CAR T Cell Immunotherapy for Pancreatic Cancer

This is a Phase I study evaluating the safety and feasibility of lentiviral transduced
huCART-meso cells in 3 cohorts with and without cyclophosphamide in a 3+3 dose escalation
design.

The trial will begin in Cohort 1 and progress to Cohorts 2 and 3 chronologically, depending
upon dose limiting toxicity (DLT) assessment. Subjects will be enrolled serially, but
infusions will be staggered to allow assessment of DLTs for determination of cohort
progression, expansion, or dose de-escalation.

Cohort 1 subjects (N=3-6) will receive a single dose of 1-3x10^7 /m^2 lentiviral transduced
huCART-meso cells on day 0 without any conditioning chemotherapeutic regimen.

Cohort 2 subjects (N=3-6) will receive a single dose of 1-3x10^8 /m^2 lentiviral transduced
huCART-meso cells on day 0 without any conditioning chemotherapeutic regimen.

Cohort 3 subjects (N=3-6) will receive a single dose of 1-3x10^8 /m^2 lentiviral transduced
huCART-meso cells on day 0, following a flat dose of 1 gram/m^2 of cyclophosphamide
administered 2-4 days prior to the huCART-meso cells (day -4 to day -2).

The maximum tolerated dose (MTD) is defined as the dose level at which 0 or 1 subject among 6
subjects in one cohort experiences a DLT within the dose range specified.

Inclusion Criteria:

1. Histologically confirmed unresectable or metastatic pancreatic adenocarcinoma

2. Confirmation of tumor mesothelin expression (≥50% of tumor cells)

3. Failure of at least one prior standard of care chemotherapy for advanced stage
disease.

4. Subjects must have measureable disease as defined by RECIST 1.1 criteria.

5. Patients > 18 years of age.

6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

7. 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
>9 g/dL; (iv) Bilirubin <2.0x the institutional normal upper limit; (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.

8. 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.

9. Provides written informed consent.

10. Subjects of reproductive potential must agree to use acceptable birth control methods,
as described in protocol

Exclusion Criteria:

1. Participation in an interventional research study within 4 weeks prior to enrollment,
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.

2. Active invasive cancer other than pancreatic adenocarcinoma. Patients with active
non-invasive cancers (such as non-melanoma skin cancer, superficial cervical and
bladder cancer, or prostate cancer with PSA level < 1.0) are not excluded.

3. HIV infection

4. Active hepatitis B or hepatitis C infection

5. 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
enrollment visit, with the exception of thyroid replacement.

6. Patients with ongoing or active infection.

7. Planned concurrent treatment with systemic high dose corticosteroids. Patients may be
on a stable low dose of steroids (<10mg equivalent of prednisone) for chronic
respiratory conditions or adrenal insufficiency. Corticosteroids treatment as
anti-emetic prophylaxis on the day of cyclophosphamide administration is allowed per
institutional guidance.

8. Patients requiring supplemental oxygen therapy.

9. Prior therapy with lentiviral gene modified cells.

10. History of allergy or hypersensitivity to study product excipients (human serum
albumin, DMSO, and Dextran 40)

11. Any clinically significant pericardial effusion, Class II-IV cardiovascular disability
according to the New York Heard Association Classification (see Appendix 2) 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.

12. Any clinically significant pleural or peritoneal effusion that cannot be drained with
standard approaches. An indwelling drainage device placed prior to enrollment is
acceptable.

13. Pregnant or breastfeeding women.

No exceptions to eligibility will be granted.