Bispecific Approach Targeting CD19 and CD22 Shows Positive Signs in B-ALL

A strategy of simultaneously targeting CD19 and CD22 appears to be feasible and safe in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), according to a new study.

Writing in the Journal of Hematology & Oncology, corresponding author Weidong Han, PhD, of the Institute of Basic Medicine, Chinese People’s Liberation Army General Hospital, in Beijing, and colleagues noted that the first 2 anti-CD19 chimeric antigen receptor-T (CAR-T) therapies approved by the FDA, tisagenlecleucel and axicabtagene, have shown promising results, but with one major caveat.

“Despite the great successes with CAR T cell therapy in leukemia that have been published previously by our group and others, up to 60% of relapses after CD19 CAR T cell therapy are characterized by CD19 antigen loss, which involves several different mechanisms,” Han and colleagues write.

The authors say improvements are needed in the design of CAR T cell therapy to target antigen loss. One potential mechanism is to target multiple antigens on cancer cells. They write that B-ALL is a “compelling” option to test out such a therapy, since anti-CD22 CAR T cell therapies have also demonstrated efficacy against the cancer.

Furthermore, while it’s relatively easy to achieve complete remission in patients with B-ALL, Han and colleagues note less than half of patients achieve a second complete remission upon relapse. They write that preclinical data have suggested a multi-antigen approach has strong potential for these patients, and note that a number of clinical trials are now underway.

In the current study, Han and colleagues enrolled 6 patients with relapsed/refractory precursor B-ALL into a phase I trial of bispecific CAR T cell therapy. The dosing ranged from 1.7 x 10⁶ to 3 x 10⁶ CAR T cells per kilogram of body weight.

The results were promising. The bispecific therapy triggered “robust” cytolytic activity against the target cells, and all 6 patients achieved minimal residual disease-negative (MRD-negative) complete remission. Autologous CD19/CD22 CAR T cells proliferated and were found in the blood, bone marrow, and cerebrospinal fluid of the patients, and none of the 6 patients experienced neurotoxicity, the investigators reported. Unfortunately, the authors also note that after roughly 5 months a single patient had a relapse with blast cells that no longer expressed CD19 and showed diminished CD22 site density.

Han and colleagues write that B-ALL patients who achieve complete remission after CAR T cell therapy don’t have many options for treatment. A possible, though controversial, choice is allogeneic hematopoietic stem cell transplantation (allo-HSCT). The therapy in this study might help allo-HSCT feasible in certain patients, Han and colleagues write.

“In our study, similar to CD19 CAR T cell therapy, bispecific CD19/CD22 CAR T cell therapy provided a temporal window for patients otherwise ineligible or eligible under very suboptimal conditions (MRD+) to bridge to potentially life-saving allo-HSCT.

Han and colleagues say the results of the study warrant further exploration, and they plan to expand their phase I study to better understand the implications in a larger group of patients.

“The results in these patients with relapsed/refractory B-ALL suggest that direct bispecific CD19/CD22 CAR T cells may be necessary to pre-empt antigen escape without exacerbating toxicity,” they conclude.

Reference

Dai, H., Wu, Z., Jia, H. et al. Bispecific CAR-T cells targeting both CD19 and CD22 for therapy of adults with relapsed or refractory B cell acute lymphoblastic leukemia. J Hematol Oncol 13, 30 (2020). https://doi.org/10.1186/s13045-020-00856-8.