Car T Cell Therapy Reshapes The Tumor Microenvironment To Promote Host Antitumor Immune Repsonses In Glioblastoma.

Abstract CAR T cell therapy is emerging as a promising strategy to treat cancer and may offer new therapeutic options for individuals diagnosed with glioblastoma (GBM) and other solid tumors. While early clinical studies evaluating CAR T cell therapy in GBM have established evidence of safety and bioactivity, objective clinical responses have been limited. It remains unclear whether productive CAR T cell therapy for solid tumors requires solely CAR T cell engagement with tumor antigen, or if it also necessitates the stimulation of a patient's endogenous immune response. Focusing on our preclinical and clinical program evaluating IL13Rα2-targeted CAR-T cells for the treatment of IL13Rα2-positive glioblastoma (GBM), we set out to mechanistically interrogate the interplay between CAR T cell therapy and the host tumor microenvironment. We designed a murine CAR T cell syngeneic platform in C57BL/6 immunocompetent mice and demonstrate that single intratumoral infusion of IL13Rα2-CAR T cells mediate potent antitumor activity against established KR158 tumors, a highly invasive and poorly immunogenic murine glioma model. We demonstrate that CAR T cell treatment of mouse syngeneic GBM alters the tumor immune landscape, activates intratumoral myeloid cells and induces endogenous T cell memory responses coupled with feed forward propagation of CAR T responses. IFNγ production by CAR T cells and IFNγ-responsiveness of host immune cells is critical for tumor immune landscape remodeling to promote a more activated and less suppressive tumor microenvironment. The clinical relevance of these findings was explored in patient samples from our on-going IL13Rα2-CAR T cell phase I clinical trial [NCT02208362]. Consistent with our preclinical findings, we show that locoregional CAR T cell infusions result in spikes in inflammatory cytokines and an influx of endogenous immune cells into the cerebrospinal fluid (CSF) and resected tumor cavity. Single cell RNA-sequencing revealed unique genes upregulated in immune cells from blood and CSF samples after treatment. One patient of particular interest, who presented with recurrent multifocal GBM, remarkably achieved a complete response (CR) following locoregional delivery of IL13Rα2-CAR T cells, despite heterogeneous IL13Rα2 tumor expression (PMID: 28029927). In this responding patient, we now show the induction of endogenous tumor-specific T cell reactivity and T cell clones whose dynamics contracted with tumor volume following IL13Rα2-targeted CAR T therapy. These studies establish that CAR T cell therapy has the potential to re-shape the tumor microenvironment, creating a context permissible for eliciting endogenous antitumor immunity and emphasize the importance of the host innate and adaptive immunity in productive CAR T cell therapy of solid tumors. Citation Format: Christine E. Brown, Darya Alizadeh, Vanessa Jonsson, Jonathan Hibbard, Stephanie Yahn, Robyn A. Wong, Xin Yang, Rachel Ng, Natalie Dullerud, Madeleine Maker, Sharahreh Gholamin, Renate Starr, Nicholas Banovich, Stephen J. Forman, Behnam Badie. CAR T cell therapy reshapes the tumor microenvironment to promote host antitumor immune repsonses in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 59.