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

Multi-institutional Prospective Phase I 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 tumor multi-antigen associated -specific cytotoxic T lymphocytes, to HSCT recipients with high risk AML and MDS.

Patients with evidence of high-risk or relapsed or persistent hematopoietic malignancies (for example but not limited to: acute myeloid leukemia and myelodysplastic syndrome (MDS)) will be eligible for this study.

Patients with high risk for relapse will be eligible to receive planned infusion of allogeneic TAA-T after HSCT (with high risk AML and MDS who have undergone allo-HSCT and are in a hematologic remission).

We will utilize our established protocol for the manufacture of tumor multi-antigen associated specific cytotoxic T lymphocytes. Peripheral blood mononuclear cells will be exposed to antigen presenting cells pulsed with peptides to tumor antigens (PRAME, WT1, Survivin) in a cytokine milieu favorable to T cell expansion/activation, inducing selective expansion of T cells targeted to kill tumor cells. Patients would be monitored for the development of toxicity. In patients with disease at the time of TAA-T infusion, efficacy would be evaluated as a secondary endpoint using standard criteria. Exploratory investigational analyses would include monitoring of cytokine and cellular milieu pre- and post- TAA-T infusion and in vitro characterization of the host tumor, donor lymphocyte product, and TAA-T product.

TAA-T will be infused any time after neutrophil engraftment post-HSCT or day 30, whichever comes first at dose level 4 . Infusions will be within first 5 months post-HSCT.

Patients will receive a TAA-T cell dose of 4 x 107 cells/m2.

Each patient will receive at least one infusion according to the enrolled dose level, where the expected volume of infusion is 1 to 10 cc.

If patients with active disease (defined as MRD+ at the time of TAA-T infusion) do not have ≥ grade 3 toxicity that is possibly, probably, or definitely attributed to TAA-T infusion and fail to rapidly progress with disease requiring urgent therapy, patients may receive a subsequent TAA-T cell dose (infusion #2). A subsequent dose (infusion #2) will also be available for those patients who have stable disease or a mixed, partial, or complete response (including continued complete response) by the International Working Group (IWG) criteria (see section 4.2.1) at the evaluation after the first TAA-T infusion.

Patients who have received at least 2 infusions of TAA-T are eligible to receive up to 6 additional doses (infusion #3 to #8) of TAA-T at monthly intervals each of which will consist of the same cell number as their enrolled dose level. Patients will not be able to receive additional doses until the initial safety profile is completed at 28 days following the second infusion. Notably, these doses will be identical to the treated dose for this patient (i.e. no subsequent dose escalation). Patients would then receive additional doses starting greater than 28 days from second infusion and be treated at the same dose level as he/she has previously received.

Recipient Inclusion Criteria to Enter Protocol:

• Aged 6 months to 80 years.
• Anticipated myeloablative or non-myeloablative allogeneic hematopoietic stem cell transplant.
• Patients with high risk AML and MDS who have received or will receive an allo-HSCT and have not had hematologic relapse of disease.
• Karnofsky/Lansky score of ≥ 50.
• 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

Recipient Exclusion Criteria to Enter Protocol:

• Patients with uncontrolled infections.
• Current evidence of GVHD > grade 2 or bronchiolitis obliterans syndrome, sclerotic GVHD, or serositis.
• Pregnancy (female of childbearing potential).

Recipient Inclusion Criteria for TAA-T Administration:

• Patients with high risk AML and MDS who have received an allo-HSCT and have not had hematologic relapse of disease.
• Steroids less than 0.5 mg/kg/day prednisone or equivalent in the context of no escalation of treatment within the preceding 2 weeks
• Karnofsky/Lansky score of ≥ 50.
• 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).
• Pulse oximetry of > 90% on room air.
• Absolute neutrophil count > 250/ µL (may be supported with Granulocyte colony-stimulating factor (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 TAA-T Administration:

• Patients who received ATG, Campath, or other T cell immunosuppressive monoclonal antibodies within 28 days prior to TAA-T infusion.
• No investigational therapies (under IND, not extensively studied in the current clinical context) within 28 days prior to TAA-T infusion.
• Uncontrolled infections.
• Active Bronchiolitis obliterans syndrome, sclerotic GVHD, or serositis.
• Active acute GVHD or chronic GVHD requiring escalation of treatment within preceding 2 weeks of any grade is exclusion for Arm C patients.
• Pregnancy or lactating (female of childbearing potential).
• Patients who have or will be receiving 2nd allogeneic HSCT

Donor Inclusion Criteria:

• Donors for allogeneic (i.e. HLA matched or mismatched related or unrelated) stem cell transplants who have undergone eligibility evaluation as per FDA regulations outlined in 21 CFR 1271 subpart C. If a donor has been chosen for the transplant based on urgent medical need, that same donor will also be used for TAA-T generation provided that there are no new reasons for ineligibility since the transplant donor evaluation.

• Aged 6 months to 80 years.

• Donor or guardian of pediatric capable of providing informed consent.

• Donor must have completed infectious Disease (ID) testing up to 7 days before or after the collection of blood from the donor (related or unrelated) for TAA-T manufacturing. The following tests will be performed:

  • HBsAg
  • HB Core antibody
  • HIV1/2 NAT
  • Syphilis (T. Pallidum IgG)
  • HTLV I/II
  • CMV total
  • HBV/HCV NAT
  • West Nile Virus NAT.
  • Cruz (Chagas) antibody
  • Hepatitis C

• Female donors of childbearing age must have a negative pregnancy test within 7 days of blood collection for TAA-T manufacturing.

Donor Exclusion Criteria:

• Donation of cells would pose a physical or psychological risk to the donor.
• Female donors of childbearing age who are known to be pregnant.