Engineered T cells secreting a CD19/CD3–targeting bispecific T-cell engager (BiTE) antibody (STAb-T19 cells) were more effective than second-generation anti-CD19 CAR T-cells (CAR T-19 cells) at inducing cytotoxicity, avoiding leukemia escape in vitro, and preventing relapse in vivo, Spanish researchers reported in a preclinical study published in Cancer Immunology Research in April.

Leukemia escape in vitro was associated with rapid, drastic CAR-induced internalization of CD-19 that, coupled with lysosome-mediated degradation, led to the emergence of transiently CD19-negative leukemic cells that evaded the immune response of the CAR-T19 cells. By contrast, the STAb-T19 cells induced the formation of canonical immunologic synapses and prevented CD19 downregulation.

Although the two strategies showed similar efficacy in short-term mouse models, in a long-term patient-derived xenograft mouse model the STAb-T19 cells eradicated leukemia cells, whereas leukemia relapse occurred after CAR-T19 therapy.

“In summary, the absence of CD19 downmodulation in the STAb-T19 strategy, coupled with the continued secretion of BiTEs, allows a rapid recruitment of the endogenous T-cell pool, resulting in a fast and efficient elimination of cancer cells, which may prevent the leukemia relapse that is frequently associated with CAR-T19 therapies,” the authors write. “Further studies are needed to fully evaluate the therapeutic capacity and toxicity profile of STAb-T19 cells in a clinical setting.”

• Blanco B, Ramírez-Fernández Á, Bueno C, et al. Overcoming CAR-Mediated CD19 Downmodulation and Leukemia Relapse with T Lymphocytes Secreting Anti-CD19 T-cell Engagers. Cancer Immunol Res. 2022;10(4):498-511. doi:10.1158/2326-6066.CIR-21-0853

Tags: Relapse, Prevention, Targeting, CAR T, BiTEs, leukemia, T-Cell, CAR T-Cell Therapy, CAR T-cell, antibody, effective, CD19 cells, t-cell engager, in vivo