1. Versatile strategy for controlling the specificity and activity of engineered T cells.
- Author
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Ma, Jennifer S. Y., Ji Young Kim, Kazane, Stephanie A., Sei-hyun Choi, Hwa Young Yun, Min Soo Kim, Rodgers, David T., Pugh, Holly M., Singer, Oded, Sun, Sophie B., Fonslow, Bryan R., Kochenderfer, James N., Wright, Timothy M., Schultz, Peter G., Young, Travis S., Chan Hyuk Kim, and Yu Cao
- Subjects
HUMAN T cells ,ANTIGEN receptors ,CANCER treatment ,CELL proliferation ,STOICHIOMETRY ,LABORATORY mice - Abstract
The adoptive transfer of autologous T cells engineered to express a chimeric antigen receptor (CAR) has emerged as a promising cancer therapy. Despite impressive clinical efficacy, the general application of current CAR-T-cell therapy is limited by serious treatment-related toxicities. One approach to improve the safety of CAR-T cells involves making their activation and proliferation dependent upon adaptor molecules that mediate formation of the immunological synapse between the target cancer cell and T-cell. Here, we describe the design and synthesis of structurally defined semisynthetic adaptors we refer to as "switch" molecules, in which anti-CD19 and anti- CD22 antibody fragments are site-specifically modified with FITC using genetically encoded noncanonical amino acids. This approach allows the precise control over the geometry and stoichiometry of complex formation between CD19- or CD22-expressing cancer cells and a "universal" anti-FITC-directed CAR-T cell. Optimization of this CAR-switch combination results in potent, dose-dependent in vivo antitumor activity in xenograft models. The advantage of being able to titrate CAR-T-cell in vivo activity was further evidenced by reduced in vivo toxicity and the elimination of persistent B-cell aplasia in immune-competent mice. The ability to control CAR-T cell and cancer cell interactions using intermediate switch molecules may expand the scope of engineered T-cell therapy to solid tumors, as well as indications beyond cancer therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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