Phase 1 Dose-Escalation and Dose-Expansion Study to Evaluate the Safety and Tolerability of Anti-CD7 Allogeneic CAR T-Cells (WU-CART-007) in Patients with CD7+ T-Cell Non-Hodgkin Lymphoma

INTRODUCTION: Effective treatment options for relapsed/refractory T-cell non-Hodgkin lymphoma (T-NHL) represent a significant unmet medical need. Chimeric antigen receptor (CAR) T-cell therapy has offered durable remissions and cures in B-cell malignancies. There are not yet FDA approved CAR T cell therapies for T-NHL, partially due to a lack of suitable markers. One potential therapeutic target is CD7, which is expressed on mature T-cells and NK-cells and is retained in many patients with T-cell lymphoma. In this study (NCT05377827), we hypothesized that CAR T therapy directed against CD7 may offer clinical benefit for patients with CD7+ T-NHL.

METHODS: WU-CART-007 is a CD7-directed, genetically modified, allogeneic, fratricide-resistant, second-generation CAR T-cell product with a 4-1BB costimulatory domain for the treatment of CD7+ hematologic malignancies. These cells have two key changes from conventional, autologous CAR T-cells. First, CD7 is deleted from WU-CART-007. This allows targeting of CD7 without fratricide (killing of WU-CART-007 cells by other WU-CART-007 cells). Second, the T-cell receptor alpha constant (TRAC) is deleted. This prevents WU-CART-007 cells from recognizing antigens other than CD7 and allows for the use of an allogeneic product while limiting the risk Graft-versus-Host-Disease (GvHD). WU-CART-007 has been tested in a recently completed phase 1 dose-escalation study for patients with T-cell acute lymphoblastic leukemia/lymphoma (NCT04984356). In this study, we are testing the safety and efficacy of WU-CART-007 in two cohorts of patients (CD7+ T-NHL and CD7+ AML). Only interim results from the T-NHL cohort are reported here. This phase 1 dose-escalation study uses an accelerated titration 3+3 design with dose-expansion of 9 additional patients for each of the two independent cohorts. All patients must have confirmed CD7 expression by IHC or flow cytometry on pre-treatment biopsy. Patients receive “enhanced” lymphodepletion with fludarabine (30 mg/m² daily x4) and cyclophosphamide (1000 mg/m² daily x3) followed by WU-CART-007 infusion 3 days after the last dose of chemotherapy. The primary objective of Part A (dose escalation) is to determine the recommended phase 2 dose of WU-CART-007 for CD7+ T-NHL. The primary objective of Part B (dose expansion) is to determine the objective response rate of WU-CART-007 for CD7+ T-NHL.

RESULTS: Five patients with T-NHL have received treatment with WU-CART-007, have completed the DLT evaluation period and are evaluable for response. In these 5 patients, toxicities have included grade 4 neutropenia (5 patients), grade 4 thrombocytopenia (5 patients), cytokine release syndrome (grade 1 in 3 patients, grade 2 in 2 patients), 1 patient with grade 2 Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome, and 1 patient with a grade 5 opportunistic fungal infection (mucormycosis). No patients have experienced Immune Effector Cell Associated Neurotoxicity Syndrome or GvHD. Of the 5 patients evaluable for response, 2 achieved a complete remission (CR; 1 with peripheral T-cell lymphoma, 1 with T-cell prolymphocytic leukemia), 2 achieved a partial remission (PR; 1 with T-cell prolymphocytic leukemic/PLL with no evidence of disease by PET/CT or bone marrow biopsy and partial count recovery; 1 with gamma-delta T-cell lymphoma) and 1 had stable disease (SD; patient with gamma-delta T-cell lymphoma). 1 patient died of mucormycosis while in a complete remission on day 37, 2 patients died of disease progression with CD7-negative/dim disease (after PR and SD), 1 patient with T-PLL continues in a PR with no evidence of disease and partial count recovery, and 1 patient with T-PLL continues in CR 4 months after treatment with complete loss of CD7 in the bone marrow despite recovery of blood counts and presence of otherwise normal appearing T-cells. Flow cytometry from peripheral blood has detected expansion of CAR T cells in several patient samples and studies to evaluate persistence of CAR T cells in this patient population are underway.

CONCLUSION: WU-CART-007, a promising therapy in patients with relapsed/refractory T-NHL, has demonstrated early signs of activity in this heavily pretreated patient population. Study enrollment (NCT05377827) is ongoing to determine the safety and preliminary efficacy of WU-CART-007 in patients with CD7+ T-NHL and AML.