Trial in Progress: Phase 1/2 Study of Donor-Derived Anti-CD33 Chimeric Antigen Receptor Expressing T Cells (VCAR33) in Patients with Relapsed or Refractory Acute Myeloid Leukemia after Allogeneic Hematopoietic Cell Transplantation

Relapse after allogeneic hematopoietic cell transplantation (alloHCT) in patients with acute myeloid leukemia (AML) is associated with a 2-year post-relapse survival rate of less than 20%. Though chimeric antigen receptor (CAR) T cells targeting tumor-associated antigens have demonstrated efficacy in several hematologic malignancies, the CAR T cell experience for relapsed/refractory (R/R) AML is limited. Challenges for autologous AML CAR T cell therapy include inadequate numbers of functional, undifferentiated T cells in the starting material, and the potential presence of AML blasts that may interfere with T cell proliferation and function during the manufacturing process. VCAR33 is a CD33-directed CAR T cell product generated using lymphocytes from each patient's prior allogeneic stem cell donor. CD33 is a preferential target for AML CAR T cell therapy as it is expressed on the majority (>80%) of AML blasts. Manufacturing CAR T cells from healthy starting material will likely eliminate delays and production failures due to lymphopenia and may also improve T cell function. Study NCT05984199 is a multi-center phase 1/2 study evaluating the safety and preliminary efficacy of VCAR33 (Figure 1). The CAR construct used for VCAR33 manufacture contains a lintuzumab-derived binding domain and a CD28 co-stimulatory domain. Key inclusion criteria include adults with relapsed or measurable residual disease positive (MRD+) CD33+ AML after undergoing alloHCT with an 8/8 HLA-matched related or unrelated donor. Patients who have undergone alloHCT with trem-cel, a CD33-deleted allogeneic stem cell product intended to facilitate the post-HCT treatment with CD33-directed therapies, may also participate. Patients will be assigned to one of two study arms based on their disease burden: (A) morphologic disease with ≥ 5% blasts in the bone marrow, or (B) MRD+ defined as < 5% blasts in the bone marrow with ≥ 0.1% CD33+ AML cells by flow cytometry. Each arm will enroll and escalate independently according to a 3+3 trial design, starting at 1 x 106 CAR T cells/kg. Lymphodepletion with fludarabine (total 120 mg/m2) and cyclophosphamide (total 1000 mg/m2) will be given prior to VCAR33 infusion. The dose limiting toxicity monitoring period is 28 days, at which time patients will undergo disease response evaluation. Secondary endpoints include incidence of cytokine release syndrome, graft-vs-host disease, and clinical response. Exploratory endpoints aim to correlate VCAR33 properties with clinical response by characterizing T cell phenotypes within the VCAR33 product and by examining VCAR33 expansion and persistence after infusion. Follow up on study will continue for up to 2 years after infusion. Patients may undergo second alloHCT for consolidation of remission or for rescue of prolonged cytopenia due to on-target off-tumor effects of VCAR33.