Evaluating a New Bispecific CAR T-Cell Therapy for B-Cell Lymphomas

In a first-in-human phase I clinical trial of a bispecific anti-CD19/CD20 chimeric antigen receptor (CAR) T-cell therapy, four of five treated patients with lymphoma experienced a complete remission (CR), according to results presented during the American Association for Cancer Research’s 2021 virtual meeting. The authors, led by Sanaz Noelle Ghafouri, MD, from UCLA Medical Center in Los Angeles, California, described the infusions as well-tolerated, with no dose-limiting toxicities.

Approximately half of patients with relapsed/refractory B-cell lymphomas who had an initial disease response to CD19-targeted CAR T-cell therapy will eventually relapse, either due to poor CAR T-cell persistence or CD19 antigen escape, the investigators explained. Preclinical data have demonstrated that engineering of bispecific CAR in naïve/memory T cells (TN/MEM) via lentiviral transduction effectively targets tumor cells, overcomes antigen escape, and enhances CAR T-cell persistence.

In this trial, investigators evaluated a bispecific CD19/CD20-targeting CAR T-cell therapy in five patients with previously treated CD19/CD20-positive B-cell lymphomas. Prior treatment criteria depended on the lymphoma subtype: two or more lines of therapy for diffuse large B-cell lymphoma or primary mediastinal B-cell lymphoma and three or more lines of therapy for mantle cell lymphoma, follicular lymphoma, or chronic lymphocytic leukemia.

To manufacture the T-cell therapy, researchers obtained autologous leukocytes by leukapheresis to be sorted for CD14-/CD25-/CD62L+ TN/MEM cells. Next, they performed lentiviral transduction of the bispecific CD19/CD20 CAR. Following lymphodepletion with fludarabine/cyclophosphamide, patients were infused with CD19/CD20 CAR TN/MEM cells. Four received a dose of 5×107 CAR-positive cells and one received a dose of 2×106 CAR-positive cells.

Patients had previously received a median of four prior lines of therapy, and four patients received bridging therapy.

The authors observed no dose-limiting toxicities. All patients experienced cytokine release syndrome, at a median onset of eight days, but all cases were grade 1. Notably, no patient experienced immune effector cell–associated neurotoxicity syndrome (TABLE).

After a median follow-up of 11.1 months, four patients were in ongoing CR. The patient whose disease did not respond had early disease progression, with CD19- and CD20-negative mediastinal lymphoma at day 14 after CAR infusion.

Median progression-free survival and overall survival were not reached and all responders demonstrated ongoing CAR T-cell persistence (with peak CAR T-cell expansion noted on day 14) and B-cell aplasia by data cutoff, the authors concluded.

Based on these findings, a bispecific CAR T-cell therapy potentially obviates the challenges of the most common causes of relapse after CAR T-cell therapy – poor CAR T-cell persistence and antigen escape mechanisms. However, these findings need to be confirmed in larger patient populations and with longer follow-up.

Study authors report no relevant conflicts of interest.

Reference

Ghafouri SN, Walthers C, Roshandell M, et al. CD19/CD20 bispecific chimeric antigen receptor (CAR) in naive/memory T-cells for the treatment of relapsed or refractory B-cell lymphomas. Abstract #CT007. Presented at the 2021 American Association for Cancer Research Annual Meeting, April 10, 2021.