Abstract IA12: Combating antigen escape with CD19/CD20 bispecific CAR-T cell therapy

Abstract

T cells expressing chimeric antigen receptors (CARs) specific for the B-cell marker CD19 have shown impressive results in the treatment of B-cell malignancies. However, multiple clinical trials have also demonstrated the vulnerability of single-input CD19 CAR-T cell therapy to antigen escape, in which patients relapse with the emergence of CD19 tumor cells. Here, we report on the rational design and systematic optimization of bispecific CAR-T cells that trigger robust cytotoxicity against target cells expressing either CD19 or CD20. We demonstrate that optimized bi-specific CARs can rapidly eliminate large, engrafted tumors in vivo. We further demonstrate the bi-specific CAR-T cells ability to prevent tumor escape while single-input CD19 CAR-T cells succumb to the selective expansion of CD19 mutant cells, which are shown to arise spontaneously in engrafted mice. The CD19-OR-CD20 CAR is fully compatible with existing T-cell manufacturing procedures and implementable by current clinical protocols. These results present an effective solution to the challenge of antigen escape in CD19 CAR T-cell therapy, and they highlight the utility of structure-based rational design in the development of receptors with higher-level complexity. Citation Format: Eugenia Zah, Meng-Yin Lin, Michael C. Jensen, Anne Silva-Benedict, Yvonne Y. Chen. Combating antigen escape with CD19/CD20 bispecific CAR-T cell therapy. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr IA12.

RETRACTED: A Deep Insight Into CAR-T Cell Therapy in Non-Hodgkin Lymphoma: Application, Opportunities, and Future Directions

“…A bispecific receptor consists of two distinguished antigen recognition domains that bind to two separate intracellular domains and are expressed as tandem scFvs in one CAR, or as two different CARs on T cell surface. At current, CD19/CD20-bispecific CAR-T cells have been presented as a new synthetic molecule that, after recognition and binding to target tumor antigens on the surface of malignant cells, can establish a synergistic cascade of executive molecules ( 186 ). If one of the target molecules is not available to CAR T cells for reasons such as removal or mutation of the target antigen on malignant cells, a dual-function machine can largely prevent tumor escape.…”

CAR T cell therapy: A new era for cancer treatment (Review)

“…At present, bispecific CAR CD19/CD20 has been introduced as a novel synthetic molecule that can recognize and bind to more than one targeted tumor antigen on the cancer cell surface. Therefore, it can create a synergistic cascade of effector molecules when it encounters two tumor antigens (53). Additionally, the bispecific CAR conserves the cytolytic capacity of T cells, i.e., if one of the objective molecules is not accessible to CAR T cells due to a cellular hindrance such as mutation of a target antigen or loss of the target antigen commonly found in malignant cells, a bispecific CAR can counterbalance the tumor evasion (54).…”