EXTH-144. Multifunctional chimeric antigen receptor immune cell communities demonstrate promising preclinical safety and efficacy against glioblastoma

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Abstract There is an unmet medical need for more effective therapies against glioblastoma. Cellular immunotherapies with engineered immune cells expressing synthetic chimeric antigen receptors (CAR) to recognize and attack cancer cells have great therapeutic potential. However, current strategies focus on single immune cell types, mostly T cells, followed by NK cells and face significant barriers that impede the breakthrough and wide implementation of these treatment strategies. These include long and costly production processes, complex infrastructure requirements and limited activity. Here, we developed and characterized a novel electroporation-based engineering platform to equip peripheral blood mononuclear cells (PBMCs) with multi-targeting CARs and pro-inflammatory cytokines (CAR-PBMC platform) rapidly within a few hours to redirect multiple immune cell lineages with a broad range of effector functions against cancer cells. CAR PBMCs were generated by ultra-rapid flow electroporation of mRNA into PBMCs isolated from healthy donors or glioblastoma patients. Cell types and states within multi-targeting and multi-functional CAR PBMCs were characterized by flow cytometry and single-cell RNA sequencing. Their anti-tumor activity and safety were assessed in vitro using patient-derived cell lines and human glioma-bearing organotypic brain slice cultures as well as in vivo using orthotopic glioma mouse models. Ultra-rapid cell manipulation resulted in highly efficient cell engineering with excellent cell viabilities and high transgene expression across immune cell types. In vitro killing assays revealed promising antigen-specific anti-glioma activity. This was also confirmed in human organotypic glioma-bearing brain slice cultures, which also revealed promising safety, as there was no off-target toxicity against neurons, microglia or astrocytes. In orthotopic glioma mouse models, multifunctional and multitargeting CAR PBMC therapy showed reduced tumor volumes and prolonged survival, without signs of toxicity. This study highlights the potential of CAR-PBMCs as a novel adoptive cell therapy for glioblastoma, offering a simplified and clinically applicable manufacturing. The demonstrated safety and efficacy provide a strong foundation for clinical translation.

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