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[Preprint]. 2023 Jun 6:rs.3.rs-2972427.
doi: 10.21203/rs.3.rs-2972427/v1.

CAR T-cell design dependent remodeling of the brain tumor immune microenvironment identify macrophages as key players that inhibit or promote anti-tumor activity

Dalia Haydar  1   2 , Jorge Ibañez-Vega  1 , Jeremy Chase Crawford  3 , Ching-Heng Chou  3 , Cliff Guy  3 , Michaela Meehl  1   4 , Zhongzhen Yi  1   2 , Deanna Langfitt  1 , Peter Vogel  5 , Christopher DeRenzo  1 , Stephen Gottschalk  1 , Martine F Roussel  6 , Paul G Thomas  3 , Giedre Krenciute  1
Affiliations

CAR T-cell design dependent remodeling of the brain tumor immune microenvironment identify macrophages as key players that inhibit or promote anti-tumor activity

Dalia Haydar et al. Res Sq. .

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Abstract

Understanding interactions between adoptively transferred immune cells and the tumor immune microenvironment (TIME) is critical for developing successful T-cell based immunotherapies. Here we investigated the impact of the TIME and chimeric antigen receptor (CAR) design on anti-glioma activity of B7-H3-specific CAR T-cells. We show that five out of six B7-H3 CARs with varying transmembrane, co-stimulatory, and activation domains, exhibit robust functionality in vitro. However, in an immunocompetent glioma model, these CAR T-cells demonstrated significantly varied levels of anti-tumor activity. We used single-cell RNA sequencing to examine the brain TIME after CAR T-cell therapy. We show that the TIME composition was influenced by CAR T-cell treatment. We also found that successful anti-tumor responses were supported by the presence and activity of macrophages and endogenous T-cells. Together, our study demonstrates that efficacy of CAR T-cell therapy in high-grade glioma is dependent on CAR structural design and its capacity to modulate the TIME.

Keywords: CAR T-cell therapy; brain tumor immune microenvironment; brain tumors; chimeric antigen receptor; immunocompetent mouse models; scRNAseq.

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Conflict of interest statement

Conflict of interest: GK and CD have patent applications in the field of immunotherapy. SG is a co-inventor on patent applications in the fields of cell or gene therapy for cancer, a consultant of TESSA Therapeutics, a scientific advisory board member of Be Biopharma, a member of the Data and Safety Monitoring Board (DSMB) of Immatics, and has received honoraria from Tidal, Catamaran Bio, and Sanofi within the last 2 years. Additional Declarations: There is NO Competing Interest.

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