CAR T therapy targeting solid tumors is restrained by limited infiltration and persistence of those cells in the tumor microenvironment (TME). Here, we developed approaches to enhance the activity of CAR T cells using an orthotopic model of locally advanced breast cancer. CAR T cells generated from Th/Tc17 cells given with the STING agonists DMXAA or cGAMP greatly enhanced tumor control, which was associated with enhanced CAR T cell persistence in the TME. Using single-cell RNA sequencing, we demonstrate that DMXAA promoted CAR T cell trafficking and persistence, supported by the generation of a chemokine milieu that promoted CAR T cell recruitment and modulation of the immunosuppressive TME through alterations in the balance of immune-stimulatory and suppressive myeloid cells. However, sustained tumor regression was accomplished only with the addition of anti–PD-1 and anti–GR-1 mAb to Th/Tc17 CAR T cell therapy given with STING agonists. This study provides new approaches to enhance adoptive T cell therapy in solid tumors.
STING agonist promotes CAR T cell trafficking and persistence in breast cancer
N.P. Restifo’s present address is Lyell Immunopharma, San Francisco, CA.
Disclosures: N. Xu reported a patent to STING on CAR T therapy against solid tumor pending. A.C. Robeson reported personal fees from Precision BioSciences, Inc. outside the submitted work. B.G. Vincent reported "other" from GeneCentric Therapeutics outside the submitted work. N.P. Restifo reported a patent to UNC/NCI pending. J.S. Serody reported grants from Merck Inc. and Glaxo Smith Kline outside the submitted work; in addition, J.S. had a patent for the use of STING agonist to enhance CAR T cell function pending. No other disclosures were reported.
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Nuo Xu, Douglas C. Palmer, Alexander C. Robeson, Peishun Shou, Hemamalini Bommiasamy, Sonia J. Laurie, Caryn Willis, Gianpietro Dotti, Benjamin G. Vincent, Nicholas P. Restifo, Jonathan S. Serody; STING agonist promotes CAR T cell trafficking and persistence in breast cancer. J Exp Med 1 February 2021; 218 (2): e20200844. doi: https://doi.org/10.1084/jem.20200844
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