Stressed target cancer cells drive nongenetic reprogramming of CAR T cells and solid tumor microenvironment

Yufeng Wang, David L. Drum, Ruochuan Sun, Yida Zhang, Feng Chen, Fengfei Sun, Emre Dal, Ling Yu, Jingyu Jia, Shahrzad Arya, Lin Jia, Song Fan, Steven J. Isakoff, Allison M. Kehlmann, Gianpietro Dotti, Fubao Liu, Hui Zheng, Cristina R. Ferrone, Alphonse G. Taghian, Albert B. DeLeo, Marco Ventin, Giulia Cattaneo, Yongxiang Li, Youssef Jounaidi, Peigen Huang, Cristina Maccalli, Hanyu Zhang, Cheng Wang, Jibing Yang, Genevieve M. Boland, Ruslan I. Sadreyev, LaiPing Wong, Soldano Ferrone and Xinhui Wang ()
Additional contact information
Yufeng Wang: Harvard Medical School
David L. Drum: Harvard Medical School
Ruochuan Sun: Harvard Medical School
Yida Zhang: Harvard Medical School
Feng Chen: Harvard Medical School
Fengfei Sun: Harvard Medical School
Emre Dal: Harvard Medical School
Ling Yu: Harvard Medical School
Jingyu Jia: Harvard Medical School
Shahrzad Arya: Harvard Medical School
Lin Jia: Harvard Medical School
Song Fan: Harvard Medical School
Steven J. Isakoff: Massachusetts General Hospital Cancer Center
Allison M. Kehlmann: Massachusetts General Hospital Cancer Center
Gianpietro Dotti: University of North Carolina
Fubao Liu: Anhui Medical University
Hui Zheng: Harvard Medical School
Cristina R. Ferrone: Cedars-Sinai Medical Center
Alphonse G. Taghian: Harvard Medical School
Albert B. DeLeo: Harvard Medical School
Marco Ventin: Harvard Medical School
Giulia Cattaneo: Harvard Medical School
Yongxiang Li: First Affiliated Hospital of Anhui Medical University
Youssef Jounaidi: Harvard Medical School
Peigen Huang: Harvard Medical School
Cristina Maccalli: Sidra Medicine
Hanyu Zhang: Harvard Medical School
Cheng Wang: Harvard Medical School
Jibing Yang: Harvard Medical School
Genevieve M. Boland: Harvard Medical School
Ruslan I. Sadreyev: Harvard Medical School
LaiPing Wong: Harvard Medical School
Soldano Ferrone: Harvard Medical School
Xinhui Wang: Harvard Medical School

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract The poor efficacy of chimeric antigen receptor T-cell therapy (CAR T) for solid tumors is due to insufficient CAR T cell tumor infiltration, in vivo expansion, persistence, and effector function, as well as exhaustion, intrinsic target antigen heterogeneity or antigen loss of target cancer cells, and immunosuppressive tumor microenvironment (TME). Here we describe a broadly applicable nongenetic approach that simultaneously addresses the multiple challenges of CAR T as a therapy for solid tumors. The approach reprograms CAR T cells by exposing them to stressed target cancer cells which have been exposed to the cell stress inducer disulfiram (DSF) and copper (Cu)(DSF/Cu) plus ionizing irradiation (IR). The reprogrammed CAR T cells acquire early memory-like characteristics, potent cytotoxicity, enhanced in vivo expansion, persistence, and decreased exhaustion. Tumors stressed by DSF/Cu and IR also reprogram and reverse the immunosuppressive TME in humanized mice. The reprogrammed CAR T cells, derived from peripheral blood mononuclear cells of healthy donors or metastatic female breast cancer patients, induce robust, sustained memory and curative anti-solid tumor responses in multiple xenograft mouse models, establishing proof of concept for empowering CAR T by stressing tumor as a promising therapy for solid tumors.

Date: 2023
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DOI: 10.1038/s41467-023-41282-x

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