Multi-institutional Prospective Research of Expanded Multi-antigen Specifically Oriented Lymphocytes for the Treatment of VEry High Risk Hematopoietic Malignancies

This Phase I dose-escalation trial is designed to evaluate the safety of administering
rapidly-generated multi-antigen-specific T lymphocytes, to HSCT recipients or future HSCT
recipients for the treatment or relapsed or refractory hematopoietic malignancies.

This study will first enroll 2 adult patients to each arm (A and B) prior to enrolling
pediatric patients, all of whom will have either relapsed or persistent hematological
malignancies pre- or post- allogeneic hematopoietic transplantation. TAA-CTLT may be
generated from host lymphocytes (pre-HSCT) or donor lymphocytes (post-HSCT) obtained from
either patient PBMC or donor PBMC. TAA-T will ONLY be generated from allogeneic donors for
patients enrolled under Arm C. If a patient has already undergone an allogeneic HSCT, it is
NOT allowed to generate TAA-T from patient blood collected post-HSCT under Arm C.

Four different dosing schedules will be evaluated. Two to four patients will be evaluated on
each dosing schedule (See below). This protocol is designed as a phase I dose-escalation
study.

For Arm A Patients (post HSCT): T cells will be infused any time after neutrophil engraftment
post-HSCT or day 30, whichever comes first.

For Arm B Patients (pre HSCT): T cells will be infused any time >7 days after previous
therapy for relapsed disease.

For Arm C Patients (post HSCT): T cells will be infused any time after neutrophil engraftment
post-HSCT or day 30, whichever comes first.

In each group, a patient will be enrolled to one of the following dosing schedule.

Dose Level One: 5 x 106 cells/m2 Dose Level Two: 1 x 107 cells/m2 Dose Level Three: 2 x 107
cells/m2 Dose Level Four: 4 x 107 cells/m2

Patients will receive at least one infusions according to the enrolled dose level, where the
expected volume of infusion is 1 to 10 cc. Patients will receive cells either because: of
prior refractory disease and/or high risk for relapse and/or detectable disease at the time
of infusion. Group A and Group B patients will use the dose escalation strategy described
above. We strongly recommend that patients should not receive other systemic antineoplastic
agents for at least 45 days after infusion of TAA-specific T-cells (for purposes of
evaluation), although such treatment may be added if deemed critical for patient care by the
attending physician.

Arm C patients will (post HSCT): T cells will be infused any time after neutrophil
engraftment post-HSCT or day 30, whichever comes first, on the top dose level determined in
the safety phase of Arm A, which is dose level 4 : ( 4 x 107 cells/m2)). To continue on Arm
C, patients need to receive TAA-Ts within first 5 months after transplant. If a patient is
enrolled to Arm C and cannot receive cells within the first 5 months after transplant to
constitute pre-emptive therapy, the patient may receive cells on study under the expanded Arm
A cohort group.

For patients on the expanded Arm A cohort, the intended dose level to treat is dose level 4.
However, should insufficient TAA be generated for a TAA infusion at dose level 4 and should
the patient desire to receive the product, a lower dose level may be administered (dose level
1-3).

TAA cells may be infused any time after neutrophil engraftment post-HSCT or day 30, whichever
comes first if patient is post-allo HSCT (Arm A), and at greater than 1 week after prior
cytoreductive therapy if patients is pre-allo HSCT (Arm B). We strongly recommend that
patients should not receive other systemic antineoplastic agents for at least 45 days after
infusion of TAA-specific T-cells (for purposes of evaluation), although such treatment may be
added if deemed critical for patient care by the attending physician and not under IND.
Exclusions to this include: agents that have shown success in disease reduction and safety
after HSCT (to include FLT3 inhibitors and BCR-ABL inhibitors). For autologous recipients,
this could include PD-1 inhibitors or other immune activators if these have been previously
tolerated without autoimmunity; however, allogeneic patients are not eligible to receive
these agents in conjunction with TAA-T cells. If patients with active disease do not have
>grade 3 toxicity that is possibly, probably, or definitely attributed to cells and fail to
rapidly progress with disease requiring urgent therapy, patients may receive subsequent
doses. Subsequent doses will be available for those patients who have stable disease or a
mixed, partial, or complete response by the International Working Group (IWG) criteria at the
evaluation after dose 1. They are eligible to receive up to 6 additional doses of TAA-Ts at
monthly intervals-each of which will consist of the same cell number as their tolerated dose
level. Notably, these doses will be identical to the treated dose for this patient (i.e. no
subsequent dose escalation). Patients will not be able to receive additional doses until the
initial 28 day evaluation for toxicity and efficacy following the second infusion.

Recipient procurement Inclusion criteria

- Patients (Arm A) who have undergone allo-HSCT with high risk for relapse or
residual/recurrent disease (see below) OR patients (Arm B) with relapsed/refractory disease
(> 2 regimens with greater than M1 marrow or persistent HD) with anticipated allo-HSCT pre-
and/or post-HSCT:

Acute lymphoblastic leukemia, Acute myeloid leukemia (AML), Ambiguous lineage leukemia or
lymphoma myelodysplastic syndrome (MDS), Chronic Myelogenous leukemia:

Evidence of active leukemia or lymphoma disease by flow cytometry, morphology, or
cytogenetic evaluation within the marrow or extramedullary sites

Hodgkin's Lymphoma that has failed or are intolerant of Brentuximab, Grey Zone Lymphoma,
ALCL, and mantle cell lymphoma:

Evidence of HD by morphology, PET/CT uptake in a site of previous disease in the absence of
other etiologies ARM C only includes patients with MDS and AML

- Age 6 months to 80 years

- Received prior or anticipated myeloablative or non-myeloablative allogeneic
hematopoietic stem cell transplant

- Karnofsky/Lansky score of > 50 (see appendix B).

- Agree to use contraceptive measures during study protocol participation (when age
appropriate)

- Patient or parent/guardian capable of providing informed consent

- T cell chimerism > 94% if collected from recipient of allo-HSCT (performed within the
last 6 months)

- If the product is procured from the recipient either in the autologous (Arm B) or
allogeneic (Arm A) setting, the absolute lymphocyte count should be greater than or
equal to 600 for procurement. Please note: If a patient has already undergone an
allogeneic HSCT, it is NOT allowed to generate TAA-T from patient blood collected
post-HSCT under Arm C.

Recipient Procurement Exclusion Criteria

- Patients with uncontrolled infections

- Patients with HIV infection

- Current evidence of GVHD > grade 2 or bronchiolitis obliterans syndrome, sclerotic
GVHD, or serositis.

- Pregnancy or lactating (female of childbearing potential)

Recipient Inclusion criteria for initial TAA-T administration and for subsequent infusions

- Steroids less than 0.5 mg/kg/day prednisone or equivalent

- Karnofsky/Lansky score of > 50

- Pulse oximetry of > 90% on room air

- Bilirubin < 2.5 mg/dL, AST/ALT <5x upper limit of normal, Serum creatinine < 1.0 or 2x
the upper limit of normal (whichever is higher)

- Absolute neutrophil count > 250/ µL (may be supported with GCSF)

- Agree to use contraceptive measures during study protocol participation (when age
appropriate)

- Patient or parent/guardian capable of providing informed consent

- LVEF > 50% or LVSF > 27% (performed within the last 6 months) if history of TBI >500
cGy for Arm A and B

- Total chimerism > 50%; or if cancer cells preclude this, donor T cell chimerism > 50%
(performed within the last 6 months)

Recipient Exclusion criteria for initial and subsequent TAA-T infusions

- Patients who received ATG, Campath or other immunosuppressive monoclonal antibodies in
the last 28 days.

- No investigational therapies (under IND, not extensively studied in the current
clinical context) within the last 28 days. For allogeneic HSCT recipients PD-1
inhibitors or other T cell activating agents will be excluded. For Arm B, if the
patient has tolerated these agents without autoimmunity, these may be continued with
the TAA-T infusion.

- Uncontrolled infections

- Active bronchiolitis obliterans syndrome, sclerotic GVHD, or serositis

- Current evidence of GVHD > grade 2 for Arm A and B. Active GVHD of any grade is
exclusion for Arm C patients.

- Pregnancy or lactating (female of child bearing potential)