Supercharged chimeric antigen receptor T cells in solid tumors
Ayush Pant, Christopher M. Jackson
Ayush Pant, Christopher M. Jackson
Published August 15, 2022
Citation Information: J Clin Invest. 2022;132(16):e162322. https://doi.org/10.1172/JCI162322.
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Commentary

Supercharged chimeric antigen receptor T cells in solid tumors

Abstract

Chimeric antigen receptor (CAR) T cells have demonstrated success in treating select hematological malignancies, but their activity in solid tumors has been comparably modest. Challenges specific to treating solid tumors include trafficking and distribution throughout the tumor site, overcoming the immunosuppressive tumor microenvironment (TME), and identifying antigenic targets that are widely expressed and indispensable to tumor biology. In this issue of the JCI, Tian et al. describe the use of bicistronic CAR T cells that target multiple antigens expressed in neuroblastoma to overcome antigenic heterogeneity. Combining this approach with interventions that enhance T cell trafficking and prevent acquired dysfunction in the TME may lead to a long-awaited breakthrough in the clinical implementation of CAR T cells for the treatment of solid tumors.

Authors

Ayush Pant, Christopher M. Jackson

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Figure 1

BiCisCAR T cells have enhanced efficacy against solid tumors.

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BiCisCAR T cells have enhanced efficacy against solid tumors. (A) Single...
(A) Single target CAR T cells recognize and kill cancer cells expressing their target antigen. However, tumor cells that do not express or downregulate the targeted antigen are resistant to killing by CAR T cells and proliferate. Chronic antigen persistence exhausts the single target CAR T cells as well as endogenous CD8+ T cells and prevents differentiation of a central memory endogenous T cell pool. (B) BiCisCAR T cells secrete increased levels of cytokines compared with single target CAR T cells. These cytokines can promote chemotaxis of inflammatory cells from the bone marrow. BiCisCAR T cells also promote apoptosis with antigen spilling and a robust local immune response. Antigen presenting cells (APCs) activate at the tumor site and migrate to the lymph nodes to prime endogenous T cells. BiCisCAR T cells with low checkpoint expression stimulate an expanded endogenous T cell response, which persists as central memory T cells, enabling tumor control.