Allogeneic CMV-Specific CD19-CAR T Cells Plus CMV-MVA Triplex Vaccine After Matched Related Donor Hematopoietic Cell Transplant for the Treatment of Patients With High-Risk Acute Lymphoblastic Leukemia

Description

PRIMARY OBJECTIVE:

I. Assess the safety and describe the toxicity profile of allogeneic anti-CD19-CAR CMV-specific T-lymphocytes (CMV-specific CD19-CAR T cells) (allo CMV-specific CD19-CAR T cells) alone and when given in combination with multi-peptide CMV-modified vaccinia ankara vaccine (CMV-MVA) triplex vaccine following allogeneic hematopoietic cell transplantation (alloHSCT) to treat participants with high-risk acute lymphoblastic leukemia (ALL).

SECONDARY OBJECTIVES:

I. Determine the feasibility of allo CMV-specific CD19-CAR T cell manufacturing, as assessed by the ability to meet the required cell dose and product release requirements.

II. Estimate the rate of CMV reactivation after CAR T cell infusion with 100 days of HSCT.

III. Estimate the incidence of secondary graft failure. IV. Estimate the incidence and severity of acute graft versus host disease (GVHD) at 100 days and chronic GVHD at 1 year after transplant.

V. Estimate the rate of 100 day non-relapse mortality. VI. Estimate disease-free and overall survival (DFS/OS) rate at 12 months post alloHSCT.

EXPLORATORY OBJECTIVES:

I. Determine short and longer-term allo CMV-specific CD19-CAR T cell expansion and persistence; II. Assess whether the allo CMV-specific CD19-CAR T cells respond to CMV-MVA triplex vaccine III. Assess whether the allo CMV-specific CD19-CAR T cells respond to CMV-MVA triplex vaccine when administered to participants that received CAR T cells only in the safety lead-in portion in the expansion phased of the study (i.e., once safety of the CMV-MVA triplex vaccine is established in the feasibility portion of the study).

OUTLINE:

DONORS: Donors undergo leukapheresis over 2-4 hours.

PART 1: Patients receive HSCT conditioning regimen followed by alloHSCT per standard of care. Starting 28-49 days after alloHSCT, patients receive allo CMV-specific CD19-CAR T cells intravenously (IV) over 10-15 minutes on day 0. Patients undergo echocardiography (ECHO) or multigated acquisition scan (MUGA), blood and optional cerebrospinal fluid (CSF) sample collection and bone marrow biopsy and aspiration throughout the study. Patient may also undergo chest x-ray and lumbar puncture as needed per principal investigator (PI) discretion and positron emission tomography (PET)/computed tomography (CT) or CT as clinically indicated throughout the study. Additionally, patients with neurological abnormalities at baseline may undergo MRI of brain throughout the study.

PART 2: This is a dose-escalation study of followed by a dose-expansion study.

Patients receive HSCT conditioning regimen followed by alloHSCT per standard of care. Starting 28-49 days after alloHSCT, patients receive allo CMV-specific CD19-CAR T cells IV over 10-15 minutes on day 0. Patients receive CMV-MVA triplex vaccine intramuscularly (IM) on day 28 in the absence of DLTs and may receive an additional CMV-MVA triplex vaccine IM on day 56 in the absence of DLTs during the second evaluation period. Patients undergo ECHO or MUGA, blood and optional CSF sample collection and bone marrow biopsy and aspiration throughout the study. Patient may also undergo chest x-ray and lumbar puncture as needed per PI discretion and PET/CT or CT as clinically indicated throughout the study. Additionally, patients with neurological abnormalities at baseline may undergo MRI of brain throughout the study.

After completion of study treatment, patients are followed up monthly for the first year, then at 18, 24, 30 and 36 months after CAR T cell infusion. Patients are then followed up yearly for up to 15 years.