Gamma Delta CAR T-Cell Therapy Shows Promising Responses in B-Cell Malignancies

ADI-001, a CD20 first-in-class allogeneic gamma delta (γδ) chimeric antigen receptor (CAR) T-cell therapy, was well-tolerated with encouraging preliminary efficacy in patients with B-cell malignancies.

New data on ADI-001 from a phase 1 trial (NCT04735471) were presented by Sattva S. Neelapu, MD, department of lymphoma and myeloma, division of cancer medicine, University of Texas MD Anderson Cancer Center, at the 2022 American Society of Clinical Oncology (ASCO) meeting, held June 3-7, 2022, held both virtually and in Chicago, Illinois.

“As compared with conventional αβ T-cells, γδ CAR T-cells may provide 3 mechanisms of anti-tumor activity, thus potentially limiting the ability for tumor escape. First, they provide innate anti-tumor activity targeting multiple surface proteins selected by evolution to mark tumors for cell killing. Second, they have adaptive anti-tumor activity by the γδ T-cell receptor, and third, they have CAR-mediated anti-tumor activity,” Neelapu said during his presentation.

The trial has enrolled 10 patients with CD20+ aggressive N-cell lymphomas as of May 31, 2022, 8 of which are evaluable: 7 with large B-cell lymphoma (LBCL) and 1 with mantle cell lymphoma (MCL). Patients had a median age of 62 years (range, 45-75) and 5 were male. Most patients were heavily pre-treated and had poor prognostic factors and relatively high tumor burdens. Patients had a median of 4 prior lines of therapy (range, 2-5) and 63% (n = 5) were refractory to the last course of systemic therapy. Median IPI score was 4 (range, 2-5). Three patients with diffuse LBCL (38%) had progressed after prior anti-CD19 therapy, including axicabtagene ciloleucel and lisocabtagene maraleucel.

READ MORE: CD20-Targeted CAR T-Cell Therapy Shows Safety, Good Response Rates in B-Cell Non-Hodgkin Lymphoma

All patients received fludarabine and cyclophosphamide conditioning therapy, whether standard lymphodepletion (sLD) or enhanced lymphodepletion (eLD), which had comparable results. Patients then received 1 of 3 ADI-001 dose levels: 3E7 (DL1; n = 3), 1E8 (DL2; n = 3), or 3E8 cells (DL3; n = 2). Participants overall had an overall response rate (ORR) of 75% and a complete response (CR) rate of 75%. DL2 and DL3 together had an ORR of 80% and a CR rate of 80%. The ORR and CR rates were 100% in 3 patients previously treated with CAR T-cell therapy. Stratified, ORR and CR rates were 67% in DL1 (n = 2), 67% in DL2 (n = 2), and 100% in DL3 (n = 2).

There were no cases of grade 3 or higher cytokine release syndrome (CRS) or immune-effector cell-associated neurotoxicity syndrome (ICANS). There was 1 case of grade 1 ICANS in DL2 which resolved within 24 hours without medical intervention, and which was the only treatment-related adverse event (AE) of special interest. There were 2 cases of CRS in DL1, of which occurred in a patient with COVID-pneumonia. This patient also had an AE of infection. There were no dose-limiting toxicities or cases of graft-versus-host disease. No patients discontinued treatment due to AEs.

Cell destination analyses found that γδ cells preferentially home to tissues including lympho nodes, breast, gastrointestinal, and lung tissue. Although progression free survival and overall survival analyses are not yet available, durability seems to be related to dose level and ADI-001 exposure in the blood. Dose escalation is continuing in the study and a fourth dose level (1E9) has been added to the protocol as well as a potential consolidation dosing at DL3 due to the safety profile and evidence of dose-related increase to ADI-001 exposure.

“In this early data, the efficacy appeared to be quite promising in patients who are heavily pretreated with aggressive B-NHL, including those who had prior CD19 CAR T-cell therapy... This early data also suggests promising durability of responses and preliminarily, there appears to be a dose-related increase in durability... This has the potential to have best-in-class clinical efficacy,” Neelapu said.

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REFERENCE

Neelapu SS, Hamadani M, Miklos DB, et al. A phase 1 study of ADI-001: Anti-CD20 CAR-engineered allogeneic gamma delta (γδ) T cells in adults with B-cell malignancies. Presented at: Presented at: 2022 ASCO Annual Meeting, June 3-7, 2022. Abstract #7509.