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bioRxiv · 10.1101/2021.01.06.425642

Enhanced Solid Tumor Recognition and T cell Stemness with SynNotch CAR Circuits

Hyrenius-Wittsten, A.·Su, Y.·Park, M.·Garcia, J. M.·Perry, N.·Montgomery, G.·Liu, B.·Roybal, K. T.
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Abstract

The lack of highly tumor-specific antigens limits the development of engineered T cell therapeutics because of life-threatening "on-target/off-tumor" toxicities. Here we identify ALPPL2 as a tumor-specific antigen expressed in a spectrum of solid tumors, including mesothelioma. ALPPL2 can act as a sole target for chimeric antigen receptor (CAR) therapy or be combined with tumor-associated antigens such as MCAM or mesothelin in synthetic Notch (synNotch) CAR combinatorial antigen circuits. SynNotch CAR T cells display superior tumor control when compared to CAR T cells to the same antigens by prevention of CAR-mediated tonic signaling allowing T cells to maintain a long-lived memory and non-exhausted phenotype. Collectively, we establish ALPPL2 as a clinically viable target for multiple solid tumors and demonstrate the multi-faceted therapeutic benefits of synNotch CAR T cells. ONE SENTENCE SUMMARYSynNotch CAR circuits targeting novel solid tumor antigens enhance specificity and improve therapeutic efficacy by regulating T cell exhaustion.

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Hyrenius-Wittsten, A., Su, Y., Park, M., Garcia, J. M., Perry, N., Montgomery, G., Liu, B., Roybal, K. T.. 2021-01-07. Enhanced Solid Tumor Recognition and T cell Stemness with SynNotch CAR Circuits. https://doi.org/10.1101/2021.01.06.425642

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