A pioneering bispecific chimeric antigen receptor (CAR) T-cell therapy targeting both CD19 and CD20 antigens has shown early promise in treating patients with relapsed or refractory B-cell lymphoma, according to phase I clinical trial data presented at the AACR Annual Meeting 2021.
The study, led by researchers at UCLA Jonsson Comprehensive Cancer Center, enrolled five patients with B-cell malignancies positive for both CD19 and CD20 tumor antigen expression. After a median follow-up of 13 months, four of the five patients achieved ongoing complete remission, representing a significant advancement in addressing treatment resistance that commonly affects conventional CAR-T therapies.
Addressing Treatment Resistance Through Dual Targeting
"Patients with relapsed/refractory B-cell lymphoma tend to have a more aggressive disease trajectory and limited treatment options," said presenting author Sanaz Ghafouri, MD, a fellow of hematology and oncology at University of California Los Angeles Medical Center. Current anti-CD19 CAR-T cell therapy faces significant limitations, with approximately half of patients relapsing within six months due to lack of CAR-T cell persistence and downregulation of the CD19 target antigen.
The bispecific approach represents a strategic advancement to overcome these challenges. "One of the reasons CAR T cell therapy can stop working in patients is because the cancer cells escape from therapy by losing the antigen CD19," explained Sarah Larson, MD, assistant professor of hematology/oncology at UCLA and principal investigator on the trial. "By using both CD19 and CD20, the thought is that it will be more effective and prevent the loss of the antigen, which is known as antigen escape."
Novel Manufacturing Approach Using Naïve Memory Cells
This study marks the first bispecific CAR-T cell therapy developed with naïve memory T cells to be tested in patients. The researchers hypothesized that this approach might increase CAR-T cell persistence and expansion while limiting relapses due to loss of tumor antigens.
The treatment process involved extracting naïve memory T cells from each patient, engineering them to express an anti-CD19/CD20 CAR, expanding the cells, and infusing them back at one of two different doses (either 5×10⁷ cells or 2×10⁸ cells). The engineered CARs were developed by Yvonne Chen, PhD, co-director of the UCLA Jonsson Comprehensive Cancer Center's Tumor Immunology Program, based on molecular understanding of CAR architecture and antigen binding interactions.
Safety Profile and Clinical Outcomes
The therapy demonstrated a favorable safety profile with no dose-limiting toxicities or immune effector cell-associated neurotoxicity observed in any patients. All patients experienced grade 1 cytokine release syndrome, and all responding patients had ongoing B-cell aplasia at the time of data cutoff.
Patients enrolled in the trial had received a median of four prior lines of therapy, with four patients having received bridging therapy. All had measurable disease after undergoing multiple lines of therapy for various B-cell lymphoma subtypes including primary mediastinal B-cell lymphoma, mantle cell lymphoma, or follicular lymphoma.
The single non-responding patient experienced early disease progression with CD19/CD20-negative disease by day 14 after infusion. Median progression-free and overall survival were not reached at the time of follow-up, and all responding patients continued to have CAR-T cell persistence at data cutoff.
Future Directions and Clinical Implications
"We believe that this investigational anti-CD19/CD20 CAR product has substantial potential to become standard of care in the armamentarium of therapeutics for patients with aggressive B-cell lymphomas," noted Dr. Larson.
The research team plans to expand their patient cohort and evaluate the therapy in additional B-cell lymphoma subtypes. "We are hopeful that dual targeting CD19/CD20 CARs in naïve memory T-cells will provide patients with relapsed or refractory aggressive B-cell lymphomas, that are otherwise chemotherapy-refractory, a chance at a possible cure or at the very least a lasting long-term remission," said Dr. Ghafouri.
The study acknowledges limitations including the small sample size and need for longer-term follow-up. The research was supported by the Parker Institute of Cancer Immunotherapy and a donation from Stephen and Joan Kaplan.
