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While recent advances in immunotherapies have shown promise in extracranial tumors, Glioblastoma Multiforme (GBM) has remained challenging. We have previously developed a novel approach to the treatment of primary GBM by combining simultaneous intracranial administration of gene-modified γδ T cells expressing O-6-Methylguanine-DNA Methyltransferase (MGMT) and standard temozolomide (TMZ) chemotherapy. To further improve tumor targeting and the efficacy of the γδ T cell against GBM, we modified γδ T cells with a CAR using chlorotoxin (CLTX), a small peptide derived from scorpion venom that specifically binds the glioma-specific chloride channel, as binding domains (CLTX-CARs). MGMTp140k was co-expressed within the same CLTX-CAR vectors to confer TMZ resistance to the CAR-T cells. We optimized the CAR constructs as CLTX-CD8a-CD28TM-CD28co-CD3z-P2A-MGMT and the activation of CD69 was verified in CLTX-CAR transduced Jurkat T cells with GBM cell co-culture. We further tested dual-CLTX-CAR constructs with 2x CLTX peptide as binding domains (dCLTX-CAR) and demonstrated dCLTX-CAR-Jurkat T cells can activate T cells efficiently with improved persistence compared to the mono-CLTX-CAR-Jurkat T cells 3 weeks after transduction (84% vs 37%). In order to preserve the powerful innate-recognition properties of γδ T cells, we developed CLTX-CARs without CD3z activation domain (NoZ-CLTX-CAR) to mitigate activation induced cell death (AICD) and tonic signaling issues. NoZ-CLTX-CAR-Jurkat T cells showed no CD69 activation with GBM cells co-culture and superior CAR-T persistence compared to CLTX-CARs with a CD3z signaling domain. Furthermore, we were able to efficiently transduce (up to 70% transduction efficiency) γδ T cells with NoZ-dCLTX-CAR lentiviral which demonstrated enhanced cytotoxicity against GBM cells compare to non-transduced control γδ T cells. Our approach of combining the dCLTX-CAR and TMZ resistance will be further validated in animal model experiments and could be a potential candidate for clinical development for GBM.

EXTH-39. DUAL CHLOROTOXIN CAR AND MGMT ΓΔ T CELLS FOR DRUG RESISTANT IMMUNOTHERAPY OF GLIOBLASTOMA MULTIFORME