Precision Tumor Recognition by T Cells With Combinatorial Antigen Sensing Circuits

By Kole T. Roybal, Levi J. Rupp, Leonardo Morsut, Whitney J. Walker, Krista A. McNally, Jason S. Park, Wendell A. Lim. Cell, 2016

918 citations recorded by the source corpus.

SUMMARY T cells can be re-directed to kill cancer cells using chimeric antigen receptors (CARs) or T cell receptors (TCRs). This approach, however, is constrained by the rarity of tumor-specific single antigens. Targeting antigens also found on bystander tissues can cause life-threatening adverse effects. A powerful way to enhance ON-target activity of therapeutic T cells is to engineer them to require combinatorial antigens. Here we engineer a combinatorially activated T cell circuit in which a synthetic Notch receptor for one antigen induces the expression of a CAR for a second antigen. These dual receptor AND-gate T cells are only armed and activated in the presence of dual antigen tumor cells. These T cells show precise therapeutic discrimination in vivo – sparing single antigen “bystander” tumors while efficiently clearing combinatorial antigen “disease” tumors. This type of precision dual receptor circuit opens the door to immune recognition of a wider range of tumors.

Subfields: Biomedical Engineering, Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/1e660c8f8300d1913a7444f977695af5c3ae1f6f

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In Biomedical Engineering

James J. Collins

In Immunology

In Oncology

Citations in the corpus

Cytotoxic CD8+ T cells in cancer and cancer immunotherapy (2020, positive): “To minimise CAR T-cell toxicity and increase therapeutic efficacy, the use of synthetic Notch (SynNotch) receptors and bispecific T-cell engagers (BITEs) might provide ways to customise immune cell responses.(60) SynNotch receptors have demonstrated specificity enhancement in CAR T-cell therapy.”
The Principles of Engineering Immune Cells to Treat Cancer (2017, background): “For example, the synNotch receptor system described earlier can be used to engineer T cells that produce specific secreted payloads in response to recognition of a target antigen (Roybal et al., 2016b).”
Engineering Customized Cell Sensing and Response Behaviors Using Synthetic Notch Receptors (2016, background): “We show in the accompanying manuscript (Roybal et al., 2016) how this flexibility can be used to engineer novel, highly customized T cell response behaviors.”
Engineering T cells with Customized Therapeutic Response Programs Using Synthetic Notch Receptors (2016, positive): “Therefore, this is yet another way to engineer T cells with AND logic where T cells must sense multiple antigens to activate (Kloss et al., 2013; Roybal et al., 2016).”
Universal Chimeric Antigen Receptors for Multiplexed and Logical Control of T Cell Responses (2018, positive): “In addition, to increase tumor specificity, CARs were developed that allow combinatorial antigen sensing (Kloss et al., 2013; Lanitis et al., 2013; Roybal et al., 2016) or target two tumor-specific antigens that can reduce tumor antigen escape rate (Grada et al., 2013; Zah et al., 2016).”