Data from CAR T-cell Design-dependent Remodeling of the Brain Tumor Immune Microenvironment Modulates Tumor-associated Macrophages and Anti-glioma Activity

• DOI: 10.1158/2767-9764.c.6957588.v1
• Publication Date: 2023-12-01T02:21:56Z
• Authors: Dalia Haydar; Jorge Ibañez-Vega; Jeremy Chase Craw...; Ching-Heng Chou; Clifford S. Guy; Michaela Meehl; Zhongzhen Yi; Scott Perry; Jonathan Laxton; Trevor Cunningham; Deanna Langfitt; Peter Vogel; Christopher DeRenzo; Stephen Gottschalk; Martine F. Roussel; Paul G. Thomas; Giedre Krenciute

<div>Abstract<p>Understanding the intricate dynamics between adoptively transferred immune cells and brain tumor microenvironment (TIME) is crucial for development of effective T cell–based immunotherapies. In this study, we investigated influence TIME chimeric antigen receptor (CAR) design on anti-glioma activity B7-H3–specific CAR T-cells. Using an immunocompetent glioma model, evaluated a panel seven fully murine B7-H3 CARs with variations in transmembrane, costimulatory, activation domains. We then changes following T-cell therapy using high-dimensional flow cytometry single-cell RNA sequencing. Our results show that five out six single costimulatory domains demonstrated robust functionality <i>in vitro</i>. However, these had significantly varied levels antitumor vivo</i>. To enhance therapeutic effectiveness persistence, incorporated 41BB CD28 costimulation through transgenic expression 41BBL CD28-based This was associated improved efficacy vitro</i> but did not result similar improvements Analysis revealed influenced composition TIME, recruitment distinct macrophage endogenous subsets successful responses. Indeed, complete depletion CSF1R inhibitor abrogated activity. sum, our study highlights critical role its modulation mediating adoptive immunotherapy high-grade glioma.</p>Significance:<p>CAR immunotherapies hold great potential treating cancers; however, they are hindered by challenging environment dampens their effectiveness. influences makeup tumors, underscoring need to target specific components improve performance, highlighting significance models functional systems optimize therapy.</p></div>