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Neuro Spot Light Oral

Neuro Spotlight

Intracranial IL12 Secreting CAR-T Cells Obviate the Need for Lymphodepletion and Combat Heterogeneity via Microglial Interactions

Saturday, May 4, 2024
2:24 PM – 2:26 PM CT
Location:  Booth 745 Neuro Spotlight
Disclosure(s):
Aditya Mohan: No financial relationships to disclose
Introduction: Epidermal growth factor receptor variant III (EGFRvIII) is a tumor-specific antigen (TSA) prevalently expressed on GBM, presenting a potential immunotherapeutic target, however, the heterogeneity in its expression represents a challenge its use as a Chimeric Antigen Receptor (CAR) T cell target. Interleukin-12 (IL12) is emerging as a potent cytokine in treating solid tumors, prompting exploration into its combined use with CARs against GBM.

Methods: Mice were injected with a 50/50 mix of CT2A or CT2A EGFRvIII+ cells to model tumor heterogeneity. EGFRvIII-specific third generation CAR T cells engineered with or without single chain IL12 were cloned in a MSGV retrovirus backbone and were transduced into murine T cells. Antitumor efficacy of CAR-T cells were assessed using survival. Further, the ability of CAR-T cells to extend survival and re-polarize the tumor microenvironment were analyzed using single cell sequencing.

Results: While EGFRvIII CARs alone fail to cure mice implanted with hetergeneous tumors, we show that EGFRvIII CARs co-expressing IL12 are able to cure 60% of mice. Intriguingly EGFRvIII CARs secreting IL12 persisted longer in vivo compared to EGFRvIII CARs and could persist without mice needing mice to be lymphodepleted prior to ALT administration. We demonstrate that EGFRvIII CARs expressing IL12 facilitate killing of EGFRvIII negative tumor cells by recruiting the endogenous CD8 T cell compartment. Furthermore, of all the Antigen Presenting Cell (APC) populations in the tumor microenvironment, IL12 acts on microglia to increase antigen presentation pathways and contribute to epitope spreading.

Conclusion : EGFRvIII CARs engineered to secrete IL12 treat antigen heterogenous tumors by polarizing local APCs and recruiting endogenous T cells. IL12 secreting CARs are able to persist longer without needing lymphodepletion when compared to traditional EGFRvIII CARs. Using CAR-T cells that secrete IL12 represents a promising approach to counter tumor heterogeneity, offering therapeutic potential against GBM in clinical settings.