Infusions of tandem CD19- and CD20-targeting chimeric antigen receptor (CAR) T cells (TanCAR7) led to potent and durable antitumor responses in patients with relapsed/refractory non-Hodgkin lymphoma (NHL), according to results from a phase I/IIa trial published in Blood. The study authors, led by Chuan Tong, MD, from the Institute of Basic Medicine at the PLA General Hospital in Beijing, China, also noted that there were no cases of grade ≥3 CAR T-cell–related encephalopathy syndrome (CRES).
“Based on these results, bispecific CAR against both CD19 and CD20 should, in my opinion, a new structure triggering T-cell–signaling transduction,” said corresponding author Weidong Han, PhD, also of PLA General Hospital.
To evaluate the safety and tolerability of this tandem CAR T-cell approach, researchers generated a series of TanCARs targeting CD19 and CD20 in 33 patients with relapsed/refractory NHL. Prior to infusion, patients received lymphodepleting doses of cyclophosphamide and fludarabine. A total of 28 patients received an infusion of TanCAR7 following conditioning chemotherapy.
Adverse events (AEs) were monitored and recorded between enrollment and 3 months following TanCAR7 T-cell infusion. Secondary objectives included efficacy, progression-free survival (PFS), and overall survival.
Most enrolled patients (82%) had stage 3 or 4 disease and 46% of patients had an Eastern Cooperative Oncology Group performance status score of 2. In addition, 25% of patients had bulky disease, 64% were positive for Ki-67 in >70% of baseline lesions, and 61% had extranodal organ involvement. Refractory disease was reported in 86% of patients.
Half of the participants experienced cytokine release syndrome (CRS). Of this group, 10 patients had grade 1 or 2 CRS, and 4 patients had grade 3 CRS. The median time from infusion to the onset of CRS was 1 day (range = 1-5), and the CRS lasted for a median of 6 days (range = 1-9).
The most common grade 3 or higher AEs observed within 1 month of infusion included:
- neutropenia (61%)
- pyrexia (36%)
- thrombocytopenia (25%)
Neurologic events occurred in 6 patients within 4 weeks of infusion, all of which were grade 1 or 2, and included tremor (18%), anxiety (11%), and disturbance in attention (11%). No cases of grade ≥3 CRES were reported. A treatment-associated severe pulmonary infection led to 1 patient death.
In efficacy analyses, the response rates were as follows:
- overall response: 79%
- complete response (CR): 71%
- partial response (PR): 7%
In 4 patients who had CD19-negative disease at baseline, 2 achieved a CR, 1 had a PR, and 1 had progressive disease. According to the investigators, future research should assess “whether TanCAR7 is less effective in such patients.” The median PFS was not reached and the 12-month PFS rate was 64%.
Antigen loss relapse was reported in only 1 patient. CD19 and CD20 double-positive relapse was observed in the remaining patients following T-cell infusion.
Researchers also found that the TanCAR7 T cells formed stable immunologic synapse structures. The immunologic synapse is a discrete structural entity, the investigators explained, which forms following “the ligation of specific activating receptors and leads to the destruction of tumor cells.”
The investigators noted that CAR T cells were detectable for a longer duration in patients who achieved a clinical response than in those without a response. “These clinical data show that TanCAR7 T cells exert a durable antitumor response with a high expansion peak in relapsed/refractory NHL,” they wrote.
Limitations of this study included the small sample size and the lack of a placebo group or active comparator arm.
Dr. Han noted that he and his colleagues have since treated nearly 90 patients with the TanCAR7 T cells and hope to publish the updated data in the near future, which he believes will provide “undoubted” PFS benefits in these patients.
Study authors report no relevant conflicts of interest.
Tong C, Zhang Y, Liu Y, et al. Optimized tandem CD19/CD20 CAR-engineered T cells in refractory/relapsed B-cell lymphoma. Blood. 2020;136(14):1632-1644.