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Immune-restoring CAR-T cells display antitumor activity and reverse immunosuppressive TME in a humanized ccRCC mouse model

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posted on 2024-02-15, 12:19 authored by Yufei Wang, Jae Won Cho, Gabriella Kastrunes, Alicia Buck, Cecile Razimbaud, Aedin CulhaneAedin Culhane, Jiusong Sun, David A. Braun, Toni K. Choueiri, Catherine J Wu, Kristen Jones, Quang-De Nguyen, Zhu Zhu, Kevin Wei, Quan Zhu, Sabina Signoretti, Gordon J. Freeman, Martin Hemberg, Wayne A. Marasco

One of the major barriers that have restricted successful use of chimeric antigen receptor (CAR) T cells in the treatment of solid tumors is an unfavorable tumor microenvironment (TME). We engineered CAR-T cells targeting carbonic anhydrase IX (CAIX) to secrete anti-PD-L1 monoclonal antibody (mAb), termed immune-restoring (IR) CAR G36-PDL1. We tested CAR-T cells in a humanized clear cell renal cell carcinoma (ccRCC) orthotopic mouse model with reconstituted human leukocyte antigen (HLA) partially matched human leukocytes derived from fetal CD34+ hematopoietic stem cells (HSCs) and bearing human ccRCC skrc-59 cells under the kidney capsule. G36-PDL1 CAR-T cells, haploidentical to the tumor cells, had a potent antitumor effect compared to those without immune-restoring effect. Analysis of the TME revealed that G36-PDL1 CAR-T cells restored active antitumor immunity by promoting tumor-killing cytotoxicity, reducing immunosuppressive cell components such as M2 macrophages and exhausted CD8+ T cells, and enhancing T follicular helper (Tfh)-B cell crosstalk.

Funding

Pre-IND Studies of First-Generation Dual-Targeted, Fine-Tuned, Immune-Restoring (DFIR) CAR-T Cell Therapy to Achieve Cures of Clear Cell Renal Cell Carcinoma (ccRCC)

Congressionally Directed Medical Research Programs

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Further Optimizing 2nd Generation Dual-targeted Fine-tuned Immune-Restoring (DFIR) CAR T Cells to Achieve Cures of Advanced ccRCC

Congressionally Directed Medical Research Programs

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DF/HCC Kidney Cancer SPORE

National Cancer Institute

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History

Publication

iScience, 2024, 27,(2)

Publisher

CellPress

Sustainable development goals

  • (3) Good Health and Well-being

Department or School

  • School of Medicine

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