Editors' ChoiceCancer

Bispecific CAR T cells have a dual grasp on tumors

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Science Translational Medicine  28 Oct 2020:
Vol. 12, Issue 567, eabf2636
DOI: 10.1126/scitranslmed.abf2636

Abstract

Bispecific CD19/CD20 chimeric antigen receptor T cells show high efficacy in B cell malignancies.

Cell therapy using chimeric antigen receptor (CAR) T cells is considered a breakthrough in the treatment of multiple tumor types. Non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) are two types of CD19-positive B cell cancers that have been treated with CAR T cells that recognize CD19. Although CD19 is classic molecule on the surface of B cells, targeting CD19 alone can lead to its down-regulation, resulting in treatment failure.

To overcome this limitation, Shah et al. created a bispecific anti-CD19 and anti-CD20 CAR T cell treatment using an automated cell processing platform. In this paper, the authors present the first results of a Phase 1 dose escalation and expansion trial in which patients with NHL or CLL were treated using these bispecific CAR T cells. Twenty-six patients who had previously failed several lines of anti–B cell therapy were enrolled in the study. Overall, the therapy was considered therapeutically safe. Cytokine release syndrome and neurotoxicity were present in 64% and 32% of patients, respectively. The overall response rate was 82%, and all 12 patients who received high dose, freshly produced anti-CD19/20 CAR T cells responded. In contrast, treatment failed in 43% of patients receiving cryopreserved T cells. This suggests that the application of freshly produced T cells might be critical for successful treatment. Finally, three patients did not respond to therapy. All non-responders demonstrated high levels of circulating CAR T cells, suggesting antigen stimulation, but the killing activity of their CAR T cells was markedly decreased.

In summary, dual targeting of tumor cell surface markers by CAR T cells can provide highly effective antitumor therapy for patients with B cell malignancies. For successful clinical use, manufacturing challenges have to be solved to reduce the requirement for fresh, rather than cryopreserved, T cells. Furthermore, resistance to CAR T cell therapy even in the context of antigen availability warrants further research. Targeting of dual antigens on tumor cells is a promising approach that will help pave the way for future CAR T cell therapies.

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