CART-PSMA-TGFβRDN Cells for Castrate-Resistant Prostate Cancer

This is a Phase I study evaluating the safety and feasibility of lentivirally transduced
PSMA-TGFβRDN autologous CAR T cells administered with and without cyclophosphamide in a 3+3
dose escalation design. Cohort 1 subjects (N=3 or 6) will receive a single dose of 1-3 x
107/m2 lentivirally transduced CART-PSMA-TGFβRDN cells on day 0 without any conditioning
chemotherapeutic regimen. If the number of manufactured CAR T cells does not meet the
pre-specified minimum infused dose of 1 x 107/m2 cells, then dose will not be administered,
and the subject will be replaced in the study. If 1 DLT/3 subjects occurs, the study will
enroll an additional 3 subjects at this dose level. If 0 DLT/3 subjects or 1 DLT/6 subjects
occurs, the study will advance to Cohort 2.

If 2 DLT/3 subjects occurs at dose of 1-3 x 107/m2 cells, then enrollment in this Cohort will
be stopped and the dose will be de-escalated by 10-fold to 1-3 x 106 cells/m2 (Cohort -1). In
this situation, up to 6 subjects will be enrolled in Cohort

-1. Cohort 2 subjects (N=3 or 6) will receive a single dose of 1-3 x 108/m2 lentivirally
transduced CART-PSMA-TGFβRDN cells on day 0 without any conditioning chemotherapeutic
regimen. If the number of manufactured CAR T cells does not meet the protocol-specified
minimum of 1 x 108/m2 cells, but does meet the minimum dose requirement of at least 1 x
107/m2 cells, then the subject may receive the dose and will not be included in the DLT
assessment for Cohort 2. This subject would be replaced for DLT assessment. If, however, the
number of manufactured CAR T cells does not meet the pre-specified minimum infused dose as
outlined for Cohort 1, then no dose will be administered, and the subject will be replaced in
the study. If 1 DLT/3 subjects occurs, the study will enroll an additional 3 subjects at this
dose level. If 0 DLT/3 subjects or 1 DLT/6 subjects occurs, the study will advance to Cohort
3. If 2 DLT/3 subjects occur, then the study will stop and declare maximum tolerated dose
(MTD). Cohorts 1 and 2 will serve to identify the MTD of CART-PSMA-TGFβRDN cells. The maximum
tolerated dose is defined as the highest dose at which 0/3 or 1/6 DLTs occur. Cohort 3
subjects (N=3 or 6) will receive a single infusion at the MTD of lentivirally transduced
CART-PSMA-TGFβRDN cells on day 0, following a single dose of 1.0 gram/m2 of cyclophosphamide
administered up to 4 days prior to the CAR T cells (day -3 ± 1 day). If 0 DLT /3 subjects
occur, the study will enroll an additional 3 patients to confirm tolerability. If 1 DLT/3
subjects occurs, the study will enroll an additional 3 subjects at this dose level. If two of
the initial three subjects experience a DLT, three additional patients will be accrued with a
dose reduction in the lymphodepleting chemotherapy to 500 mg/m2 administered up to 4 days
prior to the CAR T cells (day -3 ± 1 day). The DLT observation period will be 28 days. The
highest dose level where only 0/3 or 1/6 DLTs were observed in a given cohort will be defined
as the MTD. Adverse event reporting will begin on Day 0 (Cohorts 1 and 2) or Day -3 ±1 day
(Cohort 3) and continue through 2 years after the infusion or until subjects begin an
alternative cancer-related treatment, whichever comes first. While on study, subjects will be
continually reassessed for evidence of acute and cumulative toxicities.

Inclusion Criteria:

- Metastatic castrate resistant prostate cancer

≥10% tumor cells expressing PSMA as demonstrated by immunohistochemistry analysis on
fresh tissue.

- Radiographic evidence of osseous metastatic disease and/or measurable, non-osseous
metastatic disease (nodal or visceral)

- Patients > 18 years of age

- ECOG performance status of 0 - 1

- Adequate organ function, as defined by:

- Serum creatinine ≤ 1.5 mg/dl or creatinine clearance ≥ 60 cc/min

- Serum total bilirubin < 1.5x ULN

- Serum ALT/AST < 2x ULN

- Adequate hematologic reserve within 4 weeks of study enrollment as defined by:

- Hgb > 10 g/dl

- PLT > 100 k/ul

- ANC > 1.5 k/ul

- Note: Subjects must not be transfusion dependent

- Evidence of progressive castrate resistant prostate adenocarcinoma, as defined by:

- Castrate levels of testosterone (< 50 ng/ml) with or without the use of androgen
deprivation therapy AND

- Evidence of one of the following measures of progressive disease in the 12 weeks
preceding study enrollment: soft tissue progression by RECIST 1.1 criteria, osseous
disease progression with 2 or more new lesions on bone scan(as per PCWG2 criteria),
increase in serum PSA of at least 25% and an absolute increase of 2ng/ml or more from
nadir (as per PCWG2 criteria)

- Prior therapy with at least one standard 17α lyase inhibitor or second-generation
anti-androgen therapy for the treatment of metastatic castrate resistant prostate
cancer

- Provides written informed consent

- Subjects of reproductive potential must agree to use acceptable birth control methods

Exclusion Criteria:

- Prior treatment with an immune-based therapy for the treatment of prostate cancer,
including cancer vaccine therapies (such as SipuleucelT, PROSTVAC), immune checkpoint
inhibitors,radium-223 and immunoconjugate therapies

- History of an active non-curative non-prostate primary malignancy within the prior 5
years

- Subjects with a rising PSA, but who have never had radiologic evidence of metastatic
disease(i.e. 'biochemical recurrence')

- Subjects who require the chronic use of systemic corticosteroid therapy

- Subjects who have received > 3 prior therapies for the treatment of castrate resistant
prostate cancer (excluding luteinizing hormone-releasing hormone agonists or
antagonists, or first generation anti-androgen therapies). This includes subjects who
received Taxotere in noncastrate setting.

- Subjects with Class III/IV cardiovascular disability according to the New York Heart
Association Classification

- Subjects with symptomatic vertebral metastases affecting spinal cord function (as
determined by clinical history, physical exam, or MRI imaging)

- History of active autoimmune disease requiring immunosuppressive therapy

- Patients with ongoing or active infection.

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

- Active hepatitis B, hepatitis C or HIV infection.