Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells

By Christopher C. Kloss, M. Condomines, M. Cartellieri, M. Bachmann, Michel Sadelain. Nature Biotechnology, 2012

841 citations recorded by the source corpus.

Current T-cell engineering approaches redirect patient T cells to tumors by transducing them with antigen-specific T-cell receptors (TCRs) or chimeric antigen receptors (CARs) that target a single antigen. However, few truly tumor-specific antigens have been identified, and healthy tissues that express the targeted antigen may undergo T cell–mediated damage. Here we present a strategy to render T cells specific for a tumor in the absence of a truly tumor-restricted antigen. T cells are transduced with both a CAR that provides suboptimal activation upon binding of one antigen and a chimeric costimulatory receptor (CCR) that recognizes a second antigen. Using the prostate tumor antigens PSMA and PSCA, we show that co-transduced T cells destroy tumors that express both antigens but do not affect tumors expressing either antigen alone. This 'tumor-sensing' strategy may help broaden the applicability and avoid some of the side effects of targeted T-cell therapies.

Subfields: Biomedical Engineering, Oncology, Radiology, Nuclear Medicine and Imaging

View Paper: https://www.semanticscholar.org/paper/6f4b74eefaf25889359fedc89372ddb28b2862db

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In Biomedical Engineering

In Oncology

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Citations in the corpus

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, methodology): “We chose these signaling domains because they have been used previously for demonstrating combinatorial antigen detection in vivo (Kloss et al., 2013).”
The Principles of Engineering Immune Cells to Treat Cancer (2017, background): “One general strategy has been to express two separate CARs—one for each target antigen—but where one receptor bears the CD3zeta signaling chain of the TCR and the other bears the co-stimulatory motif (Kloss et al., 2013; Lanitis et al., 2013; Wilkie et al., 2012).”
Global Manufacturing of CAR T Cell Therapy (2016, background): “A preclinical study showed that CAR T cells could be used to target tumors expressing two antigens, PSCA and PSMA; the CAR T cells did not kill tumor cells expressing only one of these antigens.(58) Combinatorial antigen recognition strategies may, therefore, be important to consider when designing ”
Precision Tumor Recognition by T Cells With Combinatorial Antigen Sensing Circuits (2016, neutral): “Prior strategies to engineer multi-input control of T cells have focused on expressing two CARs in the same cell, each with partial signaling function and distinct extracellular antigen recognition domains (Kloss et al., 2013; Wilkie et al., 2012).”
Engineering strategies to overcome the current roadblocks in CAR T cell therapy (2019, background): “The promise of this approach has been demonstrated in pre-clinical models of prostate cancer 96 , breast cancer 97 and other experimental systems 98 .”