subjects in Cohort 2) and no DLTs were identified.  However, when the dose was 
escalated to 1-3x108 huCART-meso cells/m2 (Cohort 3), unacceptable toxicity was experienced, thus 1-
3x107 huCART-meso cells/m2 was established as the MTD.  This dose level will be further explored using 
local delivery methods as well as through additional IV infusions (given approximately 21-42 days apart).   
 
The minimum acceptable dose for infusion will continue to be 1x106 huCART-meso cells/m2. 
2 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
Determine the safety and feasibility of intravenous administration and local delivery of lentiviral 
transduced huCART-meso cells, with and without lymphodepleting chemotherapy in the target 
population.   
2.2 
Secondary Objectives 
Clinical Objectives: 
• 
Assess the clinical anti-tumor effect by standard criteria (RECIST [modified RECIST for 
mesothelioma] and immune-related response criteria [where feasible]) for each tumor type.  
• 
Assess progression-free survival (PFS) and overall survival (OS). 

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Correlative Objectives: 
• 
Evaluate peripheral engraftment and persistence huCART-meso cells in peripheral blood and body 
fluid. 
• 
Determine the bioactivity of huCART-meso cells in peripheral blood and body fluid. 
• 
Evaluate the development of anti-CART immune responses favoring rejection of huCART-meso 
cells (where scientifically relevant). 
• 
Evaluate the development of secondary cellular and humoral anti-tumor responses as a 
consequence of epitope spreading.  
• 
Where tumor material or body fluids can be obtained: 
a. Measure trafficking of huCART-meso   
b. Evaluate mesothelin expression on tumor cells to assess for antigen-escape. 
c. Evaluate genetic editing (if feasible) 
d. Analyze tumor microenvironment and cell interactions (if feasible) 
3 
STUDY DESIGN 
3.1 
General Design 
This protocol will test the safety of 2 dose level of huCART-meso cells administered intravenously alone 
or after lymphodepleting chemotherapy. huCART-meso cells have been permanently modified to be 
directed to mesothelin protein with an anti-mesothelin CAR fused to the signaling domains of 4-1BB and 
TCRζ. The study population includes patients with mesothelin-expressing cancers.  
 
The original protocol included a 3+3 dose escalation design.  However, as of protocol amendment 5, the 
maximum tolerated dose has been established (1-3x107 huCART-meso cells/m2) and Cohorts 3 and 4 have 
been permanently closed due to unacceptable toxicity.  Moving forward, the MTD will be further 
evaluated utilizing different routes of administration, including local delivery methods (intrapleural and 
intraperitoneal) as well as repeat administration via IV infusion.  
 
Once subjects are determined to be eligible and the monitoring visit for eligibility is completed, subjects 
will be scheduled for apheresis and huCART-meso cell manufacturing. If patients have an apheresis 
product collected prior to enrollment into this study, this apheresis product may be used for CAR T cell 
manufacturing.  In this instance, the subject will not need to undergo another apheresis, and CAR T 
manufacturing may be initiated immediately after the monitoring visit for eligibility has been completed.   
 
All subjects will be assigned a cohort for the interventional portion of the protocol (see below).  Subjects 
will be followed for safety and research assessments as detailed in the Schedule of Events (Appendices 1-
3).   
 
Adverse events will be collected and evaluated during the protocol specified adverse event reporting 
period outlined in Section 9.1. While on study, subjects will be reassessed on an ongoing basis for evidence 
of acute and cumulative toxicity. At the time a subject progresses and/or initiates another therapy, the 
subject will be encouraged to enroll in the separate long-term follow-up study that is requested of all 
subjects who have received therapy with cells that have been gene-modified with an integrating vector, 
such as huCART-meso cells.  

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3.2 
Cohort Assignment 
This is a Phase I study evaluating the safety and feasibility of both intravenous administration and local 
delivery of lentiviral transduced huCART-meso cells with and without lymphodepleting chemotherapy. 
 
Dose Escalation Cohorts: 
• 
Cohort 1 (N = 3-6): will receive a single dose of 1-3x107 huCART-meso cells/m2 on day 0 without 
any conditioning chemotherapeutic regimen.   
• 
Cohort 2 (N = 3-6): will receive a single dose of 1-3x107 huCART-meso cells/m2 on day 0, following 
a flat dose of 1 gram/m2 of cyclophosphamide administered 2-4 days prior to huCART-meso cells 
(day -4 to day -2).   
• 
Cohort 3 subjects (N=3-6): will receive a single dose of 1-3x108 /m2 lentiviral transduced huCART-
meso cells on day 0 without any conditioning chemotherapeutic regimen.  Cohort 3 permanently 
closed with Protocol V5.  
• 
Cohort 4 subjects (N=3-6) will receive a single dose of  1-3x108 /m2 lentiviral transduced huCART-
meso cells on day 0, following a flat dose of 1 gram/m2 of cyclophosphamide administered 2-4 
days prior to huCART-meso cells (day -4 to day -2). Cohort 4 permanently closed with Protocol 
V5.  
 
Historical Cohort Advancement Plan: 
Subjects will be enrolled serially. Infusions will be staggered to allow assessment of DLTs for cohort 
progression, expansion, or dose de-escalation. For example, the 2nd and 3rd subjects in each cohort may 
be infused and followed in parallel but only after the 1st subject in that cohort completes the day 28 visit 
without DLT.  
 
If 0 DLTs occur in the 2nd and 3rd subjects, the study may advance to the next cohort. If there is 1 DLT in 
the 2nd or 3rd subject the cohort will be expanded to treat up to 6 subjects. If a total of 2 DLTs occur in the 
2nd and 3rd subjects, further enrollment in that cohort will be discontinued, and additional subjects will be 
enrolled into the dose de-escalation cohort. Alternatively, the 1st and 2nd subjects in each cohort may be 
infused and followed in parallel. If there are 0 DLTs in the 1st and 2nd subjects, a 3rd subject would be dosed 
at the same regimen/cohort. If there is 1 DLT in the 1st or 2nd subjects, the cohort would be expanded to 
enroll up to 6 subjects. If a total of 2 DLTs occur in the 1st and 2nd subjects, further enrollment in that 
cohort will be discontinued, and additional subjects will be enrolled into a dose de-escalation cohort.  
 
The clinical PI and Medical Director will perform official DLT assessments and make formal determinations 
regarding cohort advancement (where applicable).  Please refer to Section 5.4 for the definition of dose-
limiting toxicity as well as additional information on cohort progression.   
 
The Maximum Tolerated Dose (MTD) is defined as the dose at which 0-1 DLT occurs in 6 evaluable subjects 
tested within the dose range of this study.  As of protocol amendment V5, the maximum tolerated dose 
has been established as 1-3x107 huCART-meso cells/m2. 
 
Subsequent enrollment will occur in the dose expansion cohorts (Cohorts 5-7) at the MTD only.  
Enrollment in these cohorts may occur in parallel and will include up to 6 subjects/cohort.  All subjects 
will be continually evaluated for dose-limiting toxicities (DLT).  In the event of 2 DLTs in a specific cohort, 
additional enrollment and treatment activity within that cohort will be paused to allow for further 
investigation.    
 

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Dose Expansion Cohorts: 
• 
Cohort 5 (N = up to 6): will receive a single dose of 1-3x107 huCART-meso cells/m2  on day 0 by 
intrapleural infusion (IP) through an indwelling pleural catheter without any conditioning 
chemotherapeutic regimen. The safety of this dose level has been established by Cohorts 1 and 
2. 
• 
Cohort 6 (N = up to 6): will receive a dose of 1-3x107 huCART-meso cells/m2 via IV infusion on Day 
0, following a flat dose of 1 gram/m2 of cyclophosphamide administered 2-4 days prior to huCART-
meso cells (~Day -4 to -2).  This initial infusion may be followed by up to two additional IV infusions 
of huCART-meso cells at the same dose level, given approximately 21-42 days apart, if the subject 
meets eligibility to receive additional infusions (See Section 6.8.2).  Cyclophosphamide will not be 
repeated prior to subsequent doses of huCART-meso cells. Cohort 6 was activated with Protocol 
V6. Enrollment into Cohort 6 will occur in parallel with Cohort 5. 
• 
Cohort 7 (N = up to 6): will receive a single dose of 1-3x107 huCART-meso cells/m2 via 
intraperitoneal 
(i.p.) 
administration, 
following 
lymphodepleting 
chemotherapy 
with 
cyclophosphamide 300 mg/m2/day and fludarabine 30 mg/m2/day given over 3 days by 
intravenous infusion.  Lymphodepleting chemotherapy will be scheduled such that the last day of 
chemotherapy is 3 days (+/- 1 day) prior to the infusion of huCART-meso cells.  This initial i.p. 
infusion may be followed by up to two additional infusions of huCART-meso cells via intravenous 
(IV) administration at the same dose level, given between 21-42 days apart.  The subject must 
meet eligibility to receive additional infusions (See Section 6.9.2).  Lymphodepleting 
chemotherapy will not be repeated prior to additional infusions of huCART-meso cells. Infusion 
#1 for the first three subjects in Cohort 7 will be staggered by at least 21 days to allow for the 
assessment of DLTs. Enrollment into Cohort 7 will occur in parallel with Cohort 5 and Cohort 6. 
 
If the harvest of the huCART-meso product is unsuccessful (does not meet release criteria) or if the target 
dose is not reached, subjects will have the option to undergo a second leukapheresis for a second 
manufacturing process. Subjects have the option to receive a lower than target dose, if the huCART-meso 
product meets CVPF release criteria, and the subject cannot or is not willing to perform a second 
apheresis, or if the second manufacturing process fails.  If a subject receives a lower dose, they will be 
considered evaluable for safety, but will not be evaluable for response and will not be included in DLT 
evaluations (i.e. will be replaced in that cohort), but will follow all of the study visits as described in the 
Schedule of Events (Appendices 1-3). The minimum acceptable dose for infusion is 1x106 huCART-
meso/m2. 
3.3 
Study Endpoint Analysis 
Please refer to Sections 8.4 and 8.5 for a complete description of primary and secondary endpoint 
analysis. Please refer to Section 7.2.2 for correlative endpoint analysis.  
4 
SUBJECT SELECTION AND WITHDRAWAL 
4.1 
Inclusion Criteria 
1. Histologically confirmed cancer (one of the following): 
a. Cohorts 1-4 and 6 patients: 
Note: Cohorts 3 and 4 permanently closed with Protocol V5. 
i. Metastatic or recurrent lung adenocarcinoma. 

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ii. Persistent or recurrent serous epithelial ovarian cancer or primary peritoneal 
carcinoma or fallopian tube carcinoma 
iii. Malignant pleural and peritoneal mesothelioma (histologically confirmed 
epithelial) 
b. Cohort 5 patients:  
i. Metastatic or recurrent lung adenocarcinoma with cytologically or 
pathologically confirmed malignant pleural effusion. RECRUITMENT OF NON-
SMALL CELL LUNG CANCER PATIENTS INTO COHORT 5 SUSPENDED WITH 
PROTOCOL VERSION 10 
ii. Persistent or recurrent serous epithelial ovarian cancer or primary peritoneal 
carcinoma or fallopian tube carcinoma with cytologically or pathologically 
confirmed malignant pleural effusion 
iii. Malignant pleural and peritoneal mesothelioma (histologically confirmed 
epithelial) with documented pleural effusion 
c. Cohort 7 patients:  
i. Persistent or recurrent serous epithelial ovarian cancer or primary peritoneal 
carcinoma or fallopian tube carcinoma 
ii. Malignant peritoneal mesothelioma (histologically confirmed epithelial) 
2. Confirmation of tumor mesothelin expression (≥50% of tumor cells) RETIRED WITH PROTOCOL 
VERSION 9. 
3. Failure of at least one prior standard of care chemotherapy for advanced stage disease.  Prior 
therapies against PD-1 or PDL-1 are permissible if > 4 weeks from enrollment. ALLOWANCE FOR 
PRIOR PD-1 or PDL-1 THERAPIES REMOVED WITH PROTOCOL VERSION 5.  
4. Patients must have measurable disease as defined by RECIST 1.1 criteria or modified RECIST 
criteria (mesothelioma only). 
5. Patients with asymptomatic CNS metastases that have been treated (and are off steroids for the 
treatment of CNS disease) are allowed. They must meet the following at the time of enrollment:  
a. No concurrent treatment for the CNS disease  
b. No progression of CNS metastasis on MRI at screening scans  
c. No evidence of leptomeningeal disease or cord compression 
6. Patients > 18 years of age. 
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
8. Satisfactory organ and bone marrow function as defined by the following: 
i. Absolute neutrophil count > 1,000/μl 
ii. Platelets >75,000/μl 
iii. Hemoglobin > 8 g/dL 
iv. Direct Bilirubin < 2.0 mg/dl; unless secondary to bile duct obstruction by tumor 
or Gilbert’s syndrome (≤ 3.0 mg/dl). 
v. Creatinine < 1.5x the institutional normal upper limit 
vi. Albumin ≥2 
vii. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) < 5x 
the institutional normal upper limit 
viii. Cardiac ejection fraction of >40% as measured by resting echocardiogram, with 
no clinically significant pericardial effusion.  
9. Blood coagulation parameters: PT such that international normalized ratio (INR) is ≤ 1.5 and a PTT 
< 1.2 time the upper limit of normal unless the patient is therapeutically anti-coagulated for 
history of cancer-related thrombosis and has stable coagulation parameters. 
10. Provides written informed consent. 

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11. Subjects of reproductive potential must agree to use acceptable birth control methods, as 
described in protocol Section 4.3.  
4.2 
Exclusion Criteria 
1. Sarcomatoid and biphasic mesothelioma  
2. Known leptomeningeal carcinomatosis or spinal cord compression. Screening for this is not 
required unless suspicious symptoms. 
3. Patients with symptomatic CNS metastases are excluded. 
4. Participation in a therapeutic investigational study within 4 weeks prior to eligibility confirmation 
by physician-investigator, or anticipated treatment with another investigational product while on 
study. This refers to non-commercially approved investigational drugs different than those used 
in this protocol. RETIRED WITH PROTOCOL VERSION 7. 
5. Active invasive cancer other than the one of the three cancers in this study. Patients with active 
non-invasive cancers (such as non-melanoma skin cancer, superficial cervical and bladder and 
prostate cancer with PSA level < 1.0) are not excluded. 
6. HIV infection 
7. Active hepatitis B or hepatitis C infection 
8. Active autoimmune disease (including but not limited to: systemic lupus erythematosus, Sjogren’s 
syndrome, rheumatoid arthritis, psoriasis, multiple sclerosis, inflammatory bowel disease, etc.) 
requiring immunosuppressive therapy within 4 weeks prior to eligibility confirmation by 
physician-investigator, with the exception of thyroid replacement. 
9. Patients with ongoing or active infection. 
10. Dependence on systemic steroids or immunosuppressant medications.  Please refer to Section 
5.6 for complete details.   
11. Patients requiring supplemental oxygen therapy. 
12. Prior therapy with lentiviral gene modified cells.  
13. History of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, 
and Dextran 40) 
14. Any clinically significant pericardial effusion, Class II-IV cardiovascular disability according to the 
New York Heart Association Classification (see Appendix 4) or other cardiovascular condition that 
would preclude assessment of mesothelin induced pericarditis or that may worsen as a result of 
toxicities expected for this study. This determination will be made by a cardiologist if cardiac 
issues are suspected. 
15. Any clinically significant pleural or peritoneal effusion that cannot be drained with standard 
approaches. An indwelling drainage device placed prior to eligibility confirmation by physician-
investigator is acceptable. 
16. Pregnant or breastfeeding women.  
17. Interleukin-15 (IL15) > 100 pg/ml RETIRED WITH PROTOCOL VERSION 9. 
18. Treatment with a PD-1 or PD-L1 inhibitor, including but not limited to nivolumab, pembrolizumab, 
atezolizumab, and/or durvalumab, within 2 months prior to eligibility confirmation by a physician-
investigator. RETIRED WITH PROTOCOL VERSION 11 
19. Patients with significant lung disease as follows: 
1) Patients with radiographic evidence of greater than lobar lymphangitic pulmonary 
involvement, greater than lobar bronchial wall thickening suggestive of peribronchial 
lymphatic disease extension, and/or evidence of extensive bilateral parenchymal 
metastatic burden.  
2) Patients with radiographic and/or clinical evidence of active radiation pneumonitis.  

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3) Patients with radiographic evidence of underlying interstitial lung disease, including 
evidence of unresolved drug toxicity from any agent (e.g. chemotherapy, targeted 
agents, amiodarone, nitrofurantoin, etc.) 
 
Please refer to the Concomitant Therapy Section 5.6 for windows related to apheresis and huCART-
meso infusion. 
4.3 
Reproductive Risks 
Female subjects of reproductive potential (women who have reached menarche or women who have not 
been post-menopausal for at least 24 consecutive months, i.e., who have had menses within the 
preceding 24 months, or have not undergone a sterilization procedure [hysterectomy or bilateral 
oophorectomy]) must have a negative serum or urine pregnancy test performed at screening as per the 
Schedule of Events in Appendices 1-3. 
 
Due to the unknown risks of huCART-meso cells with respect to pregnancy, as well as risk associated with 
lymphodepleting chemotherapy, it is recommended that all subjects of reproductive potential use at least 
one medically acceptable form of contraception during the study and for at least 1 year after their last 
infusion of huCART-meso cells.  Investigators shall counsel subjects on the importance of pregnancy 
prevention and the implications of an unexpected pregnancy. It is possible the huCART-meso cells may 
also affect male/female fertility. It is also recommended that Investigators discuss options for fertility 
preservation, if not already discussed as part of their routine cancer care. 
 
Acceptable birth control includes the following methods: 
• 
Abstinence 
• 
Condoms (male or female) with or without a spermicidal agent 
• 
Diaphragm or cervical cap with spermicide 
• 
Intrauterine device (IUD) 
• 
Hormonal-based contraception 
 
Subjects who are not of reproductive potential (women who have been post-menopausal for at least 24 
consecutive months or have undergone hysterectomy, salpingotomy, and/or bilateral oophorectomy or 
men who have documented azoospermia) do not require use of contraception. Acceptable 
documentation of sterilization, azoospermia, or menopause is required and may take the form of written 
or oral attestation by clinician or clinician’s staff of one of the following: 
• 
Physician report/letter 
• 
Operative report or other source documentation in the subject record (a laboratory 
report of azoospermia is required to document successful vasectomy) 
• 
Discharge summary 
• 
Laboratory report of azoospermia 
• 
Follicle stimulating hormone measurement elevated into the menopausal range 
4.4 
Subject Recruitment 
Potential participants are identified through the clinical practices of the investigators or sub-investigators 
and through referrals from outside hospitals and physicians. This study will be posted on ClinicalTrials.gov 
and publicized via University of Pennsylvania and Abramson Cancer Center websites/press releases. No 
direct-to-patient advertising will be performed.  

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4.5 
Subject Withdrawal / Discontinuation 
4.5.1 
Reasons for Subject Discontinuation 
Subjects who enroll but do not receive huCART-meso cells will be prematurely discontinued from the 
study, will not be followed, and will be replaced in the study. Reasons for premature discontinuation prior 
to receipt of huCART-meso cells may include, but are not limited to, the following: 
1. The subject is lost to follow-up.   
2. The principal investigator judges that the subject, prior to huCART-meso infusion, is too ill to 
continue. 
3. Pregnancy is documented prior to huCART-meso infusion.  If pregnancy occurs after the subject 
has received huCART-meso cells, they will be kept active in the study for safety and pregnancy 
follow-up and outcome. No subsequent huCART-meso infusions will be administered. 
4. Voluntary withdrawal: a subject may remove himself/herself from the study at any time.   
5. Significant and rapid progression of malignancy, requiring alternative medical, radiation or 
surgical intervention, prior to huCART-meso infusion. 
6. Development of a medical condition that precludes CAR T cell infusion.   
7. Technical difficulties are encountered in the T cell genetic modification and expansion procedure 
that precludes the generation of clinical cell doses that meet all Quality Control release criteria as 
specified by FDA. 
8. Termination of the study. 
 
Reasons for discontinuation of subjects after receipt of huCART-meso cells include the following.   
1. Voluntary withdrawal: a subject may remove himself/herself from the study at any time.   
2. Completion of protocol required follow-up 
3. Death 
4. Termination of the study 
 
The reasons for discontinuation must be recorded appropriately.  
4.5.2 
Data Collection and Follow-up  
Follow-up data collection after receipt of gene-modified cell therapy clinical trials is specified by the FDA.  
 
Subjects who complete the 2 year follow-up as part of this protocol or discontinue participation early for 
any reason (per Section 4.4.1 above), will be offered participation in a long-term follow-up protocol to 
further evaluate long term adverse events related to the study product for up to 15 years after study 
treatment.  Once subjects are enrolled on the long-term follow-up protocol, all follow-up data collection 
under this protocol will be discontinued. 
 
In the event that a subject cannot return to the study site for follow-up visits because of subject 
preference or geographical concerns, the subject’s primary care physician and/or local oncologist will be 
asked to provide information from the subject’s medical record to the study team at protocol defined 
time points (including the results of any routine care examinations and/or laboratory assessments), and 
assist in the collection of protocol required blood samples (if applicable), which will be sent to the 
University of Pennsylvania for protocol-required analysis.  The subject and local provider will also be 
contacted via the Penn patient portal called MyPennMedicine (MPM), telephone and/or email/mail by a 
member of the study team to assess any potential toxicity. 
 

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In numerous previous cell therapy trials at the University of Pennsylvania, loss of follow-up is estimated 
to occur in less than 5% of cases. Every effort will be made to contact subjects who appear to be lost to 
follow-up in order to at least obtain survival data. In the event a subject fails to complete the follow-up 
requirements, documentation of all attempts to contact the subject includes at least 3 telephone contacts 
(on different days and at different times of the day), and a certified letter. 
4.5.3 
Replacement of Subjects 
All subjects who do not receive huCART-meso cells will be replaced.  Subjects have the option to receive 
a lower than target dose if the huCART-meso product meets CVPF release criteria and the subject cannot 
or is not willing to perform a second apheresis, or if the second manufacturing process fails.  If a subject 
receives a lower dose, they will be considered evaluable for safety, but will not be evaluable for response 
and will not be considered for DLT evaluations and cohort advancement decisions, and they will be 
replaced in that cohort.  However, these subjects will still be followed for overall safety and included in 
the analysis of secondary and exploratory endpoints in accordance with the Schedule of Events 
(Appendices 1-3).  
5 
INVESTIGATIONAL PRODUCTS  
5.1 
Description 
5.1.1 
huCART-meso cells 
huCART-meso cells are autologous T cells that have been engineered to express an extracellular single 
chain variable fragment (scFv) with mesothelin specificity. The T cells express an intracellular signaling 
molecule comprised of the TCR ζ chain, and 4-1BB. The huCART-meso cells are cryopreserved in infusible 
cryomedia (Section 5.3.1.2). Each bag will contain a dose of CART positive cells corresponding to their 
assigned dose level as per cohort assignment. The total cell dose is dependent on the transduction 
efficiency; the volume of cells is dependent on the total cell dose with a minimum of 10 mL per bag. The 
minimum acceptable dose for infusion is 1x106 huCART-meso cells/m2. 
5.1.2 
Cyclophosphamide 
Cyclophosphamide (Cytoxan®) is considered investigational therapy for subjects participating in targeted 
Cohorts (Section 6.4). Cyclophosphamide is an alkylating agent with antineoplastic activity. The main goal 
of using cyclophosphamide is to achieve lymphodepletion that may enhance engraftment of adoptive T 
cells, while minimizing complications from neutropenia.  
 
Cohorts 2 and 6: 
Cyclophosphamide will be administered as a flat dose of 1 gram/m2 2-4 days prior to the huCART-meso 
infusion. In Cohort 6, cyclophosphamide will only be administered prior to the first huCART-meso infusion. 
The proposed regimen has been used widely in other studies and has been tolerated well. The ultimate 
criterion by which to assess the efficacy of the proposed regimen to facilitate T cell engraftment is the 
lymphocyte count 1-3 weeks after adoptive transfer. 
 
Cohort 7: 
Cyclophosphamide will be administered as 300 mg/m2/day over 3 days so that the last day of 
chemotherapy falls 3 days (±1 day) prior to the first huCART-meso infusion (Day 0). The proposed regimen 
has been used widely in other studies and has been tolerated well. 

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5.1.3 
Fludarabine 
Fludarabine is considered investigational therapy for subjects participating in Cohort 7 only. Fludarabine 
is a purine analog that inhibits DNA synthesis through interference with DNA polymerase and 
ribonucleotide reductase enzymes. Fludarabine is widely used in the treatment of lymphocytic 
hematologic malignancies and possesses potent immunosuppressive activity. It is excreted principally in 
the urine as an active metabolite. The main goal of using fludarabine (in combination with 
cyclophosphamide) is to achieve lymphodepletion that may enhance engraftment of adoptive T cells, 
while minimizing complications from myelosuppression.  
 
Cohort 7: 
Fludarabine will be administered as 30 mg/m2/day over 3 days so that the last day of chemotherapy falls 
3 days (±1 day) prior to the first huCART-meso infusion (Day 0). The proposed regimen has been used 
widely in other studies and has been tolerated well. Fludarabine doses will be rounded down to the 
nearest 50 mg vial size, if the rounded dose does not differ by > 10% of the original dose prescribed. 
 
5.2 
Treatment Regimen 
The treatment regimen received will be dependent on cohort assignment as follows: 
• 
Cohort 1 (N = 3-6): will receive a single dose of 1-3x107 huCART-meso cells/m2 on day 0 without 
any conditioning chemotherapeutic regimen.   
• 
Cohort 2 (N = 3-6): will receive a single dose of 1-3x107 huCART-meso cells/m2 on day 0, following 
a flat dose of 1 gram/m2 of cyclophosphamide administered 2-4 days prior to huCART-meso cells 
(day -4 to day -2).   
• 
Cohort 3 subjects (N=3-6) will receive a single dose of 1-3x108 /m2 lentiviral transduced huCART-
meso cells on day 0 without any conditioning chemotherapeutic regimen.  Cohort 3 permanently 
closed with Protocol V5.  
• 
Cohort 4 subjects (N=3-6) will receive a single dose of  1-3x108 /m2 lentiviral transduced huCART-
meso cells on day 0, following a flat dose of 1 gram/m2 of cyclophosphamide administered 2-4 
days prior to huCART-meso cells (day -4 to day -2). Cohort 4 permanently closed with Protocol 
V5.  
• 
Cohort 5 (N = up to 6): will receive a single dose of 1-3x107 huCART-meso cells/m2 on day 0 by 
intrapleural infusion (IP) through an indwelling pleural catheter without any conditioning 
chemotherapeutic regimen. The safety of this dose level has been established by Cohorts 1 and 
2.  
• 
Cohort 6 (N = up to 6): will receive a dose of 1-3x107 huCART-meso cells/m2 via IV infusion on Day 
0, following a flat dose of 1 gram/m2 of cyclophosphamide administered 2-4 days prior to huCART-
meso cells (~Day -4 to -2).  This initial infusion may be followed by up to two additional IV infusions 
of huCART-meso cells at the same dose level, given approximately 21-42 days apart, if the subject 
meets eligibility to receive additional infusions (See Section 6.8.2).  Cyclophosphamide will not be 
repeated prior to subsequent doses of huCART-meso cells. Cohort 6 was activated with Protocol 
V6. Enrollment into Cohort 6 will occur in parallel with Cohort 5. 

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• 
Cohort 7 (N = up to 6): will receive a single dose of 1-3x107 huCART-meso cells/m2 via 
intraperitoneal 
(i.p.) 
administration, 
following 
lymphodepleting 
chemotherapy 
with 
cyclophosphamide 300 mg/m2/day and fludarabine 30 mg/m2/day given over 3 days by 
intravenous infusion.  Lymphodepleting chemotherapy will be scheduled such that the last day of 
chemotherapy is 3 days (+/- 1 day) prior to the infusion of huCART-meso cells.  This initial i.p. 
infusion may be followed by up to two additional infusions of huCART-meso cells via intravenous 
(IV) administration at the same dose level, given between 21-42 days apart.  The subject must 
meet eligibility to receive additional infusions (See Section 6.9.2).  Lymphodepleting 
chemotherapy will not be repeated prior to additional infusions of huCART-meso cells. Infusion 
#1 for the first three subjects in Cohort 7 will be staggered by at least 21 days to allow for the 
assessment of DLTs. Enrollment into Cohort 7 will occur in parallel with Cohort 5 and Cohort 6. 
 
Lymphodepleting chemotherapy will be administered according to standard institutional procedures in 
the outpatient setting as per cohort assignment above. All subjects will receive huCART-meso cells on an 
inpatient basis at the Hospital of the University of Pennsylvania. Subjects will remain as inpatients for 
observation for a minimum of 48 hours after each huCART-meso infusion.  The subject may then be 
discharged in accordance with hospital policy after this observation period is complete and the subject is 
medically stable. Clinic visits, hematology, and other safety laboratory tests will be performed according 
to the Schedule of Events (Appendices 1-3). Additional assessments may be performed as necessary to 
evaluate specific adverse events until they resolve to baseline or CTCAE Grade < 1.  
5.3 
Preparation and Administration of Investigational Product(s) 
5.3.1 
huCART-meso cells 
In addition to the language below, please refer to the Investigational Product Handling Manual for further 
details on product transport, thaw, and labeling.  
5.3.1.1 
Manufacturing of huCART-meso  
huCART-meso cell product manufacturing will be performed by the Clinical Cell and Vaccine Production 
(CVPF) at the University of Pennsylvania, using the patients’ apheresis product.  The weight obtained prior 
to the apheresis procedure will be used for dosing and will not be modified as a result of changes in the 
subject’s weight.   
 
 
Each huCART-meso cell dose will be cryopreserved in infusion bag(s) containing cryomedia.  The volume 
of each dose will be dependent on the total cell number and transduction efficiency.  The minimum 
volume will be 10mL per infusion bag.  The cells will be stored in the CVPF until ready for product 
release/administration 
5.3.1.2 
Release and Preparation of huCART-meso 
When ready for administration, the huCART-meso cell product will be dispensed to the clinical team for 
administration per CVPF standard operating procedures and in accordance with the Investigational 
Product Handling Manual.   
 
Packaging and Labeling 
The investigational product will be affixed with a label containing information regarding the dose, the 
method of manipulation, the vector, and the following statements: “FOR AUTOLOGOUS USE ONLY” and 

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“Caution:  New Drug – Limited by Federal Law to Investigational Use”.  In addition, the label will include 
at least two unique identifiers, including the subject’s study identification number.    Prior to each infusion, 
two individuals will independently verify that the product is correctly matched to the subject.  
 
Receipt of huCART-meso Cells/Cell Thawing  
The cryopreserved huCART-meso cells will be transported in dry ice to the subject’s bedside. The cells will 
be thawed at the bedside using a water bath maintained between 36°C to 38°C. There should be no frozen 
clumps left in the container at the time of infusion. If the CAR T cell product appears to have a damaged 
or leaking bag, or otherwise appears to be compromised, it should not be infused and should be returned 
to the CVPF as specified below. 
Return or Destruction of Investigational Product 
huCART-meso cells may need to be returned to the CVPF for a variety of reasons, including but not limited 
to: 1) Mislabeled product; 2) Condition of patient prohibits infusion/injection, and 3) Subject refuses 
infusion. Any unused product will be returned to CVPF.  Final disposition of the investigational product is 
to be documented. 
5.3.1.3 
Administration of huCART-meso  
Subjects in Cohorts 5-7 will receive huCART-meso cells on an inpatient basis at the Hospital of the 
University of Pennsylvania. Please refer to Section 6.5 for criteria that subject must meet in order to 
proceed with huCART-meso infusion. 
 
Side effects following T cell infusions may include transient fever, chills, rigors, myalgias/arthralgias, 
headache, fatigue, and/or nausea. Subjects will be pre-medicated with acetaminophen 650 mg by mouth 
and diphenhydramine hydrochloride by mouth or IV prior to huCART-meso cell infusion. If Benadryl is 
contraindicated, an H2-blocker, such as ranitidine, will be administered. These medications may be 
repeated every six hours as needed. A course of non-steroidal anti-inflammatory medication may be 
prescribed if the subject continues to have fever not relieved by acetaminophen. It is recommended that 
subjects do not receive systemic corticosteroids such as hydrocortisone, prednisone, prednisolone (Solu-
Medrol), or dexamethasone (Decadron). If corticosteroids are required for an acute infusional reaction, 
an initial dose of hydrocortisone 100 mg is recommended.  
 
huCART-meso infusions in Cohorts 5-7 will take place on an inpatient basis at the Hospital of the University 
of Pennsylvania using precautions for immunosuppressed patients.  Prior to the infusion, two 
independent individuals will verify the information on the label of each bag in the presence of the subject 
and confirm that the information correctly matches the participant. The investigational CAR T cell 
products should be infused into the subject while cold, within 30 minutes after they are thawed. There 
should be no frozen clumps left in the bag prior to infusion. 
5.3.1.3.1 
For huCART-meso cell IV administration  
T cell infusions will be performed by a licensed Registered Nurse at the Hospital of the University of 
Pennsylvania. The transduced T cells will be infused at a rate of 10-20 ml/minute into an intravenous 
catheter, either through a peripheral vein (preferred) or central vein.  A macrodrip intravenous tubing will 
be used to infuse the CART cells by gravity (i.e. no infusion pump).  The macrodrip intravenous tubing will 
be connected to a “Y” adapter with one end of the adapter spiked to the CART cell product bag and the 
other to a normal saline solution bag.  A leukoreduction filter must not be used for the infusion of the T 
cell product. 

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5.3.1.3.2 
huCART-meso cell intrapleural administration  
IP administration will be performed by a licensed provider at the Hospital of the University of 
Pennsylvania.  Subjects without an existing intra-pleural catheter must have one placed for IP 
administration. The timing of placement and subsequent removal of the intra-pleural catheter will be per 
clinical discretion.  Pleural fluid may be collected for research purposes at the time of catheter placement.  
 
Prior to huCART-meso cell administration, the pleural cavity will be maximally drained. After drainage is 
complete, the transduced T cells will be instilled through the intrapleural catheter into the affected pleural 
space. The cells are infused by gravity at a rate of 10-20 ml/minute. After huCART-meso cell infusion is 
complete, the tube is flushed with 20ml of sterile saline and clamped. The end of the tube is swabbed 
with alcohol swabs, a new valve cap is placed and the site is re-dressed. 
5.3.1.3.3 
huCART-meso intraperitoneal (i.p.) instillation: 
Some subjects may already have a catheter in place; however, in the event a catheter must be placed for 
Intraperitoneal (i.p.) Instillation, placement of the catheter will be performed by Interventional Radiology 
(IR) or other appropriately licensed provider. The subject will have an intraperitoneal catheter placed by 
IR or appropriately licensed provider according to standard hospital procedure, prior to their first planned 
huCART-meso infusion.  Ideally, the catheter will be placed on the day of the i.p. infusion.  Location (IR or 
bedside) of the paracentesis procedure will depend on the ascites volume (moderate/large amount of 
ascites, i.e. a 3 cm pocket, is required for bedside placement).  If ascites is present at the time of catheter 
placement, the peritoneal cavity will be maximally drained (if clinically appropriate). Following catheter 
placement and appropriate routine care monitoring, the subject will be transported back to the inpatient 
floor for continued care and receipt of huCART-meso cells. 
 
The T cell infusion will be performed by a licensed provider at the Hospital of the University of 
Pennsylvania.  The transduced T cells will be instilled through the indwelling peritoneal catheter into the 
affected peritoneal space at an infusion rate of 10-20 mL/min.  
 
Following the infusion, the subject should lie in the lateral decubitus position on the opposite side of the 
catheter for 15 minutes, if feasible.  The intraperitoneal catheter will be removed prior to subject 
discharge per clinical discretion.  Timing of placement and subsequent removal of the intraperitoneal 
catheter will be per clinical discretion. 
5.3.1.3.4 
Safety Monitoring 
Emergency medical equipment (i.e. a crash cart) must be available for an emergency situation during the 
infusion in the event that the subject has an allergic response, or severe hypotensive crisis, or any other 
reaction to the infusion.    
 
Vital signs (temperature, respiration rate, heart rate, blood pressure, and oxygen saturation by pulse 
oximetry) will be measured within 10 minutes prior and within 15 minutes after the infusion.  Thereafter, 
vital signs will be measured at 30 (+/- 5) minutes, 45 (+/- 5) minutes, and 60 (+/- 5) minutes after the 
infusion, and then every hour (+/- 10 minutes) for the next two hours until these signs are satisfactory 
and stable. If vital signs are not satisfactory and stable 3 hours after the huCART-meso infusion, vital signs 
will continue to be monitored as clinically indicated until stable.   
 
Subjects in Cohorts 5-7 will remain inpatient for observation for a minimum of 48 hours after each 
huCART-meso infusion.  Please refer to Sections 6.6 and 6.8.2 for additional information.  The subject may 

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then be discharged in accordance with hospital policy after this observation period is complete and the 
subject is medically stable.  
5.3.2 
Cyclophosphamide (Applicable Cohorts) 
5.3.2.1 
Receipt of Cyclophosphamide 
Cyclophosphamide will be purchased through the clinical site pharmacy for research purposes. 
5.3.2.2 
Storage 
Cyclophosphamide will be a stored according to the manufacturer instructions. 
5.3.2.3 
Premedication for Cyclophosphamide 
It is anticipated that subjects receiving cyclophosphamide may experience nausea and vomiting as a side 
effect of the treatment. Anti-emetic prophylaxis premedication for nausea (including corticosteroids) can 
be administered prior to infusion of chemotherapy according to the institutional standards. Choice of 
specific agent will be left to the discretion of the investigator, and may include corticosteroids as 
appropriate. For more details, see Sections 5.6 and 6.4. 
5.3.2.4 
Administration 
For Cohort 2 and Cohort 6 subjects: Cyclophosphamide will be administered as a flat dose of 1 gram/m2 
by IV infusion 2-4 days prior to the first huCART-meso cell infusion (Section 6.4).  
 
For Cohort 7 subjects: Cyclophosphamide will be administered as 300 mg/m2/day over 3 days by IV 
infusion so that the last day of chemotherapy falls 3 days (±1 day) prior to the first huCART-meso cell 
infusion (Section 6.4).  
 
Appropriate institutional procedures for proper handling and disposal of antineoplastic drugs should be 
followed. 
5.3.2.5 
Cyclophosphamide Toxicity Management Considerations  
Potential risks of cyclophosphamide administration and their management are described in Section 1.7 
and 6.4.   
5.3.3 
Fludarabine (Cohort 7) 
5.3.3.1 
Receipt of Fludarabine 
Fludarabine will be purchased through the clinical site pharmacy for research purposes. 
5.3.3.2 
Storage 
Fludarabine will be a stored according to the manufacturer instructions. 
5.3.3.3 
Premedication for Fludarabine 
It is anticipated that subjects receiving fludarabine may experience nausea and vomiting as a side effect 
of the treatment. Anti-emetic prophylaxis premedication for nausea (including corticosteroids) can be 
administered prior to infusion of chemotherapy according to the institutional standards. Choice of specific 

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agent will be left to the discretion of the investigator, and may include corticosteroids as appropriate. For 
more details, see Sections 5.6 and 6.4. 
5.3.3.4 
Administration 
Fludarabine will be administered as 30 mg/m2/day over 3 days so that the last day of chemotherapy falls 
3 days (±1 day) prior to the first huCART-meso infusion (Day 0). Fludarabine doses will be rounded down 
to the nearest 50 mg vial size, if the rounded dose does not differ by > 10% of the original dose prescribed. 
Appropriate institutional procedures for proper handling and disposal of antineoplastic drugs should be 
followed. 
5.3.3.5 
Fludarabine Toxicity Management Considerations  
Potential risks of fludarabine administration and their management are described in Section 1.7 and 6.4.   
5.4 
Dose-Limiting Toxicity (DLT) and Cohort Progression 
Dose limiting toxicity is defined as either hematologic or non-hematologic toxicity (NCI Common 
Terminology Criteria for Adverse Events (CTCAE v4.03) which develops following dosing, is new (not a pre-
existing condition ongoing at the time of infusion, regardless of grading), at least possibly related to T 
cells, and non-manageable to Grade 1-2 within 7 days of onset.  The duration of the DLT monitoring period 
will be dependent on cohort assignment as follows: 
• 
Cohorts 1-5: Through the Day 28 safety follow-up visit. 
• 
Cohorts 6-7: Through the Day 21 safety follow-up visit.  
 
The following events will be considered DLTs if determined to be related to huCART-meso cell therapy  
and the event meets all other criteria in the above definition: 
 
• 
Grade 3 or higher non-hematological toxicity except; with the following exceptions:  
o Grade 3 electrolyte abnormalities 
o Nausea 
o Vomiting 
o Diarrhea 
o Fatigue  
• 
Grade 3 or higher hematologic toxicity; except those expected following lymphodepleting 
chemotherapy administration (e.g. thrombocytopenia, lymphopenia, neutropenia, anemia, etc).  
 
Historical Cohort Advancement Plan: 
Subjects will be enrolled serially. Infusions will be staggered to allow assessment of DLTs for cohort 
progression, expansion, or dose de-escalation. For example, the 2nd and 3rd subjects in each cohort may 
be infused and followed in parallel but only after the 1st subject in that cohort completes the day 28 visit 
without DLT.  
 
If 0 DLTs in 2nd and 3rd subjects, the study may advance to the next cohort. If there is 1 DLT in the 2nd or 
3rd subject the cohort will be expanded to treat up to 6 subjects. If a total of 2 DLTs occur in the 2nd and 
3rd subjects, further enrollment in that cohort will be discontinued, and additional subjects will be enrolled 
into the dose de-escalation cohort. Alternatively, the 1st and 2nd subjects in each cohort may be infused 
and followed in parallel. If there is 0 DLTs in the 1st and 2nd subjects, a 3rd subject would be dosed at the 
same regimen/cohort. If there is 1 DLT in the 1st or 2nd subjects, the cohort would be expanded to enroll 
up to 6 subjects. If a total of 2 DLTs occur in the 1st and 2nd subjects, further enrollment in that cohort will 
be discontinued, and additional subjects will be enrolled into the dose de-escalation cohort. The study 

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will be stopped if 2 DLTs occur at the de-escalated dose level (either cohort with or without 
cyclophosphamide).   
 
The clinical PI and Medical Director will perform official DLT assessments and make formal determinations 
regarding cohort advancement (where applicable).  Please refer to Section 5.4 for the definition of dose-
limiting toxicity as well as additional information on cohort progression.   
 
As of Protocol Amendment V5, Cohort 3 and 4 have been permanently closed due to unacceptable 
toxicity, and the maximum tolerated dose has been established as 1-3x107 huCART-meso cells/m2.   
 
Subsequent enrollment will occur in the dose expansion cohorts (Cohorts 5-7) at the MTD only.  
Enrollment in these cohorts may occur in parallel and will include up to 6 subjects/cohort.  All subjects 
will be continually evaluated for dose-limiting toxicities (DLT).  In the event of 2 DLTs in a specific cohort, 
additional enrollment and treatment activity within that cohort will be paused to allow for further 
investigation.    
5.5 
Subject Compliance Monitoring 
Adherence to scheduled follow-up visits is important in order to assess the primary safety endpoint 
associated with this study. During the process of informed consent, each patient will be clearly informed 
of the study schedule, associated procedures, and the requirement for follow-up. Patients that are not 
able to commit to the study schedule will not be enrolled in the study. 
5.6 
Prior and Concomitant Therapy 
All prescription and nonprescription medication, vitamins, devices, and herbal and nutritional 
supplements, taken by the subject during the 30 days prior to consent will be recorded.  Concomitant 
medications will continue to be collected at every visit following consent and until the subject has 
completed primary follow-up or has been discontinued from participation in the study.  Any additions, 
deletions, or changes of these medications will be documented. All prior oncology therapies for their 
targeted disease will be collected in the appropriate eCRF. 
 
Concomitant medications and therapies deemed necessary for the supportive care and safety of the 
patient are allowed throughout the subject’s participation.  Subjects may also continue to receive 
standard therapies and/or undergo routine care procedures for the management of their disease prior to 
receipt of study treatment and while their product is being manufactured. However, the following 
guidelines must be adhered to during the study: 
• 
Apheresis: 
o Steroids or other immunosuppressant drugs should NOT be used within 5 days prior to 
the apheresis procedure. Patients may be on a stable low dose of steroids (≤10mg daily 
equivalent of prednisone).  Topical and inhaled steroids are permitted at any time as per 
clinical discretion. 
o Concurrent cancer treatment is not allowed within 1 week prior to the apheresis 
procedure.  Medication intended solely for supportive care (e.g. analgesics, antiemetics, 
antidiarrheals, antidepressants or bisphosphonates, etc.) may be used at the 
investigator’s discretion. Palliative focal radiation therapy for symptom management is 
allowed. 
o Subjects must not have received an investigational product within 2 weeks prior to 
apheresis collection.   

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• 
Lymphodepleting Chemotherapy (Applicable Cohorts): 
o Prophylactic antibiotics are recommended post lymphodepleting chemotherapy and 
prior to CAR T cell administration per institutional standards and practices for cellular 
therapies.   
o Steroid or other immunosuppressant drugs: 
 
Corticosteroids treatment as anti-emetic prophylaxis on the day of 
lymphodepleting chemotherapy administration is allowed per institutional 
guidance.   
 
Topical and inhaled steroids are permitted at any time as per clinical discretion. 
• 
huCART-meso Cells: 
o Alternative cancer treatment is not allowed within 2 weeks prior to huCART-meso cell 
infusion.  Medication intended solely for supportive care (e.g. analgesics, antiemetics, 
antidiarrheals, antidepressants or bisphosphonates, etc.) may be used at the 
investigator’s discretion. Palliative focal radiation therapy for symptom management is 
allowed. 
o Subjects must not have received an investigational product within 4 weeks or 5 half-lives 
(whichever is shorter) of the first huCART-meso cell infusion. 
o GM-CSF should be avoided due to potential to worsen CRS symptoms.  Therapeutic use 
in patients with serious neutropenic complications such as tissue infection, sepsis 
syndrome, fungal infection, etc. may be considered at the investigator’s discretion, 
consistent with American Society of Clinical Oncology guidelines. The use of 
erythropoietin is also permitted at the discretion of the treating physician.  Prophylactic 
use of granulocyte colony-stimulating factor (G-CSF, filgrastim) may be used if medically 
indicated, particularly in a patient who is experiencing recurrent difficulties with 
neutropenia, however the effects of G-CSF on product manufacturing are unknown.  
o Steroid or other immunosuppressant drugs: 
 
Should NOT be used within 24 hours prior to, or following, the huCART-meso cell 
infusion(s) unless under life-threatening circumstances or at the physician-
investigator’s discretion for CRS Management. Patients may continue on a stable 
low dose of steroids (≤10mg daily equivalent of prednisone).   
 
Therapeutic doses of steroids must be stopped >48 hours prior to huCART-meso 
infusion(s).  However, physiological replacement doses of steroids are allowed (6-
12 mg/m2/day hydrocortisone or equivalent).  
 
Topical and inhaled steroids are permitted at any time as per clinical discretion. 
• 
Prophylaxis/Toxicity Management: 
o Subjects with severe signs and symptoms attributable to cytokine release syndrome (i.e. 
CRS) should be managed with administration of tocilizumab or other anti-cytokine 
directed therapies (Refer to Section 9.4.2 and to the current version of the huCART-meso 
Investigator’s Brochure for complete details). 
• 
Primary Follow-up: 
o huCART-meso infusions may also be discontinued at any time in favor of resuming 
standard of care treatment at the physician-investigator’s discretion.   
o Data from all additional treatment received, as well as the subject’s response to this 
treatment, will be collected/reported for research purposes.  

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6 
STUDY PROCEDURES 
Overview 
The study consists of 1) a screening/enrollment phase, 2) apheresis and T cell manufacturing, 3) pre-
infusion safety check, 4) an intervention phase consisting of huCART-meso cell administration alone or 
following study-mandated chemotherapy, and 5) safety follow-up visits. The Schedule of Events is 
included in Appendices 1-3.  
6.1 
Screening  
Informed consent must be obtained before the subject can undergo any research-related procedures.  
Results obtained in routine clinical care prior to informed consent may also be used for screening purposes 
as long as they are obtained within the protocol required windows.   
 
Screening procedures include: 
• Complete medical history 
• Physical examination including vital signs, height, and weight 
• Review of concomitant medications and prior therapies (including timing of previous checkpoint 
inhibitors if given) 
• ECOG performance status  
• Leukapheresis screening - Subjects can be given the opportunity to undergo temporary central 
venous access for apheresis if peripheral access cannot be obtained.  
• Complete blood count and differential 
• Chemistry panel - including sodium, potassium, chloride, CO2, blood urea nitrogen, creatinine, 
glucose, phosphate, total protein, albumin, calcium, alkaline phosphatase, total bilirubin, ALT, AST, 
uric acid, LDH 
• Coagulation Factors - PT, PTT, fibrinogen, INR, d-dimer 
• Viral serologies: HIV, Hepatitis B surface antigen (HBsAg), Hepatitis B surface antibody, Hepatitis B 
core antibody, and Hepatitis C antibody. If the HCV antibody is positive, a screening HCV RNA by 
any RT-PCR or bDNA assay must be performed. Eligibility will be determined based on the 
screening value. The test is not required if documentation of a negative result of a HCV RNA test 
performed within 60 days prior to screening is provided. 
• Autoantibody panel: ANA  
• Urinalysis 
• 12 lead Electrocardiogram (EKG) 
• Resting echocardiogram (ECHO) 
• Urine β HCG pregnancy (women of childbearing potential) 
• MRI Brain - For suspected brain metastasis (performed within 8 weeks of eligibility confirmation 
by a physician-investigator) 
• Tumor assessments with computed tomography performed with or without contrast within 8 
weeks of eligibility confirmation by a physician-investigator.  The types of scans performed will be 
per clinical discretion based on the patient population and disease status.   
 
In the event that the time between the screening visit and the infusion of huCART-meso cells exceeds the 
8 week Screening/Enrollment Window the following will be repeated: Physical Examination, Performance 
Status Assessment, Complete Blood Count with differential and Platelet Count, Chemistry Panel, 
Pregnancy test, HIV and Hepatitis B/C tests, and ECHO scan.   
 

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Monitoring Visit for Eligibility 
Assignment of subject numbers will occur at initial consent, will be in sequential order (i.e. 02916-01, 
02916-02, etc.), and no numbers will be omitted. Subject numbers will be used on all study 
documentation.  Once assigned, the subject number must not be reused for any other subject and it must 
not be changed, even if the subject is rescreened. 
 
At the time a subject consents to participate in this study, a Consent Notification Form should be 
completed.  Once required screening tests have been completed and the subject has been determined 
eligible by the physician-investigator, provide the documents listed below to: 
 
Sponsor Protocol Monitor and Sponsor Project Manager 
Center for Cellular Immunotherapies (CCI) 
 
Documents required: 
• 
Completed Eligibility Form  
• 
Redacted copy of signed patient informed consent and HIPAA Authorization 
• 
Redacted source documentation to confirm enrollment/eligibility (including patient past medical 
history, laboratory, radiological reports, physical exam, concomitant medications and any other 
source documentation to support that the patient meets eligibility criteria and has completed all 
required screening assessments). 
 
Upon informed consent completion and receipt of screening and eligibility documentation, the Sponsor 
Protocol Monitor will review and provide documentation that the monitoring visit for eligibility has been 
completed.  This documentation must be received prior to apheresis and cell product manufacturing. If T 
cells have already been collected during a previous apheresis, it is not necessary to repeat the apheresis 
procedure.  
6.2 
Leukapheresis 
A large volume apheresis procedure will be carried out at the University of Pennsylvania Apheresis Center 
according to standard clinical procedures (~4-6 weeks prior to infusion of the huCART-meso cells). PBMC 
are obtained for CAR T cells during this procedure. From a single leukapheresis, the intention is to harvest 
at least 5 x 109 white blood cells to manufacture huCART-meso cells. The huCART-meso cell product is 
expected to be ready for release approximately 4 weeks later.  If the harvest of cells or the T cells 
manufacture is unsuccessful, patients will have the option to undergo a second leukapheresis for a second 
manufacturing process. Subjects have the option to receive a lower than target dose if the huCART-meso 
product meets CVPF release criteria, and the subject cannot or is not willing to perform a second 
apheresis, or if the second manufacturing process fails.  If a subject has previously had an adequate 
apheresis collection banked according to current Good Manufacturing Practices at the Clinical Cell and 
Vaccine Production Facility, these cells may be used as the source of cells for huCART-meso cell 
manufacturing.  
 
Recommended criteria for apheresis product acceptance to initiate processing for clinical 
manufacturing to meet the dosing requirements includes the following specifications:  It is 
recommended that the patient have an absolute lymphocyte count (ALC) ≥500/µl, prior to undergoing 
apheresis.  If the patient’s ALC is <500/µl, it is recommended that a lymphocyte subset analysis (CD3, CD4, 
CD8 counts) be performed to confirm that the patient has an absolute CD3 count of ≥150/µl.  If the 

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absolute CD3 count is <150/µl, it is recommended that the leukapheresis procedure be delayed until their 
ALC is ≥500/µl or absolute CD3 count is ≥150/µl.   
 
The apheresis product is transported to the CVPF for processing. A portion of the peripheral blood 
leukocytes will be saved for the TCSL laboratory at the University of Pennsylvania and used for baseline 
immunoassessment research assays and biobanking, and the other portion used for huCART-meso cell 
manufacturing in CVPF. Baseline blood leukocytes for FDA look-back requirements will also be obtained 
and cryopreserved.  
 
Historical Apheresis Sample 
Cryopreserved historical apheresis products collected from the patient prior to study entry are usable for 
huCART-meso manufacturing if the sample was collected at an appropriately certified apheresis center 
and if the product meets adequate mononuclear cell yields. If a historical apheresis product is not 
available, an apheresis procedure (as described above) will be performed for cell procurement after study 
eligibility has been confirmed.  
6.3 
Pre-infusion safety visit (Week -2 to -1) 
Subjects will undergo the following evaluations within 14 days prior to their 1st study infusion (unless 
otherwise specified below).  Please refer to the Schedule of Events in Appendices 1-3. 
 
• 
Review of current medical conditions 
• 
Physical examination- including vital sign measurements, ECOG performance status, and review 
of concomitant medications. Vital sign measurements include weight, temperature, heart rate, 
blood pressure, and oxygen saturation by pulse oximetry.  
• 
Complete blood count and differential 
• 
Chemistry panel- including sodium, potassium, chloride, CO2, blood urea nitrogen, creatinine, 
glucose, phosphate, total protein, albumin, calcium, alkaline phosphatase, total bilirubin, ALT, 
AST, uric acid, LDH 
• 
Coagulation Factors- PT, PTT, fibrinogen, d-dimer 
• 
Serum pregnancy test (females of childbearing potential only) 
• 
Baseline ferritin, triglycerides, haptoglobin and CRP  
• 
EKG 
• 
Subjects must undergo a Respiratory Virus Panel (RVP, inclusive of SARS-CoV-2) within 10 days 
prior to the first planned huCART-meso infusion and prior to receipt of lymphodepleting 
chemotherapy. If the subject is positive for influenza, Tamiflu® or equivalent, should be 
administered per package insert. The subject must complete treatment prior to receiving 
lymphodepleting chemotherapy (if applicable) and huCART-meso cells. The test does not need to 
be repeated prior to these infusion(s), however if influenza sign and symptoms are present, the 
infusion(s) should be delayed until the subject is asymptomatic. If the subject is positive for 
another virus on the RVP, the infusion(s) will be delayed for at least 7 days to be sure clinical 
symptoms of a viral infection do not develop, or longer if clinically appropriate for the respective 
pathogen. If clinical symptoms develop, the infusion(s) will be delayed until resolution of these 
symptoms. 
• 
Clinical Tumor Markers: CA125. 
• 
Radiographic Imaging:  Baseline scans should be obtained within 28 days prior to infusion of 
huCART-meso cells and after any cancer therapy administered between collection and huCART-

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meso infusion.  In applicable cohorts, baseline scans should also be obtained prior to 
lymphodepleting chemotherapy administration. 
• 
A baseline tumor biopsy will be performed prior to huCART-meso infusion (and administration of 
lymphodepleting chemotherapy if applicable), if the subject has an accessible tumor.  The baseline 
biopsy may occur any time prior to infusion between Day -14 to Day -1.  This baseline biopsy 
sample will be used to evaluate the level of mesothelin expression and if feasible, other immune 
markers at baseline.  If a subject does not have an accessible tumor or a biopsy is not felt to be 
clinically appropriate, an archived tumor tissue specimen may be obtained for research purposes.  
• 
Research blood sample collection- please refer to the Schedule of Evaluations (Appendices 1-3) 
for complete details. 
6.4 
Lymphodepleting Chemotherapy Administration  
Lymphodepleting chemotherapy will be administered prior to the huCART-meso cell infusion for subjects 
participating in targeted cohorts only: 
• 
Cohorts 2 and 6: a single flat dose of 1 gram/m2 cyclophosphamide by intravenous infusion given 
2-4 days prior to the huCART-meso infusion. In Cohort 6, cyclophosphamide will only be 
administered prior to the first huCART-meso infusion.  Note: Cohort 4 (which also included 
Cyclophosphamide administration) was permanently closed with Protocol V5.  
• 
Cohort 7:  cyclophosphamide 300 mg/m2/day and fludarabine 30 mg/m2/day given over 3 days 
by intravenous infusion.  Lymphodepleting chemotherapy will be scheduled such that the last 
day of chemotherapy is 3 days (+/- 1 day) prior to the 1st infusion of huCART-meso cells.  
Fludarabine doses will be rounded down to the nearest 50 mg vial size, if the rounded dose does 
not differ by > 10% of the original dose prescribed. 
 
The main goal of using lymphodepleting chemotherapy is to achieve lymphodepletion that may enhance 
engraftment of adoptive T cells, while minimizing complications from neutropenia. The proposed regimen 
has been used widely in other studies and has been tolerated well. At the discretion of the investigator, 
some subjects may require hospitalization for administration of lymphodepleting chemotherapy. In this 
event, the hospitalization will not be recorded as an SAE. 
 
Prior to lymphodepleting chemotherapy administration, subjects will undergo tests/procedures 
performed according to the Schedule of Events in Appendices 1-3.  A CBC with differential and 
comprehensive chemistry panel must be performed within 48 hours prior to initiating lymphodepleting 
chemotherapy. If already performed within this window, these laboratory tests do not need to be 
repeated on the day of lymphodepleting chemotherapy.  Tests/procedures do not need to be repeated 
prior to subsequent lymphodepleting chemotherapy infusions unless clinically indicated. 
 
Subjects who receive lymphodepleting chemotherapy, but in whom the huCART-meso infusion is 
subsequently delayed >2 weeks after the first day of lymphodepleting chemotherapy, may receive a 
second cycle of lymphodepleting chemotherapy prior to huCART-meso infusion at the clinical 
investigator’s discretion. 
 
The following criteria must be met in order to proceed with lymphodepleting chemotherapy 
administration:  
1) Subjects should not have received systemic chemotherapy within 2 weeks prior to the planned 
huCART-meso infusion.  If systemic chemotherapy was administered, then this procedure will be 
re-scheduled. 

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2) Subjects must meet all concomitant therapy guidelines as outlined in Section 5.6.  This includes 
restrictions on checkpoint inhibitor therapies while on study, and receipt of prior anti-PD-1 or 
PDL1 therapy within 4 months of the planned huCART-meso infusion. 
3) Subjects who have received chemotherapy or other immunotherapies > 2 weeks and < 6 weeks 
of the planned huCART-meso cell infusion, must have recovered from all toxicities, including 
myelosuppression.  
4) Subjects should not experience a significant change in performance status compared to initial 
eligibility criteria that would, in the opinion of the treating physician, increase the risk of 
experimental cell infusion.  
5) Subjects must not have laboratory abnormalities after enrollment that, in the opinion of the 
treating investigator or PI, may impact subject safety or the subjects’ ability to receive 
lymphodepleting chemotherapy or the huCART-meso cells. If this occurs, patients may have their 
treatment delayed until both the treating investigator and PI determine it is clinically appropriate 
to proceed.  
6) Subjects must undergo a Respiratory Virus Panel (RVP, inclusive of SARS-CoV-2) within 10 days 
prior to the planned huCART-meso cell infusion and prior to receipt of lymphodepleting 
chemotherapy. If the subject is positive for influenza, Tamiflu® or equivalent, should be 
administered per package insert. The subject must complete treatment prior to receiving 
lymphodepleting chemotherapy. The RVP does not need to be repeated prior to infusion; 
however, if influenza signs and symptoms are present, the infusions should be delayed until the 
subject is asymptomatic. If the subject is positive for another virus on the RVP, the infusions will 
be delayed for at least 7 days to be sure clinical symptoms of a viral infection do not develop, or 
longer if clinically appropriate for the respective pathogen. If clinical symptoms develop, the 
infusions will be delayed until resolution of these symptoms 
7) Subjects should not experience any of the following specific toxicities:  
a. Pulmonary: New requirement for supplemental oxygen or presence of progressive 
radiographic abnormalities on chest x-ray (chest x-ray is not required at this juncture but 
should be evaluated if performed for clinical purposes).   
b. Cardiac: New cardiac arrhythmia not controlled with medical management.  
c. Hypotension requiring pressor support.  
d. Active Infection: Positive blood cultures for bacteria, fungus, or virus within 48-hours of 
lymphodepleting chemotherapy. 
 
Anti-emetic prophylaxis: 
It is anticipated that subjects receiving lymphodepleting chemotherapy may experience nausea and 
vomiting as a side effect of the treatment. Premedication for nausea can be administered prior to infusion 
of chemotherapy. Choice of specific agent will be left to the discretion of the investigator. Corticosteroid 
treatment as anti-emetic prophylaxis prior to lymphodepleting chemotherapy administration is allowed 
per institutional guidance per Section 5.6.   
 
Prophylactic antibiotics are recommended post lymphodepleting chemotherapy per institutional 
standards and practices for cellular therapies.  
 
Potential Side Effects 
Chemotherapy is an integral part of this study and therefore subjects will be evaluated for toxicity that 
may be related to the chemotherapy conditioning regimen. See Section 1.7/Risks of cyclophosphamide 
and fludarabine for complete information.     

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6.5 
huCART-meso product administration (Day 0) 
Subjects in Cohorts 5-7 will receive huCART-meso cells on an inpatient basis at the Hospital of the 
University of Pennsylvania. The subjects will remain inpatient for observation for a minimum of 48 hours 
after the huCART-meso infusion (Study Visit Days 1 and 2).  The subject may then be discharged in 
accordance with hospital policy after this observation period is complete and the subject is medically 
stable.   The subject may remain hospitalized beyond this protocol-required window if deemed necessary 
for medical management of serious adverse events.  
 
Prior to the administration of huCART-meso cells, all subjects will undergo tests/procedures in accordance 
with the Schedule of Events in Appendices 1-3.  Results of CBC with differential and chemistry panel must 
be reviewed by a physician-investigator prior to administration of study treatment; otherwise, results of 
other laboratory testing are not required prior to the huCART-meso infusion except as necessary for 
investigator to evaluate criteria to proceed with the huCART-meso infusion as described below.  A CBC 
with differential and comprehensive chemistry panel must be performed within 48 hours prior to the 
huCART-meso infusion (and after receipt of lymphodepleting chemotherapy if applicable). If already 
performed within this window, these laboratory tests do not need to be repeated on Day 0.   
 
The following criteria must be met in order to proceed with the huCART-meso infusion:  
1) Subjects should not have received systemic chemotherapy within 2 weeks prior to the huCART-
meso infusion, with the exception of protocol-required lymphodepleting chemotherapy 
(applicable cohorts).  If chemotherapy was administered, then this infusion will need to be re-
scheduled. 
2) Subjects must meet all concomitant therapy guidelines as outlined in Section 5.6.   
3) Subjects should not experience a significant change in performance status compared to initial 
eligibility criteria that would, in the opinion of the treating physician, increase the risk of 
experimental cell infusion.  
4) Subjects must not have laboratory abnormalities after enrollment that, in the opinion of the 
treating investigator or PI, may impact subject safety or the subjects’ ability to receive huCART-
meso cells. If this occurs, patients may have their treatment delayed until both the treating 
investigator and PI determine it is clinically appropriate to proceed.  
5) Subjects must undergo a Respiratory Virus Panel (RVP, inclusive of SARS-CoV-2) within 10 days 
prior to the huCART-meso cell infusion. If the subject is positive for influenza, Tamiflu® or 
equivalent, should be administered per package insert. The subject must complete treatment 
prior to receiving huCART-meso cells. The RVP does not need to be repeated prior to infusion; 
however, if influenza signs and symptoms are present, the infusion should be delayed until the 
subject is asymptomatic. If the subject is positive for another virus on the RVP, the infusion will 
be delayed for at least 7 days to be sure clinical symptoms of a viral infection do not develop. If 
clinical symptoms develop, or longer if clinically appropriate for the respective pathogen, the 
infusion will be delayed until resolution of these symptoms. 
6) Subjects should not experience any of the following specific toxicities:  
a. Pulmonary: New requirement for supplemental oxygen or presence of progressive 
radiographic abnormalities on chest x-ray (chest x-ray is not required at this juncture but 
should be evaluated if performed for clinical purposes).  
b. Cardiac: New cardiac arrhythmia not controlled with medical management.  
c. Hypotension requiring pressor support.  
d. Active Infection: Positive blood cultures for bacteria, fungus, or virus within 48-hours of T 
cell infusion. 

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Please refer to Section 5.3 [Preparation and Administration of Investigational Product(s)] for complete 
details. 
6.6 
Post-Infusion Inpatient Observation (Cohorts 5-7 only) 
The subject will remain inpatient for observation for a minimum of 48 hours after the huCART-meso 
infusion.  During post-infusion observation, the subject will undergo vital sign assessments (temperature, 
respiration rate, heart rate, blood pressure, and oxygen saturation by pulse oximetry) every 4-6 hours (+/- 
30 minutes) from the end of the infusion vital sign monitoring period until 48 hours post infusion.   
Additional monitoring may be performed per clinical discretion.  Subjects will also undergo physical 
examinations, clinical labs, and collection of research samples as per the Schedule of Events (Appendices 
1-3).  Additional assessments will be performed as deemed clinically appropriate. The subject may then 
be discharged after this observation period is completed when medically stable and in accordance with 
hospital policy.  The subject may remain hospitalized beyond this protocol-required window if deemed 
necessary for medical management of serious adverse events. 
6.7 
Post-infusion Visits (Cohorts 1-5)* 
* Note: Cohorts 3 and 4 are permanently closed as of Protocol V5. 
6.7.1 
Safety Follow-up Visits 
Subjects will have safety follow-up visits on Days 6 (±1), 9 (±1), 14 (±1), and 21 (±1) post-infusion as per the 
Schedule of Events in Appendix 1.  
 
If the subject’s tumor is measurable by CT and accessible by image-guided biopsy, subjects will undergo a 
tumor biopsy under image guidance at Day 14(±7) to evaluate the impact of therapy on the tumor 
microenvironment and to assess for the presence of CAR T cells and mesothelin expression. These will be 
compared to baseline values from fresh biopsies and/or stored surgical tumor specimens, if available. 
Please refer to the Laboratory Manual for complete details. 
 
In case of unexpected AEs or SAEs, additional samples may be collected for research analysis, focused at 
evaluating the potential causality with the infused huCART-meso cells see Section 3.3/Collection of 
Research Samples. 
6.7.2 
Day 28 (+/- 5 days): Safety and Tumor Staging 
At this study visit, subjects will undergo tests and procedures in accordance with the Schedule of Events 
in Appendix 1.  Tumor response will be assessed as described in Section 7.1.  A mini-apheresis procedure 
(~5 L) will also be performed at this visit for research purposes.  A 60 ml blood draw may be substituted 
for the mini-apheresis procedure at the discretion of the treating investigator.  
6.7.3 
Month 2 (+/- 5 days): Safety  
Subjects will return to the center at Month 2 following huCART-meso infusion. At this study visit, subjects 
will undergo tests and procedures in accordance with the Schedule of Events in Appendix 1.   
6.7.4 
Month 3 (+/- 5 days): Safety and Tumor Staging 
Subjects will return to the center at Month 3 following huCART-meso infusion. At this study visit, subjects 
will undergo tests and procedures in accordance with the Schedule of Events in Appendix 1.  In addition, 

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tumor staging (CT imaging as clinically indicated as per patient population and disease status) will be 
performed. A CT scan within 4 weeks of this visit is acceptable. Tumor response will be assessed as 
described in Section 7.1. 
6.7.5 
Month 6 (+/- 5 days): Safety and Tumor Staging 
Subjects will return to the center at Month 6 following huCART-meso infusion.  At this study visit, subjects 
will undergo tests and procedures in accordance with the Schedule of Events in Appendix 1.  In addition, 
tumor staging (CT imaging as clinically indicated as per patient population and disease status) will be 
performed.  A CT scan within 4 weeks of this visit is acceptable.  Tumor response will be assessed as 
described in Section 7.1. 
6.7.6 
Quarterly Evaluations for up to 2 Years Post-Infusion 
After month 6, subjects will be evaluated on a quarterly basis until 2 years post infusion. At these study 
visits, subjects will undergo tests and procedures in accordance with the Schedule of Events in Appendix 
1.   
6.8 
Post-Infusion Visits (Cohort 6 only) 
6.8.1 
Safety Follow-up Visits (Post Infusion #1) 
Subjects will have safety follow-up visits on Days 6 (±1), 9 (±1), and 14 (±1) post-infusion as per the Schedule 
of Events in Appendix 2.  
6.8.2 
Additional huCART-meso Infusion(s)  
Cohort 6 subjects may receive up to two additional IV infusions of huCART-meso cells at the same dose 
level, if determined clinically appropriate by the physician-investigator.  Each additional infusion may be 
given approximately 21 and 42 days after the Day 0 infusion, allowing for a +3 week window as needed.  
Therefore, huCART-meso Infusion #2 is targeted for Day 21 (+3 weeks) and huCART-meso Infusion #3 is 
targeted for Day 42 (+ 3 weeks).  Additional huCART-meso infusions performed outside of this window 
require approval from the Principal Investigator and Sponsor Medical Director. The subject must be 
evaluated for the below criteria prior to each additional infusion.   Subjects will not receive 
lymphodepleting chemotherapy prior to additional huCART-meso infusions. 
 
The following criteria must be met in order to proceed with additional infusions of huCART-meso cells:  
1) Subjects must have manufactured huCART-meso cell product available which meets the minimum 
acceptable dose for infusion (1x106 huCART-meso cells/m2).  
2) Subjects should not experience a significant change in performance or clinical status that would, 
in the opinion of the treating physician-investigator or PI, increase the risk of experimental cell 
infusion.  
3) Subjects experiencing laboratory abnormalities that, in the opinion of the physician-investigator 
or PI, may impact subject safety or the subjects’ ability to receive huCART-meso cells, may have 
their infusion delayed until determined to be clinically appropriate to proceed with the CAR T cell 
infusion. If this occurs, patients may have their treatment delayed until both the treating 
investigator and PI determine it is clinically appropriate to proceed.  
4) Subjects should not be experiencing signs/symptoms of an active infection. 

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5) Subjects should not be experiencing any ongoing treatment-related grade > 3 events, that in the 
opinion of the treating physician-investigator and PI are anticipated to be exacerbated by 
additional infusions of huCART-meso cells.   
6) Subjects should not be experiencing signs/symptoms of cytokine release syndrome (CRS) or other 
severe CAR T cell related toxicities.   
7) Subjects must undergo a Respiratory Virus Panel (RVP, inclusive of SARS-CoV-2) within 10 days 
prior to each huCART-meso cell infusion. If the subject is positive for influenza, Tamiflu® or 
equivalent, should be administered per package insert. The subject must complete treatment 
prior to receiving huCART-meso cells. The RVP does not need to be repeated prior to infusion; 
however, if influenza signs and symptoms are present, the infusion should be delayed until the 
subject is asymptomatic. If the subject is positive for another virus on the RVP, the infusion will 
be delayed for at least 7 days to be sure clinical symptoms of a viral infection do not develop, or 
longer if clinically appropriate for the respective pathogen. If clinical symptoms develop, the 
infusion will be delayed until resolution of these symptoms. 
 
If the additional huCART-meso infusions are delayed by greater than 7 days or not performed for any 
reason, the additional infusion study visits [at Day 21 and Day 42] will still be performed as scheduled, 
however they will be repurposed as a safety follow-up visit only.  These safety follow-up visits will be 
identified as the actual study visit from Day 0 (i.e. Day 26), and should be performed within +7 days of the 
planned study timepoint.  If the additional huCART-meso infusions are then subsequently performed 
within the protocol allowable window (+3 weeks), the actual infusion day will be calculated as the actual 
study visit day from Day 0 (i.e. Day 35) and the study visit assessments required for an infusion visit will 
be repeated prior to the infusion as per the Schedule of Events (Appendix 2).  
 
The subject will remain inpatient for observation for a minimum of 48 hours after each huCART-meso 
infusion.  During post-infusion observation, the subject will undergo vital sign assessments (temperature, 
respiration rate, heart rate, blood pressure, and oxygen saturation by pulse oximetry) every 4-6 hours (+/- 
30 minutes) from the end of the infusion vital sign monitoring period until 48 hours post infusion.   
Additional monitoring may be performed per clinical discretion.  Subjects will also undergo physical 
examinations, clinical labs, and collection of research samples as per the Schedule of Events (Appendix 
2).   
 
Additional assessments will be performed as deemed clinically appropriate. Should evidence of cytokine 
release syndrome or respiratory symptoms appear, the subject will be supported as noted in Section 
9.4.2, and may require a more prolonged admission. The subject may then be discharged after this 
observation period is complete and the subject is medically stable.  The subject may remain hospitalized 
beyond this protocol-required window if deemed necessary for medical management of serious adverse 
events. 
6.8.3 
Post-Infusion Safety Follow-up (Infusions #2 and #3) 
As described above, the additional huCART-meso infusions may be performed within a +3 week window 
from the targeted infusion days i.e. [Day 21 (+3 weeks) and Day 42 (+3 weeks)]. Given the allowable 
window for these additional infusions, the timing of the post-infusion safety follow-up visits will be 
dependent on the actual timing of the additional huCART-meso infusions as follows.  
• 
The timing of the post-infusion safety follow-up visits will be calculated as the actual study day 
they occurred post Infusion #2 and Infusion #3 (i.e. + 6 days post Infusion #2,+7 days post Infusion 
#2, +13 days post Infusion #3, etc.). This should be recorded as the actual study day, even if an 

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assessment falls within the allowable visit window (i.e. Day +6 visit occurs on Day +7, record as 
Day +7).  This guidance applies to the timing of study procedures (i.e. imaging, etc) as well as study 
visits.   
• 
In addition, the actual study visit day calculated from Day 0 (the initial huCART-meso infusion) 
must also be captured (i.e. Day 30, Day 31, etc).   
• 
Example: 
• 
Infusion # + Study Visit Day Post Additional Infusion/Study Visit Day from Day 0 
• 
Infusion #2 Day +6/Day 28 
• 
Both time points must be reported for tests/procedures performed during post-infusion safety 
follow-up visits for Infusion #2 and Infusion #3 only.  
 
In addition to the required inpatient observation Day +1 and +2 post each additional huCART-meso 
infusion, subjects will have safety follow-up visits on Day +6 (±1), +9 (±1), and +14 (±1) post each infusion 
as per the Schedule of Events in Appendix 2.  An additional safety follow-up visit will be performed Day 
+21 (±1) after the last huCART-meso infusion.   If an infusion is omitted, these post-infusion safety follow-
up visits will not be required.  If an infusion is delayed, these additional safety follow-up visits will be 
shifted to align with the timing of the infusion (as indicated above). Please refer to the Cohort 6 Schedule 
of Events in Appendix 2 for complete details.  
 
Day +14 (±7) Post the huCART-meso Infusion #2: 
• 
Tumor Biopsy:  
o If the subject’s tumor is measurable by CT and accessible by image-guided biopsy, 
subjects will undergo a tumor biopsy under image guidance to evaluate the impact of 
therapy on the tumor microenvironment and to assess for the presence of CAR T cells and 
mesothelin expression. These will be compared to baseline values from fresh biopsies or 
stored surgical tumor specimens, if available. Please refer to the Laboratory Manual for 
complete details. 
• 
Tumor Imaging 
• 
Tumor Biomarkers 
 
If huCART-meso Infusion #2 is not performed for any reason, the post-infusion biopsy/tumor markers/ 
imaging will be performed at the time the decision is made by the physician-investigator not to administer 
additional infusions.  Tumor imaging may also be performed at any time as per clinical discretion.  
 
Day +21 (±7) Post the 3rd huCART-meso Infusion (or last huCART-meso infusion if all three infusions are 
not received for any reason): 
• 
Apheresis – A mini-apheresis procedure (~5 L) will also be performed at this visit for research 
purposes.  A 60 ml blood draw may be substituted for the mini-apheresis procedure at the 
discretion of the treating investigator. 
 
In case of unexpected AEs or SAEs, additional samples may also be collected for research analysis, focused 
at evaluating the potential causality with the infused huCART-meso cells see Section 3.3/Collection of 
Research Samples. 
6.8.4 
Month 3 (+/- 5 days): Safety and Tumor Staging 
The timing of this study visit will be calculated from the initial huCART-meso infusion (Day 0). At this study 
visit, subjects will undergo tests and procedures in accordance with the Schedule of Events in Appendix 

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2.  In addition, tumor staging (CT imaging as clinically indicated as per patient population and disease 
status) will be performed. A CT scan within 4 weeks of this visit is acceptable. Tumor response will be 
assessed as described in Section 7.1. 
6.8.5 
Month 6 (+/- 5 days): Safety and Tumor Staging 
The timing of this study visit will be calculated from the initial huCART-meso infusion (Day 0). At this study 
visit, subjects will undergo tests and procedures in accordance with the Schedule of Events in Appendix 
2.  In addition, tumor staging (CT imaging as clinically indicated as per patient population and disease 
status) will be performed.  A CT scan within 4 weeks of this visit is acceptable.  Tumor response will be 
assessed as described in Section 7.1. 
6.8.6 
Quarterly Evaluations for up to 2 Years Post-Infusion 
After month 6, subjects will be evaluated on a quarterly basis until 2 years post infusion or until the 
subjects’ progress and/or initiate another cancer-related therapy. The timing of these study visits will be 
calculated from the initial huCART-meso infusion (Day 0). At these study visits, subjects will undergo tests 
and procedures in accordance with the Schedule of Events in Appendix 2.   
6.9 
Post-Infusion Visits (Cohort 7) 
6.9.1 
Safety Follow-up Visits (Post Infusion #1) 
Subjects will have safety follow-up visits on Days 6 (±1), 9 (±1), and 14 (±1) post-infusion as per the Schedule 
of Events in Appendix 3.  
 
If the subject’s tumor is measurable by CT and accessible by image-guided biopsy, subjects will undergo a 
tumor biopsy at Day 14 (+/- 7 days) after the 1st huCART-meso infusion (Day 0).  This biopsy sample will 
be used to evaluate the impact of therapy on the tumor microenvironment and to assess for the presence 
of CAR T cells and mesothelin expression.  These samples will be compared to baseline values from fresh 
biopsies or stored surgical tumor specimens, if available.  Please refer to the Laboratory Manual for 
complete details.   
6.9.2 
Additional huCART-meso Infusion(s)  
Cohort 7 subjects may receive up to two additional infusions of huCART-meso cells via intravenous (IV) 
administration at the same dose level, if determined clinically appropriate by the physician-investigator.  
Each additional infusion may be given approximately 21 and 42 days after the Day 0 infusion, allowing for 
a +3 week window as needed.  Therefore, huCART-meso Infusion #2 is targeted for Day 21 (+3 weeks) and 
huCART-meso Infusion #3 is targeted for Day 42 (+ 3 weeks).  Additional huCART-meso infusions 
performed outside of this window require approval from the Principal Investigator and Sponsor Medical 
Director. The subject must be evaluated for the below criteria prior to each additional infusion.   Subjects 
will not receive lymphodepleting chemotherapy prior to additional huCART-meso infusions. 
 
The following criteria must be met in order to proceed with additional infusions of huCART-meso cells:  
1) Subjects must have manufactured huCART-meso cell product available which meets the minimum 
acceptable dose for infusion (1x106 huCART-meso cells/m2).  
2) Subjects should not experience a significant change in performance or clinical status that would, 
in the opinion of the treating physician-investigator or PI, increase the risk of experimental cell 
infusion.  

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3) Subjects experiencing laboratory abnormalities that, in the opinion of the physician-investigator 
or PI, may impact subject safety or the subjects’ ability to receive huCART-meso cells, may have 
their infusion delayed until determined to be clinically appropriate to proceed with the CAR T cell 
infusion. If this occurs, patients may have their treatment delayed until both the treating 
investigator and PI determine it is clinically appropriate to proceed.  
4) Subjects should not be experiencing signs/symptoms of an active infection. 
5) Subjects should not be experiencing any ongoing treatment-related grade > 3 events, that in the 
opinion of the treating physician-investigator and PI are anticipated to be exacerbated by 
additional infusions of huCART-meso cells.   
6) Subjects should not be experiencing signs/symptoms of cytokine release syndrome (CRS) or other 
severe CAR T cell related toxicities.   
7) Subjects must undergo a Respiratory Virus Panel (RVP, inclusive of SARS-CoV-2) within 10 days 
prior to each huCART-meso cell infusion. If the subject is positive for influenza, Tamiflu® or 
equivalent, should be administered per package insert. The subject must complete treatment 
prior to receiving huCART-meso cells. The RVP does not need to be repeated prior to infusion; 
however, if influenza signs and symptoms are present, the infusion should be delayed until the 
subject is asymptomatic. If the subject is positive for another virus on the RVP, the infusion will 
be delayed for at least 7 days to be sure clinical symptoms of a viral infection do not develop, or 
longer if clinically appropriate for the respective pathogen. If clinical symptoms develop, the 
infusion will be delayed until resolution of these symptoms. 
 
If the additional huCART-meso infusions are delayed by greater than 7 days or not performed for any 
reason, the additional infusion study visits [at Day 21 and Day 42] will still be performed as scheduled, 
however they will be repurposed as a safety follow-up visit only.  These safety follow-up visits will be 
identified as the actual study visit from Day 0 (i.e. Day 26), and should be performed within +7 days of the 
planned study timepoint.  If the additional huCART-meso infusions are then subsequently performed 
within the protocol allowable window (+3 weeks), the actual infusion day will be calculated as the actual 
study visit day from Day 0 (i.e. Day 35) and the study visit assessments required for an infusion visit will 
be repeated prior to the infusion as per the Schedule of Events (Appendix 3).  
 
The subject will remain inpatient for observation for a minimum of 48 hours after each huCART-meso 
infusion.  During post-infusion observation, the subject will undergo vital sign assessments (temperature, 
respiration rate, heart rate, blood pressure, and oxygen saturation by pulse oximetry) every 4-6 hours (+/- 
30 minutes) from the end of the infusion vital sign monitoring period until 48 hours post infusion.  
Additional monitoring may be performed per clinical discretion.  Subjects will also undergo physical 
examinations, clinical labs, and collection of research samples as per the Schedule of Events (Appendix 
3).   
 
Additional assessments will be performed as deemed clinically appropriate. Should evidence of cytokine 
release syndrome or respiratory symptoms appear, the subject will be supported as noted in Section 
9.4.2, and may require a more prolonged admission. The subject may then be discharged after this 
observation period is complete and the subject is medically stable.  The subject may remain hospitalized 
beyond this protocol-required window if deemed necessary for medical management of serious adverse 
events. 

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6.9.3 
Post-Infusion Safety Follow-up (Infusions #2 and #3) 
As described above, the additional huCART-meso infusions may be performed within a +3 week window 
from the targeted infusion days i.e. [Day 21 (+3 weeks) and Day 42 (+3 weeks)]. Given the allowable 
window for these additional infusions, the timing of the post-infusion safety follow-up visits will be 
dependent on the actual timing of the additional huCART-meso infusions as follows.  
• 
The timing of the post-infusion safety follow-up visits will be calculated as the actual study day 
they occurred post Infusion #2 and Infusion #3 (i.e. + 6 days post Infusion #2, +7 days post Infusion 
#2, +13 days post Infusion #3, etc.). This should be recorded as the actual study day, even if an 
assessment falls within the allowable visit window (i.e. Day +6 visit occurs on Day +7, record as 
Day +7).  This guidance applies to the timing of study procedures (i.e. imaging, etc) as well as study 
visits.   
• 
In addition, the actual study visit day calculated from Day 0 (the initial huCART-meso infusion) 
must also be captured (i.e. Day 30, Day 31, etc).   
• 
Example: 
• 
Infusion # + Study Visit Day Post Additional Infusion/Study Visit Day from Day 0 
• 
Infusion #2 Day +6/Day 28 
• 
Both timepoints must be reported for tests/procedures performed during post-infusion safety 
follow-up visits for Infusion #2 and Infusion #3 only.  
 
In addition to the required inpatient observation Day +1 and +2 post each additional huCART-meso 
infusion, subjects will have safety follow-up visits on Day +6 (±1), +9 (±1), and +14 (±1) post each infusion 
as per the Schedule of Events in Appendix 3. If an infusion is omitted, these post-infusion safety follow-
up visits will not be required.  If an infusion is delayed, these additional safety follow-up visits will be 
shifted to align with the timing of the infusion (as indicated above). Please refer to the Cohort 7 Schedule 
of Events in Appendix 3 for complete details.  
 
Day +14 (±7) Post the huCART-meso Infusion #2: 
• 
Tumor Imaging 
• 
Tumor Biomarkers 
• 
60mL blood draw- for research purposes  
 
If huCART-meso Infusion #2 is not performed for any reason, the post-infusion tumor imaging will be 
performed at the time the decision is made by the physician-investigator not to administer additional 
infusions.  Tumor imaging may also be performed at any time as per clinical discretion.  
 
Day +14 (±7) Post the 3rd huCART-meso Infusion: 
• 
60mL blood draw- for research purposes  
 
If a subject does not receive either huCART-meso Infusion #2 or Infusion #3, the subject will undergo this 
60mL blood draw at the Day 42 (+7) Safety Follow-up Visit, which still must be performed in the absence 
of Infusion #3.  
 
In case of unexpected AEs or SAEs, additional samples may also be collected for research analysis, focused 
at evaluating the potential causality with the infused huCART-meso cells see Section 3.3/Collection of 
Research Samples. 

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6.9.4 
Month 3 (+/- 5 days): Safety and Tumor Staging 
The timing of this study visit will be calculated from the initial huCART-meso infusion (Day 0). At this study 
visit, subjects will undergo tests and procedures in accordance with the Schedule of Events in Appendix 
3.  In addition, tumor staging (CT imaging as clinically indicated as per patient population and disease 
status) will be performed. A CT scan within 4 weeks of this visit is acceptable. Tumor response will be 
assessed as described in Section 7.1. 
6.9.5 
Month 6 (+/- 5 days): Safety and Tumor Staging 
The timing of this study visit will be calculated from the initial huCART-meso infusion (Day 0). At this study 
visit, subjects will undergo tests and procedures in accordance with the Schedule of Events in Appendix 
3.  In addition, tumor staging (CT imaging as clinically indicated as per patient population and disease 
status) will be performed.  A CT scan within 4 weeks of this visit is acceptable.  Tumor response will be 
assessed as described in Section 7.1. 
6.9.6 
Quarterly Evaluations for up to 2 Years Post-Infusion 
After month 6, subjects will be evaluated on a quarterly basis until 2 years post infusion. The timing of 
these study visits will be calculated from the initial huCART-meso infusion (Day 0). At these study visits, 
subjects will undergo tests and procedures in accordance with the Schedule of Events in Appendix 3.   
6.10 Long-term Follow-up Protocol 
All infused subjects who complete or prematurely discontinue participation in this study (as defined in 
Section 4.5.1), will be asked to participate in a separate 15-year long-term follow-up destination protocol. 
This long-term follow-up protocol includes evaluations performed for up to 15 years on all subjects as 
recommended by the FDA for protocols utilizing integrating viral vectors.  
7 
ASSESSMENTS 
7.1 
Disease Assessments 
All subjects who receive the target dose of huCART-meso cells infusion will be considered evaluable for 
response [including progression-free survival (PFS) and overall survival (OS)]. All subjects with 
radiologically confirmed measurable disease (per RECIST 1.1) at baseline will also be considered evaluable 
for overall radiologic response (ORR).  
 
Radiographic Imaging 
Participants will undergo radiographic imaging by CT/MRI with or without contrast.  Baseline scans should 
be obtained within 28 days prior to infusion of huCART-meso cells and after any cancer therapy 
administered between collection and huCART-meso infusion.  In applicable cohorts, baseline scans should 
also be obtained prior to administration of lymphodepleting chemotherapy.  
 
Post infusion imaging will be performed as described in the Schedule of Events (Appendices 1-3). 
 
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 when both methods have been used to assess the anti-tumor effect of a treatment. 
 

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Radiographic Response 
Radiographic responses will be measured using two imaging assessment approaches: 1) Response 
Evaluation Criteria in Solid Tumors (RECIST 1.1) and 2) immune related response criteria (irRC) when 
feasible. Note: irRC will not be evaluated in mesothelioma subjects. 
 
For RECIST 1.1 evaluation, the determination of antitumor efficacy will be based on objective tumor 
assessments made according to the system of unidimensional evaluation.  Mesothelioma will be assessed 
using the modified RECIST criteria.  The same method and technique should be used to characterize each 
identified and reported lesion at baseline, during the study treatment period, and during follow-up. 
Imaging-based evaluation rather than clinical examination is the required technique when either could be 
used to assess the antitumor effect of the treatment. Computed Tomography (CT) scan is the preferred 
method for the tumor assessment. Tumor assessment scans may be performed with or without contrast.  
Because immune therapy can cause an initial tumor volume increase due to inflammation prior to 
subsequent tumor shrinkage, an exploratory analysis of response status will also be conducted using the 
recently developed immune related response criteria (irRC)(Wolchok et al., 2009). Novel to the irRC is the 
measurement of overall tumor burden as a metric of disease progression, compared to the limitation of 
using only baseline lesion measurements according to RECIST 1.1. According the irRC, new lesions do not 
constitute disease progression if net tumor burden including new lesions is stable or decreases. The irRC 
also permit disease progression at a subsequent time point after first detection. This accounts for the 
period required for activated T-cells to infiltrate the tumor, which may cause initial tumor volume increase 
due to inflammation but can subsequently translate into tumor shrinkage. The irRC also classify durable 
stable disease as clinical activity. Thus, this protocol will explore two distinct imaging criteria for 
determination of disease outcome in response to treatment with huCART-meso cells.   
 
Tumor biomarkers 
Tumor biomarkers as appropriate for each malignancy will also be measured.  For ovarian cancer patients, 
CA125 will be measured. There are no clinical tumor markers routinely evaluated in mesothelioma 
patients.  
 
Mesothelin is the receptor for CA125, and the interaction between mesothelin and CA125 is thought to 
play a role in tumor progression (details in Section 1.7). Therefore, binding of mesothelin by huCART-meso 
cells may directly affect the level of circulating CA125 irrespective of disease activity. Therefore, tumor 
biomarker assessment alone is not sufficient to determine response or progression in this study.   
7.2 
Research Correlative Studies Assessment 
7.2.1 
Collection of Research Samples 
Research samples (including peripheral blood, fluid, and tumor tissue) will be obtained at defined time 
points to monitor for measures of safety and T cell persistence. This includes an image-guided minimally 
invasive biopsy pre-infusion and post-infusion for research purposes.  Please refer to the Schedule of 
Events (Appendices 1-3) for required time points.  
 
In case of unexpected AEs or SAEs, additional samples may also be collected for research analysis, focused 
at evaluating the potential causality with the infused huCART-meso cells. Additional blood work for 
research evaluation may also be requested at any time at the investigators’ discretion, and is especially 
encouraged whenever there is a clinical concern for a potential toxicity related to huCART-meso cells, but 
also for patients with an unusual efficacy; additional studies may identify critical biomarkers of potency 

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which may inform future trial designs. The additional samples collected for research will not exceed 3 
tablespoons of blood twice in a week, and one procedure for collecting tissue/lymph node samples in a 
month. 
 
Tissue samples (e.g. fluids, tissue biopsy) that are obtained as part of standard of care procedures for 
clinical indications will also be sent for research analysis, wherever feasible. Fluid samples that would 
otherwise be discarded may also be diverted for research purposes.   
7.2.2 
Planned Correlative Studies 
The planned correlative studies are as follows: 
1. Determine the persistence of huCART-meso cells in peripheral blood.  
Peripheral blood mononuclear cells’ DNA will be evaluated by Q-PCR using a validated assay that 
detects a fragment unique to the CAR sequence. PBMC may also be used for a flow cytometry 
based assay for determination of huCART-meso cells. These analyses will be performed in bulk on 
each patient on peripheral blood, tumor derived material where available, or other tissues/fluids 
(ascites, pleural fluid, etc.).  CAR T cell vector sequences will be performed at pre- and all post-
infusion study visits as outlined in the Schedule of Events (Appendices 1-3).  Additional testing 
may also be performed at unscheduled time points at the discretion of the Sponsor.  This analysis 
will continue until any 2 sequential tests are negative documenting loss of CAR T cells.  
Additionally, flow cytometry may be used to detect cells expressing the anti-mesothelin CAR 
construct, if feasible.  
2. Determine the bioactivity of huCART-meso cells in peripheral blood.  
Serum or fluid (e.g. ascites) will be analyzed using Luminex and ELISA Technologies to determine 
the presence of a panel of cytokines/chemokines/immune factors. Measurements will be 
performed in bulk to maximize utilization of immune assay kits. In addition, bioactivity of the 
manufactured and infused huCART-meso cells may be assessed by functional flow cytometry via 
detection of cytokine production and cytotoxic activity of the cells stimulated with a mesothelin-
expressing cell line. 
3. Evaluate the development of immune responses favoring rejection of huCART-meso cells (where 
scientifically relevant). Development of HACA antibody responses are expected to result in 
elimination of huCART-meso cells. Cellular immune responses directed to the modified T cells may 
also develop and be measured. Correlate the occurrence of antibody responses with loss of 
engraftment of CAR T cells. 
4. Evaluate the development of secondary anti-tumor responses as a consequence of huCART-meso 
cells. Tumor cell death mediated by huCART-meso cells may expose the immune system to new 
antigens, leading to new immune responses directed to the tumor. The development of new 
antibodies and cellular immune responses that develop to established tumor cell lines may be 
assessed and displayed as appropriate to each assay. This will be determined using Protoarray or 
other appropriate technologies, or via next-generation sequencing of T cell receptor and 
immunoglobulin rearrangements in the tumor at baseline and post-infusion. 
5. Where tumor material or body fluids can be obtained: 
a. Measure trafficking of huCART-meso cells;  
b. Evaluate mesothelin expression on tumor cells to assess for antigen-escape.  
c. Evaluate genetic editing (if feasible) 
d. Analyze tumor microenvironment and cell interactions (if feasible)- Immune correlates 
such as local immune activation (using qRT-PCR); the breath and hierarchy of the B and 
T cell repertoire via deep sequencing and compare with baseline specimens. 

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8 
STATISTICAL PLAN 
8.1 
General Design Issues 
This is a single-center phase I study in cancer patients to evaluate the safety and feasibility of autologous 
T cells engineered to express a CAR that targets mesothelin.  
8.2 
Sample Size Determination 
This study will enroll up to 27 evaluable subjects depending on the occurrence of DLT.  Evaluable subjects 
are defined as those subjects who receive the target dose of huCART-meso cells as per their cohort 
assignment. 
8.3 
Subject Population(s) for Analysis 
• 
The Screened Set comprises all subjects who are consented to participate in this study. 
• 
The Enrolled Set comprises all subjects who are determined eligible to participate in the study 
(excluding screen failure).   
• 
The Safety Evaluable Set comprises all subjects who receive the target dose of huCART-meso 
cells per their cohort assignment. The Safety Set will be used for primary safety and feasibility 
analysis, official DLT evaluations, and cohort advancement decisions. 
• 
The Efficacy Evaluable Set comprises all subjects who receive the huCART-meso cells at their 
cohort assigned dose level and who have at least one post-infusion disease assessment 
available. Efficacy evaluable subjects also include those with disease progression or death prior 
to completion of study safety visits. The Efficacy Evaluable Set will be used for the secondary 
efficacy endpoint analysis.  
• 
The Efficacy Non-Evaluable Set comprises subjects who receive huCART-meso at lower than 
intended dose or do not have at least one post-infusion disease assessment available.  These 
subjects will be evaluable for safety, but will not be evaluable for response.  These subjects 
will also not be included in official DLT evaluations or cohort advancement decisions, thus will 
be replaced in that cohort. 
• 
The Full Analysis Set (FAS) comprises all subjects who received the huCART-meso cells. This 
set includes both evaluable and efficacy non-evaluable subjects and will be used for the 
primary safety and feasibility, and secondary correlative endpoints or other exploratory 
analyses. 
 
A second population of subjects in the Enrolled Set includes subjects eligible for participation in the study 
but who do not receive huCART-meso cells. Reasons subjects do not receive cell infusions are likely to 
include 1) ineffective transduction of autologous T cells or an inability to manufacture an infusible dose; 
2) rapid progression, clinical deterioration, and/or death between the time of enrollment and infusion; 
and 3) subject withdrawal. Subjects who do not receive therapy will be replaced as detailed in Section 
4.4.3. 
 
The number of subjects in the Enrolled Set versus the number of subjects in the Safety Evaluable Set will 
be described and is a measure of the feasibility of this therapy. 

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8.4 
Analysis of Primary Endpoints 
 
The primary safety endpoint will be evaluated using the Safety Evaluable Set, to determine the safety of 
huCART-meso cells based on the type, frequency, severity, and attribution of AE/SAEs and the occurrence 
of DLTs. DLT and adverse events will be collected and evaluated for all subjects during the protocol 
specified AE reporting period. AEs will be graded for severity using the National Cancer Institute (NCI) – 
Common Terminology Criteria (v4.03). All adverse events will be described using descriptive statistics and 
exact 90% confidence intervals will be produced for adverse event rates, both overall and within major 
categories. Results will be tabulated and summarized, both overall and by individual cohorts.  
 
Feasibility endpoints will be evaluated using the Enrolled Set as follows:  
• 
Study feasibility will be summarized as the proportion of subjects who receive huCART-meso cells 
out of the number of subjects enrolled, as well as the proportion of subjects who cannot receive 
all planned doses of huCART-meso cells.   
• 
Manufacturing feasibility will be evaluated by:  
o The proportion of huCART-meso products that meet release criteria as measured by CAR 
expression and T cell numbers, out of the number of subjects enrolled with products 
manufactured; and  
o The proportion of huCART-meso products that meet the targeted dose, out of the number 
of subjects enrolled with products manufactured. huCART-meso products that fail to 
meet the intended dose are considered dose failures. 
 
8.5 
Analysis of Secondary Endpoints 
For the preliminary efficacy endpoints, overall response rate (ORR), progression-free survival (PFS), and 
overall survival (OS) will be evaluated as follows: 
o Objective response rate (ORR):  will be computed as proportions with exact 90% confidence 
interval.  Overall response rate (ORR) is defined as the proportion of subjects in the efficacy-
evaluable set with radiologically confirmed measurable disease at baseline, who achieved 
partial response (PR) or better after infusion as determined by RECIST 1.1. Missing or non-
evaluable time points will not be included. 
o Progression-free survival (PFS): Progression-free survival (PFS) is defined as the time from the 
date of the infusion to the date of first documented disease progression (per RECIST 1.1) or 
death (from any cause), or censored at the date of the last adequate assessment. PFS will be 
described using Kaplan-Meier curves.  
o Overall Survival (OS): Overall survival is defined as the time from the date of the infusion to 
the date of death from any cause. If a subject is not known to have died at the date of analysis 
cut-off, OS will be censored at the last date of contact. OS will be estimated using Kaplan-
Meier curves.  Median survival times and survival probabilities at selected time points (e.g., 
6-, 12-months) will be presented.  
 
8.6 
Analysis of Correlative Endpoints 
Please refer to Section 7.2.2 for complete details.  
 

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9 
SAFETY AND ADVERSE EVENTS 
9.1 
Definitions 
9.1.1 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related.  Intercurrent illnesses or injuries should be regarded as adverse 
events.  
9.1.2 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
• 
fatal 
• 
life-threatening 
• 
requires or prolongs hospital stay 
• 
leads to a persistent or significant disability or incapacity or substantial disruption of the ability to 
conduct normal life functions 
• 
a congenital anomaly or birth defect 
• 
an important medical event 
 
Hospitalizations that meet the following criteria should not be reported as serious adverse events: 
• 
Routine treatment or monitoring of the studied indication, not associated with any deterioration 
in condition, such as preplanned study visits and preplanned hospitalizations for study procedures 
or treatment administration 
• 
Elective or pre-planned treatment for a pre-existing condition that is unrelated to the indication 
under study and has not worsened since signing the informed consent 
• 
Social reasons and respite care in the absence of any deterioration in the patient’s general 
condition 
 
Note: Treatment on an emergency outpatient basis that does not result in hospital admission and involves 
an event not fulfilling any of the definitions of a SAE given above is not a serious adverse event.   
 
Important medical events are those that may not be immediately life threatening, but are clearly of major 
clinical significance. They may jeopardize the subject, and may require intervention to prevent one of the 
other serious outcomes noted above. For example, drug overdose or abuse, a seizure that did not result 
in in-patient hospitalization, or intensive treatment of bronchospasm in an emergency department would 
typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-serious 
adverse events.  
 
9.1.3 
Unexpected adverse events 
An adverse event is considered unexpected if the event, and/or severity of the event (grade), is not 
consistent with the risk information described in the investigator brochure and/or protocol.    

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9.1.4 
Related adverse events 
An adverse event is considered related to participation in the research if there is a reasonable possibility 
that an event was caused by an investigational product, intervention, or research-required procedures.  
For the purposes of this study, "reasonable possibility" means there is evidence to suggest a causal 
relationship.  The relationship of the event to the study will be classified as possibly related, probably related, 
and definitely related. 
• 
Possibly Related: There is some evidence to suggest a causal relationship; however, other 
factors may have contributed to the event. 
• 
Probably Related: There is evidence to suggest a causal relationship, and the influence of 
other factors is unlikely.  
• 
Definitely Related: There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out.  
9.1.5 
Unanticipated Adverse Device Effect (UADE)  
(Note: Device refers to the Mesothelin Immunohistochemistry Test required for screening in subjects 
enrolled prior to Protocol Amendment V9 only) is any serious adverse effect on health or safety, or any 
life threatening problem or death caused by, or associated with, a device, if that effect, problem, or death 
was not previously identified in nature, severity, or degree of incidence in the investigational plan or 
application, or any other unanticipated serious problem associated with a device that relates to the rights, 
safety, or welfare of subjects.  
9.1.6 
Protocol-defined Adverse Event 
If/when alternative treatment is initiated post-huCART-meso administration, adverse event data 
collection/reporting requirements will be reduced. As of the start date of any new treatment, only 
protocol‐defined adverse events (PDAEs) will be collected and reported.  Any events ongoing at the 
time alternative treatment is initiated must continue to be followed through resolution.   
 
Protocol-defined adverse events that are also determined to be serious, as defined in Section 9.1.2 above, 
will be considered protocol-defined serious adverse events (PDSAEs) and will require expedited reporting 
to the sponsor per Section 9.3.  
 
PDAEs are defined as follows:  
1) New incidence or exacerbation of a pre‐existing neurologic disorder  
2) New incidence or exacerbation of a prior rheumatologic or other autoimmune disorder  
3) New incidence of hematologic disorder  
4) New malignancy (T cell & non T cell)  
5) Any adverse event or condition the investigator believes may have a reasonable relationship to 
CAR T cell therapy (including unexpected illnesses or hospitalizations in this patient population)  
 
The following correlative laboratory results will also constitute a protocol-defined adverse event, however 
these events will be identified by the Sponsor and subsequently reported to the PI/site and FDA:  
1) Positive RCL test result  
2) Vector insertion site sequencing result with a mono- or oligoclonal vector integration pattern or 
in a location near a known human oncogene.  
 

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9.1.7 
Adverse Event Reporting Period 
Collection of adverse events will begin at the time of initiation of study treatment (lymphodepleting 
chemotherapy or huCART-meso cell infusion depending on cohort assignment) and continue until the 
subject is off-study as follows:  
• 
For the Time Period Beginning with the Initiation of Study Treatment and Until Alternative 
Therapy for their Disease is Administered:  
o All adverse events must be reported. The subject’s complete baseline medical history will 
be collected prior to the initiation of study treatment.  
• 
At the Time Alternative Therapy for their Disease is Initiated: 
o Subjects will only be followed for protocol-defined adverse events (PDAEs). Any events 
ongoing at the time alternative treatment is initiated must continue to be followed 
through resolution.   
o PDAE reporting will continue until the end of study (EOS). 
9.1.8 
Preexisting Condition/General Physical Examination Findings 
A preexisting condition is one that is present prior to the start of the Adverse Event Reporting Period.  All 
clinically significant abnormalities should be recorded as a preexisting condition on the medical history 
eCRF. During the course of the study, a preexisting condition should be recorded as an adverse event if 
the frequency, intensity, or the character of the condition worsens.  Preexisting conditions that improve 
should also be recorded appropriately. 
9.1.9 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if determined to be clinically 
significant by the physician-investigator.  Repeat testing to confirm the abnormality may be performed as 
per clinical discretion.  
 
Laboratory abnormalities that meet the criteria for Adverse Events should be followed until they have 
returned to normal or an adequate explanation of the abnormality is found. When an abnormal laboratory 
or test result corresponds to a sign/symptom of an already reported adverse event, it is not necessary to 
separately record the lab/test result as an additional event. Laboratory abnormalities that do not meet 
the definition of an adverse event, should not be reported as adverse events.  A Grade 3 or 4 event 
(severe) as per CTCAE does not automatically indicate a SAE unless it meets the definition of serious 
defined above and/or as per investigator’s discretion.  Whenever possible, a diagnosis, rather than a 
symptom should be provided (i.e. anemia instead of low hemoglobin).   
9.2 
Recording of Adverse Events 
Safety will be assessed by monitoring and recording potential adverse effects of the treatment using the 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. If CTCAE grading does not exist for 
an adverse event, the severity of mild, moderate, severe, life-threatening, and death, corresponding to 
Grades 1-5, will be used whenever possible. Specialized grading systems have also been developed to more 
appropriately capture events of Cytokine Release Syndrome (Table 9.2-1) and CAR Neurotoxicity (Table 
9.2-2).  
 
Subjects will be monitored through interval medical history evaluations, physical examinations, and 
clinical laboratory assessments as per the Schedule of Evaluations (Appendices 1-3). Adverse events will 

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be collected on an ongoing basis throughout the subject’s participation; using testing/examinations, non-
directive questioning (e.g. review of systems), subject self-reporting, etc. 
 
Information on all adverse events should be recorded in the source documentation.  All clearly related 
signs, symptoms, and abnormal diagnostic procedures results should be recorded in the source document, 
though should be grouped under one diagnosis. To the extent possible, adverse events should be recorded 
as a diagnosis and symptoms used to make the diagnosis recorded within the diagnosis event.  Do not list 
symptoms or abnormal diagnostic results separately if a diagnosis can be assigned. The safety team may 
require events be reported separately if they occur as SAEs (or in the context of a SAE) even if they can also 
be considered a constituent of another AE such as CRS. 
 
All adverse events occurring during the adverse event reporting period (defined in Section 9.1.7 above) 
must be recorded. If there are no adverse events identified during a study visit occurring after the AE 
reporting period commences, physician-investigator confirmation of the absence of adverse should be 
documented.  
 
As much as possible, each adverse event should be evaluated to determine: 
1. Severity/Grade (CTCAE Grade 1-5) 
2. Duration  
3. Its relationship to the study treatment (as defined in Section 9.1.4) 
4. Expectedness to study treatment (as defined in Section 9.1.3) 
5. Action taken with respect to the investigational treatment  
6. Whether medication or therapy was administered 
7. Whether it is serious, as defined in Section 9.1.2 
 
Physician-investigator assessment of whether an adverse event is serious (as defined by Section 9.1.2) 
must occur within 24 hours from the date of knowledge of the adverse event in order to meet SAE 
reporting requirements described in Section 9.3. Additional assessment of non-serious adverse events, 
including grade and relationship to study treatment, should occur within 7 days from the date of 
knowledge of the adverse event or from the date of the study visit where the absence of adverse events 
was confirmed. Accelerated timelines for adverse event assessments and reporting may be requested in 
the event of emergent safety concerns and/or to address time-sensitive requests from the DSMB/FDA.   
 
All adverse events should be treated appropriately. If a concomitant medication or non-drug therapy is 
given, this action should be recorded. Once an adverse event is detected, it should be followed until its 
resolution or until it is judged to be permanent, and evaluated for any changes in severity, the suspected 
relationship to the study treatment, the interventions required to treat it, and the outcome. 
 
Progression of malignancy, documented appropriately in the medical records, should not be reported as 
a serious adverse event. Adverse events that occur concurrently with the progression of malignancy but 
that are not related to disease progression (i.e. deep vein thrombosis or hemoptysis) will be reported as 
an adverse event as described above.  Progression of malignancy resulting in death should be reported as 
a serious adverse event.  
 
Serious adverse events that are still ongoing at the end of the adverse event reporting period must be 
followed to determine the final outcome.  Any serious adverse event that occurs after the adverse event 
reporting period and is considered to be possibly related to the study treatment or study participation, 
should be recorded and reported. 

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At the time of the initial report, the following information should be provided: 
• 
Study identifier 
• 
Subject number 
• 
A description of the event 
• 
Date of onset 
• 
Current subject status 
• Whether study treatment was discontinued 
• The reason the event is classified as serious 
• Investigator assessment of the association 
between the event and study treatment 
• Expectedness relative to investigational 
product(s) 
9.3.1 
Investigator Reporting:  Local Regulatory Review Committees 
Report events to local regulatory review committees per institutional policy. 
9.3.2 
Pregnancies 
To ensure subject safety, each pregnancy occurring while the subject is on study treatment must be 
reported to protocol sponsor within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of the birth, 
and the presence or absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications.  If a pregnancy occurs on study, this will be reported as an SAE using an SAE Report Form. 
 
Pregnancy outcomes must be collected for the female partners of any males who took study treatment in 
this study. Consent to report information regarding these pregnancy outcomes should be obtained from 
the mother. 
9.4 
Toxicity Management, Stopping Rules and Study Termination 
It is expected that AEs may occur frequently in this population based on the underlying advanced cancer 
and that these can be SAEs. Therefore, there is no specific occurrence of SAEs that define a stopping rule, 
but the review of SAEs will form the basis for potential early stopping of the study. Only unexpected SAEs 
that are related to the huCART-meso cells would define a stopping rule. The review of these adverse 
events, and any decision to prematurely stop subject enrollment, will be determined by the Sponsor 
and/or DSMB. 
 
In addition to the above, premature termination of the clinical trial may also occur because of a regulatory 
authority decision, change in opinion of the IRB, determination that there are problems in the cell product 
generation, as a result of safety concern, or at the discretion of the PI.  Additionally, recruitment may be 
stopped for reasons of particularly low recruitment, protocol violations, or inadequate data recording.  
9.4.1 
Criteria for stopping or pausing the study 
The study will be paused and reviewed for potential stopping rules if: 
• 
Any death within 30 days of the 1st huCART-meso infusion of any subject. 
• 
Any Grade 4 respiratory adverse event.  This will require an immediate temporary hold followed 
by an urgent DSMB meeting. 
• 
The study meets the DLT safety signal for Grade 3 AEs described in Section 5.4.  
o Dose Escalation Cohorts (Cohorts 1-4): In the event of 2 DLTs at a dose level, the 
enrollment into that cohort will stop and the study will not advance to the next cohort. If 
2 DLTs occur in Cohort 1, we will dose de-escalate by 10-fold and enroll up to 6 subjects 
to be infused with huCART-meso cells only. If 2 DLTs occur at the de-escalated dose, the 
study will be stopped.  

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o Dose Expansion Cohorts (Cohorts 5-7): All subjects will be routinely evaluated for dose-
limiting toxicities (DLT).  In the event of 2 DLTs in a specific cohort, additional enrollment 
and treatment activity within that cohort will be paused to allow for further investigation.    
 
If the study accrual/treatment activity is paused in accordance with the above, a formal assessment of 
the event(s) will be generated by the Sponsor and submitted to the DSMB for review/acknowledgement.  
The outcome of DSMB review will be shared with the PI for submission to local regulatory review 
committees as required per institutional policy.  If all parties are in agreement as to the event 
resolution, then the pause will be lifted.  The sponsor will also notify the FDA as appropriate.  
 
The study will be stopped in the event of any of the following: 
• 
Any subject develops uncontrolled T cell proliferation that does not respond to management. 
• 
Grade 5 respiratory adverse event. 
• 
The PI, Sponsor, Medical Director, DSMB, or any independent review board or regulatory body 
decides for any reason that subject safety may be compromised by continuing the study. 
• 
The Sponsor decides to discontinue the development of the intervention used in this study. 
9.4.2 
General Toxicity Management Considerations 
Please refer to the current version of the huCART-meso Investigator’s Brochure for complete information. 
 
Replication-competent lentivirus (RCL) 
RCL may in theory be generated during the CAR T cell manufacturing phase or subsequently after 
introduction of vector transduced cells into the subject. However, an RCL resulting from the production 
phase is highly unlikely since elements are incorporated in the design of the vector system that minimize 
vector recombination and generation of RCL. Furthermore, the vector used to transduce the product 
undergoes sensitive assays to confirm that the vector is RCL negative before it can be released for use in 
product manufacture. Though theoretical, development of RCL could pose a risk to both the subject and 
their close contact(s), and therefore, samples will be archived during the course of the trial. In the event 
of a suspected RCL, measures to detect RCL will be followed per the recent FDA guidance, Testing of 
Retroviral Vector-Based Human Gene Therapy Products for Replication Competent Retrovirus During 
Product Manufacture and Patient Follow-up. 
 
Clonality and insertional oncogenesis 
Monitoring for T cell clonal outgrowth will be performed by qPCR analysis for CAR-expressing cells and/or 
flow cytometric analysis (if feasible), and by CBC count.  If during long-term follow-up > 1% of the subject’s 
sample is positive for vector sequences by qPCR, then the subject will be asked to return for a confirmatory 
blood test prior to the next study visit.  If > 1% of the subject’s sample is positive upon the receipt of the 
confirmatory qPCR result, then the genomic vector integration sites will be determined.  Identified vector 
integration sites will be evaluated using bioinformatics approaches to determine if the integration events 
are in regions with known relationships to human cancers (i.e. near oncogenes).    
 
If integration site analysis reveals mono- or oligoclonality and/or integration at or near an oncogenic locus, 
a monitoring plan, including follow-up molecular analyses, will be developed in collaboration between the 
PI and Regulatory Sponsor that is specific for the health care risks that are anticipated given the nature of 
the integration site and vector target cell type. 
 

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Infusion reaction 
Acetaminophen and an antihistamine may be repeated every 6 hours as needed. It is recommended that 
subjects not receive corticosteroids at any time, except in the case of a life-threatening emergency, since 
this may have an adverse effect on CAR T cells.   
 
Febrile reaction 
In the event of febrile reaction, an evaluation for infection should be initiated, and subjects managed 
appropriately with antibiotics, fluids and other supportive care as medically indicated and determined by 
the treating physician.  In the event that the subject develops sepsis or systemic bacteremia following 
CAR T cell infusion, appropriate cultures and medical management should be initiated.  If a contaminated 
CAR T cell product is suspected, the product can be retested for sterility using archived samples that are 
stored in the CVPF.  Consideration of a cytokine release syndrome (see below) should be given.   
 
Cytokine Release Syndrome (CRS) / Macrophage Activation Syndrome (MAS) 
Selective tocilizumab therapy has been utilized (described below) to manage CRS/MAS toxicity without 
precluding CAR T cell expansion in subjects. Steroids or other immunosuppressant drugs should NOT be 
used as pre-medication for CAR T cell therapy but may be considered in the management of CRS.  
 
The moderate to severe cases of CRS observed required intervention with single dose tocilizumab with or 
without high dose corticosteroids, between 2 and 9 days after T cell infusion to date. This resulted in rapid 
reversal of the high persistent fevers and hemodynamic instability associated with CRS in most but not all 
subjects. 
 
Given the clinical improvement of subjects after treatment with anti-cytokine therapy, subjects with 
moderate to severe cytokine toxicities should be managed with administration of tocilizumab.  
 
Tocilizumab should be used as a single, weight-based dose of 8 mg/kg at the time of hemodynamic 
instability. This management approach is designed to avoid life-threatening toxicities, while attempting 
to allow the CAR T cells to establish a proliferative phase that appears to correlate with clinical efficacy. 
Thus, the timing of the tocilizumab should be individualized, in close consultation with the Principal 
Investigator and/or expert consultants for the trial.  Steroids have not always been effective in this setting 
and may not be necessary given the rapid response to tocilizumab. Because steroids are thought to 
interfere with CAR T cell function and efficacy, if used, they should be rapidly tapered.  
 
Upon developing the prodrome of persistent fevers following CAR T cell infusion, subjects should then be 
followed closely. Infection and tumor lysis syndrome work up should be immediately undertaken.  The 
pharmacy should be notified of the potential need for tocilizumab.  Subject management in an intensive 
care unit may be required and the timing is dependent upon local institutional practice. In addition to 
supportive care, tocilizumab may be administered in cases of moderate to severe CRS, especially if the 
subject exhibits any of the following: 
• 
Hemodynamic instability despite intravenous fluid challenges and moderate stable vasopressor 
support 
• 
Worsening respiratory distress, including pulmonary infiltrates, increasing oxygen requirement 
including high-flow O2, and/or need for mechanical ventilation.  
• 
Any other signs or symptoms of rapid deterioration despite medical management 
 
The recommended dosing for tocilizumab is 8 mg/kg (maximum individual dose of 800 mg) i.v. every 8 
hours for a maximum of four doses; this is the dosing specified in the tocilizumab product label for 

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management of CRS. Failure of CRS to improve after two tocilizumab doses, however, should also prompt 
consideration of adjunctive therapies, as described below, in addition to further tocilizumab doses. Not 
all Grade 4 CRS reactions following CAR T cell infusions have been immediately treated with tocilizumab 
and decisions are, in part, based upon the rapidity of the syndrome onset and the individual subject’s 
physiologic reserve. 
 
Other anti-cytokine therapies, such as repeat administration of tocilizumab or use of siltuximab or 
etanercept, may also be considered if the patient does not respond to the initial dose of tocilizumab.  If 
the patient experiences ongoing CRS despite administration of anti-cytokine directed therapies, anti T-cell 
therapies such as cytoxan, ATG, campath may be considered.   
 
A detailed treatment algorithm has been established with clear criteria for CRS management following 
CART-19 administration and guidance on when to administer tocilizumab (Figure 9.4-1). This approach 
was designed to avoid life-threatening toxicities, while attempting to allow the CART-19 transduced cells 
to establish a proliferative phase which appears to correlate with tumor response. The management of 
CRS is based solely upon clinical parameters. This algorithm may be used to guide CRS management 
related to huCART-meso treatment; however, changes specific to the huCART-meso should be considered 
and based on clinical judgment. Specific CRFs have been developed for the capture of CRS elements, 
severity, management and response to intervention.  
 

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Figure 9.4-1:  CRS Management Algorithm 
 
 
 

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Off-Tumor On-Target Toxicity 
It is possible that serositis, peritonitis, or pleuropericarditis could occur due to normal mesothelin 
expression on serosal surfaces. Relevant information on the occurrence of serositis is available from the 
study done at the NCI testing an anti-mesothelin pseudomonas exotoxin conjugate (SS1P) (Hassan, 
Bullock, et al. 2007). SS1P was given by an IV bolus infusion to 34 patients. The DLT was Grade 3 pleuritis 
and was seen in two of two patients treated at a dose of 60 μg/kg and in one of nine patients treated at 
a dose of 45μg/kg. The DLT of pleuritis was characterized by fever, hypoxia, pleural effusion, and pain. 
Pleuritis developed after the second dose of SS1P in one patient and after the third dose in two patients. 
The clinical presentation was pleuritic pain leading to hypoxia due to hypoventilation. Chest x-ray showed 
unilateral or bilateral pleural effusion. Patients were treated with supplemental oxygen and narcotics for 
pain relief. Pain and hypoxia resolved within 3 to 9 days. Pleural effusion improved over time and did not 
require drainage.  
 
Serositis should be considered an on-target toxicity of huCART-meso cells. If the subject has significant 
clinical symptoms, supportive care and therapy to ablate the huCART-meso cells should be considered.  
 
Management: In the event of symptomatic pleuritis, pericarditis, or peritonitis following T cells, 
patient will have an investigation to exclude infectious causes, and then will be treated with anti-
inflammatory agents per physician preference. T cell ablating therapies include corticosteroids, 
chemotherapy such as cyclophosphamide, or immunotherapy such as alemtuzumab may also be 
considered at the investigators’ discretion. In the event of fluid accumulation, these cavities can be 
quickly and readily accessed in a minimally invasive fashion to remove the fluid as anti-lymphocyte 
therapy is initiated. Patient will be monitored by clinical exam, laboratory tests, x-ray and EKG for the 
development of serositis. 
 
Anaphylaxis 
According to our experience treating 14 subjects with SS1 CAR mRNA T cells (7 mesothelioma subjects 
under UPCC# 17510, 6 pancreatic cancer subjects under UPCC# 08212, and one pancreatic cancer subject 
under UPCC# 21211), anaphylaxis is a rare but possible toxicity created by repeated CAR T cells infusions 
with long periods of time between infusions (Please refer to the huCART-meso Investigator’s Brochure for 
additional information).  
 
Management: includes epinephrine, volume resuscitation, and corticosteroids, and other supportive 
care as needed (oxygen, ventilation, beta2 agonists for bronchoconstriction, etc.). Management is 
generally similar to that described for cytokine release syndrome (as above), but with the use of 
epinephrine as the principal therapeutic medication. The dose of epinephrine used depends on the 
degree of systemic involvement (low dose for hypotension, high dose -1 mg iv repeated every minute 
as necessary) for PEA arrest, according to ACLS guidelines.  
 
Pulmonary Toxicity 
Given experience in this trial and in a related trial of huCART-meso cells in patients with ovarian cancer, 
mesothelioma, and lung cancer, ALI/ARDS may occur secondary to direct activity of the huCART-meso 
cells on mesothelin-expressing type I pneumocytes, first pass effect, and/or initiation of an organ-specific 
immune reaction. Given these adverse events, subjects will be admitted for the huCART-meso infusion 
and remain inpatient for observation for 48 hours following huCART-meso cell infusion. Should pulmonary 
toxicity occur, the subject will be managed as below. For any subject who develops respiratory symptoms, 
including but not limited to dyspnea, cough, and hypoxia, beyond the inpatient observation time point, 
the subject will be admitted to an inpatient unit for further evaluation and care.  

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Management:  In addition to standard and research laboratory tests being drawn, a cytokine panel 
will be drawn and processed as quickly as possible to ascertain if an actionable pathway (e.g. IL-6 
treatment with tocilizumab) is activated. Should the subject develop increasing respiratory 
compromise or other signs or symptoms consistent with a cytokine release syndrome, the subject will 
be transferred to the medical intensive care unit and treated with tocilizumab per protocol. 
Subsequent doses of tocilizumab will be administered as dictated by the subject response to the initial 
dose and clinical scenario evolution. Should the subject develop increasing respiratory distress, 
standard supportive care measures for hypoxia will be initiated, including increasing oxygen delivery 
as indicated to maintain adequate oxygenation and/or utilizing non-invasive or invasive ventilation 
support if clinically indicated. Should the subject fail to respond to these supportive measures and 
tocilizumab dosing as manifest by progressive or refractory hypoxemic respiratory failure, 
consideration to lympholytic cyclophosphamide doses to abrogate all huCART-meso activity would be 
made in consultation with the critical care team. 
 
Neurologic Toxicity 
Guidelines for management of neurologic toxicity are described in Table 9.4-1. The mechanism underlying 
neurotoxicity after CAR T cell administration is poorly understood. Anecdotal evidence suggests that anti-
IL6 therapies, which are effective for CRS, do not reverse neurotoxicity. Neurotoxicity can be 
asynchronous with cytokine release syndrome, often reaching its maximum intensity later than CRS or 
even arising after resolution of CRS. This has led to the appearance in some cases that treatment of CRS 
with anti-IL6 agents worsens or precipitates neurotoxicity; a causative relationship between anti-IL6 
therapy and neurotoxicity has not been conclusively established, however, and severe neurotoxicity has 
been observed in the absence of CRS and in cases where no anti-IL6 therapy has been used. The following 
principles guide the recommended management of neurotoxicity: 
– Most instances of neurologic toxicity are self-limited, but life-threatening complications such 
as cerebral edema develop in some cases. Corticosteroid therapy aimed at dampening CAR T 
cell proliferation and activity is therefore recommended for moderate (Grade 2-3) 
neurotoxicity with the objective of preventing development of life-threatening, Grade 4 
manifestations. The efficacy of corticosteroids is unproven, however, and corticosteroids may 
adversely affect CAR T cell efficacy. The recommended dose of corticosteroids is therefore 
stratified based on perceived risk of developing life-threatening complications; low/moderate 
doses are recommended for Grade 2, moderate doses for Grade 3, and high-doses for Grade 
4. In addition, it is recommended that cytotoxic chemotherapy be considered in Grade 4 cases 
based on a report that cerebral edema improved promptly after cyclophosphamide 
chemotherapy in one case(Garfall et al. 2016). 
– Consultation with a neurologist is helpful for properly documenting and tracking neurologic 
abnormalities, evaluating for other potential etiologies of neurologic abnormalities, and 
managing neurologic emergencies such as seizure or elevated intracranial pressure.  
– Coagulopathy and thrombocytopenia should be aggressively managed. Both coagulopathy and 
thrombocytopenia often develop with CRS. Intracranial hemorrhage has been observed in 
conjunction with severe neurotoxicity. Intracranial hemorrhage may provide a portal of entry 
for CAR T cells and systemic cytokines to affect the CNS or may simply confound interpretation 
of neurologic abnormalities. In addition, a recent report suggests that thrombocytopenia is an 
independent risk factor for CAR-related neurotoxicity, and platelets may serve as a source of 
mediators that stabilize the endothelium and counteract destabilizing effects of cytokines 
elaborated during CAR T cell proliferation(Gust et al. 2017). 

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A one time, intentional action or process that departs from the IRB-approved study protocol, intended 
for one occurrence. If the action disrupts the study progress, such that the study design or outcome 
(endpoints) may be compromised, or the action compromises the safety and welfare of study subjects, 
advance documented approval from the Regulatory Sponsor and local regulatory review committees per 
institutional guidelines is required. Approval from the Regulatory Sponsor must be received prior to 
submission to local regulatory review committees for approval.   
 
Deviation 
A one time, unintentional action or process that departs from the IRB-approved study protocol, involving 
one incident and identified retrospectively, after the event occurred. If the impact on the protocol 
disrupts the study design, may affect the outcome (endpoints) or compromises the safety and welfare of 
the subjects, the deviation must be reported to the Regulatory Sponsor within 10 business days of PI 
knowledge and to local regulatory review committees per institutional guidelines. Acknowledgement 
from the Regulatory Sponsor must be received prior to submission to local regulatory review committees. 
 
Other deviations should be appropriately documented per site policies/procedures (such as a subject 
missing a visit is not an issue unless a critical/important treatment or procedure was missed and must 
have been done at that specific time).  
 
Include the following information on the Sponsor supplied exception/deviation form:  protocol number, 
subject study number, comprehensive description of the exception/deviation from the protocol, 
rationale, and corrective and preventative action plan (deviations only).  Ensure all completed 
exception/deviation forms are signed by the Principal Investigator (or physician sub-investigator) and 
submitted to the Sponsor Project Manager for review.    
 
Attention: Sponsor Project Manager  
Center for Cellular Immunotherapies (CCI) 
University of Pennsylvania 
 
Once approval of the exception request or acknowledgement of the deviation has been granted by the 
Regulatory Sponsor, the exception or deviation will be submitted to all applicable committees for review 
and approval/acknowledgement per institutional guidelines. 
9.6 
Data and Safety Monitoring Board  
An Independent Data and Safety Monitoring Board (DSMB) comprised of at least four individuals including 
physicians with experience in oncology and/or gene transfer therapy will be assembled, and will work 
under a charter specifically developed for safety oversight of this study. The DSMB will provide 
guidance/advice to the Sponsor. The DSMB will evaluate patient-subject safety as specified in the DSMB 
Charter. 
 
The DSMB will review safety data at the following time points: 
• At the end of Cohort 2 (after all subjects in the Cohort have completed their Day 28 follow-up visit) 
to allow opening of Cohort 3 and 5 in parallel  
• At the time safety data is available for the first two subjects treated with huCART-meso after May 
18, 2018. 
• Approximately every 6 months.  

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• If necessary, additional meetings of the DSMB may be held if safety issues arise in between 
scheduled meetings. 
 
It is envisioned that the DSMB may make four types of recommendations, namely: 
• No safety or efficacy issues, ethical to continue the study as planned 
• Serious safety concerns precluding further study treatment, regardless of efficacy 
• Overwhelming evidence for futility, recommend stopping the study. 
• Recommendation to continue the study but proposing an amendment to the protocol (e.g., 
incorporate an additional safety assessments) 
 
A sponsor representative will share the outcome of the DSMB meeting with the PI via email, for 
submission to local regulatory review committees as required per institutional policy.   
10 
DATA HANDLING AND RECORDKEEPING 
10.1 Confidentiality 
Information about study subjects obtained as part of this study will be kept confidential and managed 
according to the requirements of the Health Insurance Portability and Accountability Act (HIPAA) of 1996.  
Those regulations require a signed subject authorization informing the subject of the following:  
• 
What protected health information (PHI) will be collected from subjects in this study 
• 
Who will have access to that information and why 
• 
Who will use or disclose that information 
• 
The rights of a research subject to revoke their authorization for use of their PHI  
 
In the event that the subject revokes authorization to collect or use PHI, the investigator, by regulation, 
retains the ability to use all information collected prior to the revocation of subject authorization.  For 
subjects that have revoked authorization to collect or use PHI, attempts should be made to obtain 
permission to collect at least vital status (i.e. that the subject is alive) at the end of their scheduled study 
period. 
10.2 Source Documents 
Source data is all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial.  Source data are contained in 
source documents.  Examples of these original documents, and data records include: hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic negatives, microfilm 
or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, and at 
medico-technical departments involved in the clinical trial. 
 
The investigator must maintain source documents for each subject in the study, consisting of case and 
visit notes (hospital or clinical medical records) containing demographic and medical information, 
laboratory data, and the results of any other tests or assessments. All information recorded on the eCRFs 
must be traceable to source documents in the subject’s file.  
 

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Paper based records will be kept in a secure location and only be accessible to personnel involved in the 
study. Computer-based records or files will only be made available to personnel involved in the study 
through the use of access privileges and passwords. Whenever feasible, subject identifiers will be redacted 
from study related records and replaced with study assigned identification numbers. 
 
10.3 Data Management 
Data management responsibilities will be governed by CCI Clinical Operations policies/procedures 
including current Clinical Operations Standard Operating Procedures (SOPs), Guide to Daily Operations 
(GDOs) and Work Instructions (WI).   
 
A part 11 compliant electronic data capture (EDC) system will be used as the primary data collection tool 
for the purposes of this study.   All data requested on the study-specific CRF must be recorded. Data entry 
will be performed by clinical site team members who have been delegated this responsibility by the 
Principal Investigator and who have completed all required protocol and database training. The Principal 
Investigator is responsible for assuring that the data entered into eCRF is complete, accurate, and that 
entry and updates are performed in a timely manner. 
10.4 Sharing of Study Data  
Participants will have access to research related information within their medical record through Penn 
Medicine’s patient portal – called MyPennMedicine (MPM). This includes information from all clinical 
tests/procedures required as part of their study participation.  Results of research testing conducted in 
non-CLIA certified laboratories will not be included in the participant’s medical record or made available 
to the patient.  
10.5 Future Use of Research Data/Specimens 
Blood, remaining unmanufactured cells, unused manufactured huCART-meso cells or other samples 
obtained from the participant will be stored indefinitely and used for future research. Study data and 
samples may also be shared with other researchers within Penn, or other research institutions, as well as 
with for-profit pharmaceutical or biotechnology companies.  This future research may include genetic 
testing and/or whole genome sequencing. Data/specimens used for future research will be coded using 
the unique subject identifier.  
 
There are no plans to tell participants about future testing on their specimens, or share the results of this 
analysis.   
10.6 Records Retention 
Essential documents must be retained for a minimum of 2 years after the last approval of a marketing 
application in an International Conference on Harmonization (ICH) region and until there are no pending 
or contemplated marketing applications in an ICH region or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product.  These documents should 
be retained for a longer period if required by local regulations or per sponsor agreement.  In such an 
instance, it is the responsibility of the sponsor to inform the investigator/institution as to when these 
documents no longer need to be retained.  No records will be destroyed without the written consent of 
the sponsor. 

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11 
STUDY MONITORING, AUDITING, AND INSPECTING 
11.1 Study Monitoring Plan 
 This study will be monitored according to the Sponsor Data and Safety Monitoring Plan.   
 
Interim Monitoring Visits will be conducted during the course of the study. The Monitors will assure that 
submitted data are accurate and in agreement with source documentation; verify that investigational 
products are properly stored and accounted for, verify that subjects’ consent for study participation has 
been properly obtained and documented, confirm that research subjects entered into the study meet 
inclusion and exclusion criteria, and assure that all essential documentation required by Good Clinical 
Practices (GCP) guidelines are appropriately filed. 
 
At the end of the study, Monitors will conduct a close-out visit and will advise on storage of study records 
and disposition of unused investigational products. 
 
The investigator will allocate adequate time for such monitoring activities. The Investigator will also 
ensure that the monitor or other compliance reviewer is given access to all the above noted study-related 
documents and study related facilities (e.g. pharmacy, diagnostic laboratory, etc.), and has adequate 
space to conduct the monitoring visit. 
11.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, the sponsor, 
government regulatory bodies, and University compliance groups of all study related documents (e.g. 
source documents, regulatory documents, data collection instruments, study data etc.).  The investigator 
will ensure the capability for inspections of applicable study-related facilities (e.g. pharmacy, diagnostic 
laboratory, etc.).  
 
Participation as an investigator in this study implies acceptance of potential inspection by government 
regulatory authorities and applicable University compliance offices. 
 
The Principal Investigator must notify the Sponsor in real-time if an audit/inspection notification is 
received. 
12 
ETHICAL CONSIDERATIONS 
This study is to be conducted according to US and international standards of Good Clinical Practice (FDA 
Title 21 part 312 and International Conference on Harmonization guidelines), applicable government 
regulations, the revised Common Rule, and Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent Institutional 
Review Board (IRB), in agreement with local legal prescriptions, for formal approval of the study conduct.  
The decision of the IRB concerning the conduct of the study will be made in writing to the investigator and 
a copy of this decision will be provided to the sponsor before commencement of this study.   
 
All subjects for this study will be provided a consent form describing this study and providing sufficient 
information for subjects to make an informed decision about their participation in this study. All study 
consent forms will be submitted with the protocol for review and approval by the University of 

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Pennsylvania IRB.  The Investigator (according to applicable regulatory requirements), or a person 
designated by the Investigator, will facilitate the informed consent discussion with the participant, in 
language and terms they are able to understand.  All subjects must have the cognitive ability to provide 
consent, as determined by the treating physician-investigator. 
 
Written informed consent will be signed/dated by the participant and the person conducting the informed 
consent discussion.  A copy of the signed/dated informed consent will be provided to the participant, and 
the original consent should be retained for the investigator’s research records.  Participant consent, using 
the IRB-approved consent form, must be obtained before that subject undergoes any study-specific 
procedures. 
 
The protocol is listed under clinicaltrials.gov. 
13 
STUDY FINANCES 
13.1 Funding Source 
This study will be funded by the University of Pennsylvania, the NIH, and Tmunity Therapeutics. 
13.2 Conflict of Interest 
All University of Pennsylvania Investigators will follow the University of Pennsylvania Policy on Conflicts 
of Interest Related to Research.  This requires that any individuals who have a role in the design, conduct, 
or analysis of this clinical trial disclose all potential conflict of interest as part of their participation in this 
clinical trial, including changes in their conflict of interest as they occur.  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.   
13.3 Subject Stipends or Payments 
There is no subject stipend/payment for participation in this protocol. 
13.4 Study Discontinuation 
The study may be discontinued at any time by the IRB, the Sponsor, the FDA, or other government 
agencies as part of their duties that research subjects are protected. 
14 
PUBLICATION PLAN 
Publication of the results of this trial will be governed by University of Pennsylvania policies, the Center 
for Cellular Immunotherapies (CCI) Authorship Guidance, and any applicable contractual agreements. 
Neither the complete nor any part of the results of the study carried out under this protocol, nor any of 
the information provided by the sponsor for the purposes of performing the study, will be published or 
passed on to any third party without the consent of the study sponsor.  Any investigator involved with 
this study is obligated to provide the sponsor with complete test results and all data derived from the 
study. 

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15 
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8. EKG at month 6 only 
9. Tumor biomarkers as appropriate for each cancer.  
10. Cyclophosphamide for Cohorts 2 and 4 subjects only. Cohort 4 permanently closed with protocol V5. Please refer to Section 6.4 for additional details.  
11. RCL VSV-G testing will not be routinely performed as of Protocol V8.  Blood samples will be collected and banked at pre-infusion and post-infusion at Months 3, 
6, and 12.  These samples will be used for future RCL VSV-G testing if indicated.  
12. If a subject’s veins are not adequate for apheresis procedure, the subject may have a central venous apheresis catheter line placed by interventional radiology.  
It is recommended that the patient have an absolute lymphocyte count (ALC) ≥500/µl, prior to undergoing apheresis.  If the patient’s ALC is <500/µl, it is 
recommended that a lymphocyte subset analysis (CD3, CD4, CD8 counts) be performed to confirm that the patient has an absolute CD3 count of ≥150/µl.  If the 
absolute CD3 count is <150/µl, it is recommended that the leukapheresis procedure be delayed until their ALC is ≥500/µl or absolute CD3 count is ≥150/µl.  Up 
to a 4-week delay may occur; following this, further discussion is needed with the study PI and the CVPF prior to proceeding.   
13. Performed at Months 3 and 6. CT scans within 4 weeks of Month 3 and 6 visits are acceptable.  
14. Month 2 only 
15. Chemistry panel includes sodium, potassium, chloride, CO2, blood urea nitrogen, creatinine, glucose, phosphate, total protein, albumin, calcium, alkaline 
phosphatase, total bilirubin, ALT, AST, uric acid, LDH. 
16. A CBC with differential and comprehensive chemistry panel must be performed within 48 hours prior to the huCART-meso infusion.  If already performed within 
this window, these laboratory tests do not need to be repeated on Day 0.  
17. A baseline tumor biopsy will be performed prior to huCART-meso infusion (and cyclophosphamide administration if applicable), if the subject has an accessible 
tumor. The baseline biopsy may occur any time prior to infusion between Day -14 to Day -1.  This baseline biopsy sample will be used to evaluate the level of 
mesothelin expression (using GeoMx Digital Profiling analysis; for exploratory purposes only) and if feasible, other immune markers at baseline.  If a subject does 
not have an accessible tumor or a biopsy is not felt to be clinically appropriate, an archived tumor tissue specimen may be obtained for research purposes.  Please 
refer to the Tissue Handling Manual for complete details. 
18. Collection of adverse events will begin at the time of initiation of study treatment (lymphodepleting chemotherapy or huCART-meso cell infusion depending on 
cohort assignment). Cohort 5 Participants (Effective Protocol Amendment V11) Only: At the time alternative therapy for their disease is initiated, subjects will 
only be followed for protocol-defined adverse events (PDAES) as defined in Section 9.1.6.  Any events ongoing at the time alternative treatment is initiated must 
continued to be followed through resolution.  
19. INR at screening only 
20. Physical examination to include a visual examination of the throat. If toxicity is suspected, please consult with a Pulmonology Study Investigator.  
21. Tumor biopsy to be performed at Day 14 (±7 days). This biopsy sample will be used to evaluate the level of mesothelin expression (using GeoMx Digital Profiling 
analysis; for exploratory purposes only) and if feasible, other immune markers. Please refer to the Laboratory Manual for complete details. 
22. Only ferritin and CRP required; other labs repeated as clinically indicated. 
23. For suspected brain metastasis (performed within 8 weeks of eligibility confirmation by a physician-investigator).   
24. Baseline scans should be obtained within 28 days prior to infusion of huCART-meso cells and after any cancer therapy administered between collection and 
huCART-meso infusion.  In applicable cohorts, baseline scans should also be obtained prior to cyclophosphamide administration.  
25. Viral serologies:  HIV, Hepatitis B surface antigen (HBsAg), Hepatitis B surface antibody, Hepatitis B core antibody, and HIV Hepatitis C antibody. If the HCV 
antibody is positive, a screening HCV RNA by any RT-PCR or bDNA assay must be performed. Eligibility will be determined based on the screening value. The test 
is not required if documentation of a negative result of a HCV RNA test performed within 60 days prior to screening is provided. 
26. Collected at Months 2, 3. 

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27. A mini-apheresis procedure (~5 L) will also be performed at Day 28 for research purposes.  A 60 ml blood draw (6 purple top tubes) may be substituted for the 
mini-apheresis procedure at the discretion of the treating investigator. 
28. Testing for huCART-meso persistence by q-PCR will occur at pre- and all post-infusion study visits.  Additional testing may also be performed at unscheduled time 
points at the discretion of the Sponsor. This analysis will continue until any 2 sequential tests are negative documenting loss of CAR T cells. Please refer to Section 
7.2 for additional details.  
29. At the Day 14 study visit, four 10mL purple top tubes will be collected. 
30. Prior antineoplastic therapies up through study treatment will be collected.  Additional antineoplastic therapy received post study treatment and while on study, 
will also be collected. 
31. During post-infusion observation, the subject will undergo vital sign assessments (temperature, respiration rate, heart rate, blood pressure, and oxygen 
saturation by pulse oximetry) every 4-6 hours (+/- 30 minutes) from the end of the infusion vital sign monitoring period until 48 hours post infusion.  Additional 
monitoring may be performed per clinical discretion. 
32. Performed per Apheresis Unit policy.  It is recommended that the patient have an absolute lymphocyte count (ALC) ≥500/µl prior to undergoing apheresis.  If the 
patient’s ALC is <500/µl, it is recommended that a lymphocyte subset analysis (CD3, CD4, CD8 counts) be performed to confirm that the patient has an absolute 
CD3 count of ≥150/µl.  If the absolute CD3 count is <150/µl, it is recommended that the leukapheresis procedure be delayed until their ALC is ≥500/µl or absolute 
CD3 count is ≥150/µl.  Up to a 4-week delay may occur; following this, further discussion is needed with the study PI and the CVPF prior to proceeding. 
33. The subject will remain inpatient for observation for a minimum of 48 hours after the huCART-meso infusion per Section 6.6.  The subject may then be discharged 
in accordance with hospital policy after this observation period is complete and the subject is medically stable.  The subject may remain hospitalized beyond this 
protocol-required window if deemed necessary for medical management of serious adverse events. 
34. All subjects must undergo a Respiratory Virus Panel (RVP; inclusive of SARS-CoV-2) within 10 days prior to the planned huCART-meso infusion. If the subject is 
positive for influenza, Tamiflu® or equivalent, should be administered per package insert. The subject must complete treatment prior to receiving 
lymphodepleting chemotherapy (if applicable) and huCART-meso cells. The test does not need to be repeated prior to these infusion(s); however, if influenza 
sign and symptoms are present, the infusion(s) should be delayed until the subject is asymptomatic. If the subject is positive for another virus on the RVP, the 
infusion(s) will be delayed for at least 7 days to be sure clinical symptoms of a viral infection do not develop, or longer if clinically appropriate for the respective 
pathogen. If clinical symptoms develop, the infusion(s) will be delayed until resolution of these symptoms. 
35. Cohort 5 subjects only: Pleural Fluid will be collected on Day 0 prior to instillation of huCART-meso cells and at post-infusion follow-up visits through Day 28 as 
clinically appropriate.  Pleural fluid will not be collected on Day 1 and Day 2 post-infusion unless clinically indicated.  If collected as part of routine care at other 
timepoints, a sample of pleural fluid will be collected for research purposes.   
36. Monthly visits are defined as 28 day or 4 week time periods.  
37. Cohort 5 Participants (Effective Protocol Amendment V11) Only: The ICE Score may be assessed by investigators or trained study staff (study coordinators or 
research nurses).  The total ICE Score should be assessed on a 10-point scale. Therefore, if any of the assessments are missed, an ICE score cannot be reported.  
If certain assessments cannot be performed by the subject (e.g., writing sample), this individual assessment will be scored as a zero. Please refer to Appendix 5 
for the ICE scoring criteria. 
 

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This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor. 
2. Additional blood draws and tissue collection may be performed at the discretion of the investigator (for example, to evaluate unexpected clinical events). 
Moreover, additional tissue and fluid collections from the standard of care procedures may be used for research studies.  
3. Tumor Imaging: CT imaging as clinically indicated as per patient population and disease status. MRI scans may be substituted at the investigator’s discretion. 
Additional scans may be performed as clinically appropriate.  Scans may be performed with or without contrast. At the screening visit, a CT performed within 8 
weeks of confirmation of eligibility by a physician-investigator is acceptable.  
4. Research blood samples are collected to evaluate T cell persistence, cytokines, anti-CAR and anti-tumor immune responses.  
5. Subjects have the option for a second apheresis in case the T cell product is not successfully manufactured from the first apheresis. Refer to Section 6.2 for 
additional details.    
6. May be performed post-huCART-meso infusion if CRS is suspected, or as clinically indicated. 
7. Blood draw before infusion and ~1 hour after T cell infusion 
8. EKG at month 6 only 
9. Tumor biomarkers as appropriate for each cancer.  
10. Please refer to Section 6.4 for additional details.  
11. RCL VSV-G testing will not be routinely performed as of Protocol V8.  Blood samples will be collected and banked at pre-infusion and post-infusion at Months 3, 
6, and 12.  These samples will be used for future RCL VSV-G testing if indicated. 
12. If a subject’s veins are not adequate for apheresis procedure, the subject may have a central venous apheresis catheter line placed by interventional radiology.  
It is recommended that the patient have an absolute lymphocyte count (ALC) ≥500/µl, prior to undergoing apheresis.  If the patient’s ALC is <500/µl, it is 
recommended that a lymphocyte subset analysis (CD3, CD4, CD8 counts) be performed to confirm that the patient has an absolute CD3 count of ≥150/µl.  If the 
absolute CD3 count is <150/µl, it is recommended that the leukapheresis procedure be delayed until their ALC is ≥500/µl or absolute CD3 count is ≥150/µl.  Up 
to a 4-week delay may occur; following this, further discussion is needed with the study PI and the CVPF prior to proceeding.   
13. Performed at Months 3 and 6. CT scans within 4 weeks of Month 3 and 6 visits are acceptable.  
14. Month 3 only. 
15. Chemistry panel includes sodium, potassium, chloride, CO2, blood urea nitrogen, creatinine, glucose, phosphate, total protein, albumin, calcium, alkaline 
phosphatase, total bilirubin, ALT, AST, uric acid, LDH. 
16. Subjects will be asked to sign a separate pre-screening consent form requesting permission to test their tumor for mesothelin expression.  Evaluation of 
mesothelin expression will occur on archived tumor tissue, if the patient has not had an anti-mesothelin directed therapy since the collection of the archived 
sample.  However if archived tumor tissue is not available, a biopsy may be performed. If the mesothelin expression of the subjects’ tumor is known prior to 
signing the pre-screening consent for this study, the results of this testing will need to be confirmed as part of the subjects’ participation on this protocol. If a 
fresh biopsy is performed to evaluate mesothelin expression, samples will also be collected for research analysis.  Please refer to the Tissue Handling Manual for 
additional information.  Once mesothelin expression has been confirmed, subjects may proceed to the next step and be presented the main informed consent 
for the study.  
17. A baseline tumor biopsy will be performed prior to huCART-meso infusion (and cyclophosphamide administration if applicable), if the subject has an accessible 
tumor. The baseline biopsy may occur any time prior to infusion between Day -14 to Day -1.  This baseline biopsy sample will be used to evaluate the level of 
mesothelin expression and if feasible, other immune markers at baseline.  If the subject had a fresh biopsy at pre-screening in order to evaluate mesothelin 
expression, a repeat biopsy at the pre-infusion timepoint is not required.  
18. Collection of adverse events will begin at the time of initiation of study treatment (lymphodepleting chemotherapy or huCART-meso cell infusion depending on 
cohort assignment). 

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This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor. 
19. INR at screening only 
20. Physical examination to include a visual examination of the throat. If toxicity is suspected, please consult with a Pulmonology Study Investigator.  
21. Tumor biopsy to be performed at Day +14 (±7 days) after the 2nd huCART-meso infusion. Please refer to the Laboratory Manual for complete details. 
22. Only ferritin and CRP required; other labs repeated as clinically indicated. 
23. For evaluation of brain metastasis for lung adenocarcinoma patients or suspected brain metastasis in other diseases (performed within 8 weeks of eligibility 
confirmation by a physician-investigator.   
24. Baseline scans should be obtained within 28 days prior to the first infusion of huCART-meso cells and after any cancer therapy administered between collection 
and huCART-meso infusion.  Baseline scans should also be obtained prior to cyclophosphamide administration.  
25. Viral serologies:  HIV, Hepatitis B surface antigen (HBsAg), Hepatitis B surface antibody, Hepatitis B core antibody, and HIV Hepatitis C antibody. If the HCV 
antibody is positive, a screening HCV RNA by any RT-PCR or bDNA assay must be performed. Eligibility will be determined based on the screening value. The test 
is not required if documentation of a negative result of a HCV RNA test performed within 60 days prior to screening is provided. 
26. Additional infusions may be performed within a +3 week window from the targeted infusion days [Day 21 (+3 weeks) and Day 42 (+3 weeks)].  Given the allowable 
window for these additional infusions, the timing of post-infusion safety follow-up visits will be dependent on the actual timing of the additional huCART-meso 
infusions.  In summary, the timing of the post-infusion safety follow-up visits will be calculated as the actual study day they occurred post Infusion #2 and Infusion 
#3 (i.e. + 6 days post Infusion #2, +7 days post Infusion #2, +14 days post Infusion #3, etc.).  This should be recorded as the actual study day, even if an assessment 
falls within the allowable visit window.  In addition, the study day from Day 0 (the initial huCART-meso infusion) must also be captured.  Example: Infusion # + 
Study Visit Day Post Infusion/Study Visit Day from Day 0 = Infusion #2 Day +6/Day 28. Please refer to Section 6.8.3 for complete details. If an infusion is omitted, 
these safety follow-up visits will not be required. If an infusion is delayed, these additional safety follow-up visits will be shifted to align with the timing of the 
infusion.   
27. A mini-apheresis procedure (~5 L) will also be performed for research purposes at Day +21 (+/- 7 days) after the 3rd huCART-meso infusion (or the last huCART-
meso infusion if all three infusions are not received for any reason).   A 60 ml blood draw (6 purple top tubes) may be substituted for the mini-apheresis procedure 
at the discretion of the treating investigator. 
28. Testing for huCART-meso persistence by q-PCR will occur at pre- and all post-infusion study visits.  Additional testing may also be performed at unscheduled time 
points at the discretion of the Sponsor. This analysis will continue until any 2 sequential tests are negative documenting loss of CAR T cells. Please refer to Section 
7.2 for additional details.  
29. At the Day +14 study visit post each huCART-meso infusion, four 10mL purple top tubes will be collected. 
30. Prior antineoplastic therapies up through study treatment will be collected.  Additional antineoplastic therapy received post study treatment and while on study, 
will also be collected. 
31. During post-infusion observation, the subject will undergo vital sign assessments (temperature, respiration rate, heart rate, blood pressure, and oxygen 
saturation by pulse oximetry) every 4-6 hours (+/- 30 minutes) from the end of the infusion vital sign monitoring period until 48 hours post infusion.  Additional 
monitoring may be performed per clinical discretion. 
32. Performed per Apheresis Unit policy.  It is recommended that the patient have an absolute lymphocyte count (ALC) ≥500/µl prior to undergoing apheresis.  If the 
patient’s ALC is <500/µl, it is recommended that a lymphocyte subset analysis (CD3, CD4, CD8 counts) be performed to confirm that the patient has an absolute 
CD3 count of ≥150/µl.  If the absolute CD3 count is <150/µl, it is recommended that the leukapheresis procedure be delayed until their ALC is ≥500/µl or absolute 
CD3 count is ≥150/µl.  Up to a 4-week delay may occur; following this, further discussion is needed with the study PI and the CVPF prior to proceeding. Additional 
routine laboratory testing to be performed per Apheresis Unit policies/procedures. 

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This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor. 
33. The subject will remain inpatient for observation for a minimum of 48 hours after each huCART-meso infusion per Section 6.6.  The subject may then be 
discharged in accordance with hospital policy after this observation period is complete and the subject is medically stable.  The subject may remain hospitalized 
beyond this protocol-required window if deemed necessary for medical management of serious adverse events. 
34. All subjects must undergo a Respiratory Virus Panel (RVP; inclusive of SARS-CoV-2) within 10 days prior to the first planned huCART-meso infusion and prior to 
receipt of lymphodepleting chemotherapy. If the subject is positive for influenza, Tamiflu® or equivalent, should be administered per package insert. The subject 
must complete treatment prior to receiving lymphodepleting chemotherapy (if applicable) and huCART-meso cells. The test does not need to be repeated prior 
to these infusion(s), however if influenza sign and symptoms are present, the infusion(s) should be delayed until the subject is asymptomatic. If the subject is 
positive for another virus on the RVP, the infusion(s) will be delayed for at least 7 days to be sure clinical symptoms of a viral infection do not develop. If clinical 
symptoms develop, the infusion(s) will be delayed until resolution of these symptoms. 
35. Performed Day +14 (+/- 7 days) after the huCART-meso Infusion #2.  If huCART-meso Infusion #2 is not performed for any reason, the post-infusion biopsy/tumor 
imaging will be performed at the time the decision is made by the physician-investigator not to administer additional infusions.  Tumor imaging may also be 
performed at any time as per clinical discretion.  
36. Cohort 6 subjects may receive up to two additional IV infusions of huCART-meso cells at the same dose level, if determined clinically appropriate by the physician-
investigator.  Each additional infusion may be given approximately 21 and 42 days after the Day 0 infusion. huCART-meso Infusion #2 is targeted for Day 21 (+3 
weeks) and huCART-meso Infusion #3 is targeted for Day 42 (+ 3 weeks).  Additional huCART-meso infusions performed outside of this window require approval 
from the Principal Investigator and Sponsor Medical Director. The subject must be evaluated for the criteria in Section 6.8.2 prior to each additional infusion.   
Subjects will not receive lymphodepleting chemotherapy prior to additional huCART-meso infusions.  
37. Study visit time point is to be calculated from Day 0 (initial huCART-meso infusion). Monthly visits are defined as 28 day or 4 week time periods.  
38. Subjects must undergo a Respiratory Virus Panel (RVP; inclusive of SARS-CoV-2) within 10 days prior to each additional huCART-meso cell infusion. If the subject 
is positive for influenza, Tamiflu® or equivalent, should be administered per package insert. The subject must complete treatment prior to receiving huCART-
meso cells. The RVP does not need to be repeated prior to infusion; however, if influenza signs and symptoms are present, the infusion should be delayed until 
the subject is asymptomatic. If the subject is positive for another virus on the RVP, the infusion will be delayed for at least 7 days to be sure clinical symptoms of 
a viral infection do not develop. If clinical symptoms develop, the infusion will be delayed until resolution of these symptoms. 
39. A CBC with differential and comprehensive chemistry panel must be performed within 48 hours prior to cyclophosphamide administration.  If already performed 
within this window, these laboratory tests do not need to be repeated the day of cyclophosphamide administration. 
40. A CBC with differential and comprehensive chemistry panel must be performed within 48 hours prior to the huCART-meso infusion (and after receipt of 
lymphodepleting chemotherapy if applicable).  If already performed within this window, these laboratory tests do not need to be repeated on the day of the 
huCART-meso infusion.  
41. Subjects will first be asked to sign a pre-screening consent to collect information from their medical history and to test their tumor for mesothelin expression. 
Once mesothelin expression has been confirmed, subjects may be presented the main informed consent for the study.   
42. If the additional huCART-meso infusions are delayed by greater than 7 days, or not performed for any reason, the additional infusion study visits [at Day 21 and 
Day 42] will still be performed as scheduled, however they will be repurposed as a safety follow-up visit only. These safety follow-up visits will be identified as 
the actual study visit day from Day 0 (i.e. Day 26) and should be performed within +7 days of the planned study timepoint. If the additional huCART-meso infusions 
are then subsequently performed within the protocol allowable window (+3 weeks), the actual infusion day will be calculated as the actual study visit day from 
Day 0 (i.e. Day 35) and the study visit assessments required for an infusion visit will be repeated prior to the infusion.  
 
 
 

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This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor. 
3. Tumor Imaging: CT imaging as clinically indicated as per patient population and disease status. MRI scans may be substituted at the investigator’s discretion. 
Additional scans may be performed as clinically appropriate.  Scans may be performed with or without contrast. At the screening visit, a CT performed within 8 
weeks of confirmation of eligibility by a physician-investigator is acceptable.  
4. Research blood samples are collected to evaluate T cell persistence, cytokines, anti-CAR and anti-tumor immune responses.  
5. Subjects have the option for a second apheresis in case the T cell product is not successfully manufactured from the first apheresis. Refer to Section 6.2 for 
additional details.    
6. May be performed post-huCART-meso infusion if CRS is suspected, or as clinically indicated. 
7. Blood draw before infusion and ~1 hour after T cell infusion 
8. EKG at month 6 only 
9. Tumor biomarkers as appropriate for each cancer.  
10. Lymphodepleting chemotherapy will consist of cyclophosphamide 300 mg/m2/day and fludarabine 30 mg/m2/day given over 3 days by intravenous infusion.  
Lymphodepleting chemotherapy will be scheduled such that the last day of chemotherapy is 3 days (+/- 1 day) prior to the 1st infusion of huCART-meso cells.  
Please refer to Section 6.4 for additional details.  
11. RCL VSV-G testing will not be routinely performed as of Protocol V8.  Blood samples will be collected and banked at pre-infusion and post-infusion at Months 3, 
6, and 12.  These samples will be used for future RCL VSV-G testing if indicated. 
12. If a subject’s veins are not adequate for apheresis procedure, the subject may have a central venous apheresis catheter line placed by interventional radiology.   
13. Performed at Months 3 and 6. CT scans within 4 weeks of Month 3 and 6 visits are acceptable.  
14. Month 3 only. 
15. Chemistry panel includes sodium, potassium, chloride, CO2, blood urea nitrogen, creatinine, glucose, phosphate, total protein, albumin, calcium, alkaline 
phosphatase, total bilirubin, ALT, AST, uric acid, LDH. 
16. A CBC with differential and comprehensive chemistry panel must be performed within 48 hours prior to the huCART-meso infusion (and after receipt of 
lymphodepleting chemotherapy).  If already performed within this window, these laboratory tests do not need to be repeated on the day of the huCART-meso 
infusion.  
17. A baseline tumor biopsy will be performed prior to lymphodepleting chemotherapy and huCART-meso infusion, if the subject has an accessible tumor. The 
baseline biopsy may occur any time prior to infusion between Day -14 to Day -1.  This baseline biopsy sample will be used to evaluate the level of mesothelin 
expression (using GeoMx Digital Profiling analysis; for exploratory purposes only) and if feasible, other immune markers at baseline.   If a subject does not have 
an accessible tumor or a biopsy is not felt to be clinically appropriate, an archived tumor tissue specimen may be obtained for research purposes. Please refer to 
the Tissue Handling Manual for complete details. 
18. Collection of adverse events will begin at the time of initiation of lymphodepleting chemotherapy. Effective Protocol Amendment V11 Only: At the time 
alternative therapy for their disease is initiated, subjects will only be followed for protocol-defined adverse events (PDAES) as defined in Section 9.1.6.  Any 
events ongoing at the time alternative treatment is initiated must continue to be followed through resolution. 
19. Subjects must be evaluated by a physician-investigator for eligibility to receive huCART-meso cells according to criteria in Section 6.5.  The 1st huCART-meso 
infusion will occur via intraperitoneal (i.p.) administration. Subsequent infusion will take place via intravenous (IV) administration.  
20. Physical examination to include a visual examination of the throat. If toxicity is suspected, please consult with a Pulmonology Study Investigator.  
Tumor biopsy to be performed at Day +14 (±7 days) after the 1st huCART-meso infusion. This biopsy sample will be used to evaluate the level of mesothelin 
expression (using GeoMx Digital Profiling analysis; for exploratory purposes only) and if feasible, other immune markers.  
21.  Please refer to Section 6.9.1 for additional details. Please refer to the Laboratory Manual for complete details. 

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CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor. 
22. Only ferritin and CRP required; other labs repeated as clinically indicated. 
23. For evaluation of suspected brain metastasis (performed within 8 weeks of eligibility confirmation by a physician-investigator).   
24. Baseline scans should be obtained within 28 days prior to the first infusion of huCART-meso cells and after any cancer therapy administered between collection 
and huCART-meso infusion.  Baseline scans should also be obtained prior to administration of lymphodepleting chemotherapy.  
25. Viral serologies:  HIV, Hepatitis B surface antigen (HBsAg), Hepatitis B surface antibody, Hepatitis B core antibody, and HIV Hepatitis C antibody. If the HCV 
antibody is positive, a screening HCV RNA by any RT-PCR or bDNA assay must be performed. Eligibility will be determined based on the screening value. The test 
is not required if documentation of a negative result of a HCV RNA test performed within 60 days prior to screening is provided. 
26. Additional infusions may be performed within a +3 week window from the targeted infusion days [Day 21 (+3 weeks) and Day 42 (+3 weeks)].  Given the allowable 
window for these additional infusions, the timing of post-infusion safety follow-up visits will be dependent on the actual timing of the additional huCART-meso 
infusions.  In summary, the timing of the post-infusion safety follow-up visits will be calculated as the actual study day they occurred post Infusion #2 and Infusion 
#3 (i.e. + 6 days post Infusion #2, +7 days post Infusion #2, +14 days post Infusion #3, etc.).  This should be recorded as the actual study day, even if an assessment 
falls within the allowable visit window.  In addition, the study day from Day 0 (the initial huCART-meso infusion) must also be captured.  Example: Infusion # + 
Study Visit Day Post Infusion/Study Visit Day from Day 0 = Infusion #2 Day +6/Day 28. Please refer to Section 6.9.3 for complete details. If an infusion is omitted, 
these safety follow-up visits will not be required. If an infusion is delayed, these additional safety follow-up visits will be shifted to align with the timing of the 
infusion.   
27. At the Day +14 study visit post huCART-meso Infusion #2 and Infusion #3, up to 60mL (6 purple top tubes) will be collected.  If a subject does not receive either 
huCART-meso Infusion #2 or Infusion #3, the subject will undergo this 60mL blood draw at the Day 42 (+7) Safety Follow-up Visit. 
28. Testing for huCART-meso persistence by q-PCR will occur at pre- and all post-infusion study visits.  Additional testing may also be performed at unscheduled time 
points at the discretion of the Sponsor. This analysis will continue until any 2 sequential tests are negative documenting loss of CAR T cells. Please refer to Section 
7.2 for additional details.  
29. If the additional huCART-meso infusions are delayed by greater than 7 days, or not performed for any reason, the additional infusion study visits [at Day 21 and 
Day 42] will still be performed as scheduled, however they will be repurposed as a safety follow-up visit only. These safety follow-up visits will be identified as 
the actual study visit day from Day 0 (i.e. Day 26) and should be performed within +7 days of the planned study timepoint. If the additional huCART-meso infusions 
are then subsequently performed within the protocol allowable window (+3 weeks), the actual infusion day will be calculated as the actual study visit day from 
Day 0 (i.e. Day 35) and the study visit assessments required for an infusion visit will be repeated prior to the infusion.  
30. Prior antineoplastic therapies up through study treatment will be collected.  Additional antineoplastic therapy received post study treatment and while on study, 
will also be collected. 
31. During post-infusion observation, the subject will undergo vital sign assessments (temperature, respiration rate, heart rate, blood pressure, and oxygen 
saturation by pulse oximetry) every 4-6 hours (+/- 30 minutes) from the end of the infusion vital sign monitoring period until 48 hours post infusion.  Additional 
monitoring may be performed per clinical discretion. 
32. Performed per Apheresis Unit policy.  It is recommended that the patient have an absolute lymphocyte count (ALC) ≥500/µl prior to undergoing apheresis.  If the 
patient’s ALC is <500/µl, it is recommended that a lymphocyte subset analysis (CD3, CD4, CD8 counts) be performed to confirm that the patient has an absolute 
CD3 count of ≥150/µl.  If the absolute CD3 count is <150/µl, it is recommended that the leukapheresis procedure be delayed until their ALC is ≥500/µl or absolute 
CD3 count is ≥150/µl.  Up to a 4-week delay may occur; following this, further discussion is needed with the study PI and the CVPF prior to proceeding. Additional 
routine laboratory testing to be performed per Apheresis Unit policies/procedures. 

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33. The subject will remain inpatient for observation for a minimum of 48 hours after each huCART-meso infusion per Section 6.6.  The subject may then be 
discharged in accordance with hospital policy after this observation period is complete and the subject is medically stable.  The subject may remain hospitalized 
beyond this protocol-required window if deemed necessary for medical management of serious adverse events. 
34. All subjects must undergo a Respiratory Virus Panel (RVP; inclusive of SARS-CoV-2) within 10 days prior to the first planned huCART-meso infusion and prior to 
receipt of lymphodepleting chemotherapy. If the subject is positive for influenza, Tamiflu® or equivalent, should be administered per package insert. The subject 
must complete treatment prior to receiving lymphodepleting chemotherapy (if applicable) and huCART-meso cells. The test does not need to be repeated prior 
to these infusion(s), however if influenza sign and symptoms are present, the infusion(s) should be delayed until the subject is asymptomatic. If the subject is 
positive for another virus on the RVP, the infusion(s) will be delayed for at least 7 days to be sure clinical symptoms of a viral infection do not develop, or longer 
if clinically appropriate for the respective pathogen. If clinical symptoms develop, the infusion(s) will be delayed until resolution of these symptoms. 
35. Performed Day +14 (+/- 7 days) after huCART-meso Infusion #2.  If huCART-meso Infusion #2 is not performed for any reason, tumor imaging and tumor markers 
will be performed at the time the decision is made by the physician-investigator not to administer additional infusions.  Tumor imaging may also be performed 
at any time as per clinical discretion.  
36. Cohort 7 subjects may receive up to two additional infusions of huCART-meso cells via IV administration at the same dose level, if determined clinically 
appropriate by the physician-investigator.  Each additional infusion may be given approximately 21 and 42 days after the Day 0 infusion. huCART-meso Infusion 
#2 is targeted for Day 21 (+3 weeks) and huCART-meso Infusion #3 is targeted for Day 42 (+ 3 weeks).  Additional huCART-meso infusions performed outside of 
this window require approval from the Principal Investigator and Sponsor Medical Director. The subject must be evaluated for the criteria in Section 6.9.2 prior 
to each additional infusion.   Subjects will not receive lymphodepleting chemotherapy prior to additional huCART-meso infusions.  
37. Study visit time point is to be calculated from Day 0 (initial huCART-meso infusion). Monthly visits are defined as 28 day or 4 week time periods.  
38. Subjects must undergo a Respiratory Virus Panel (RVP, inclusive of SARS-CoV-2) within 10 days prior to each additional huCART-meso cell infusion. If the subject 
is positive for influenza, Tamiflu® or equivalent, should be administered per package insert. The subject must complete treatment prior to receiving huCART-
meso cells. The RVP does not need to be repeated prior to infusion; however, if influenza signs and symptoms are present, the infusion should be delayed until 
the subject is asymptomatic. If the subject is positive for another virus on the RVP, the infusion will be delayed for at least 7 days to be sure clinical symptoms of 
a viral infection do not develop, or longer if clinically appropriate for the respective pathogen. If clinical symptoms develop, the infusion will be delayed until 
resolution of these symptoms. 
39. A CBC with differential and comprehensive chemistry panel must be performed within 48 hours prior to the first dose of lymphodepleting chemotherapy, then 
as clinically necessary during remaining chemotherapy days.  If already performed within this window, these laboratory tests do not need to be repeated. 
40. Effective Protocol Amendment V11 Only: The ICE Score may be assessed by investigators or trained study staff (study coordinators or research nurses).  The total 
ICE Score should be assessed on a 10-point scale. Therefore, if any of the assessments are missed, an ICE score cannot be reported.  If certain assessments cannot 
be performed by the subject (e.g., writing sample), this individual assessment will be scored as a zero. Please refer to Appendix 5 for the ICE scoring criteria.