Immu-16. Intra-Tumoural Il-12 Delivery Enables Car T-Cell Immunotherapy for High-Grade Glioma

Abstract

Treatment with T-cells redirected to tumour specificity with a chimeric antigen receptor (CAR) may be well suited to treat intracranial tumours due to the ability of T-cells to access the central nervous system and migrate to infiltrative sites of disease. In adult glioblastoma, a case report of local and distant eradication of intracranial and spinal tumour deposits following intraventricular infusion of IL13Ra2-CAR T-cells indicates the potential of this approach. However, in contrast to the sustained complete remissions observed in haematological malignancies, in the majority of patients with glioblastoma CAR T-cell therapy has not resulted in clinical benefit. Tumour heterogeneity and the highly immune inhibitory tumour microenvironment (TME) are likely key barriers to achieving durable anti-tumour immunity. Here use intra-tumoural administration of IL-12 to enable CAR T-cell immunity. We employed CAR-T cells targeting the tumour-specific epidermal growth factor variant III (EGFRvIII). In an immunocompetent orthotopic mouse model of high-grade glioma, we show that CAR-T cells alone failed to control fully established tumour, but when combined with a single, locally delivered dose of IL-12, durable antitumor responses were achieved. IL-12 not only boosted cytotoxicity of CAR T-cells, but also reshaped the TME driving increased infiltration of proinflammatory CD4+ T-cells, decreased numbers of regulatory T-cells (Tregs) and activation of the myeloid compartment. Critically, immunotherapy enabling benefits of IL-12 were achieved with minimal systemic effects. Our findings show that local delivery of IL-12 is an effective adjuvant for CAR-T cell therapy for high-grade glioma. Assessment of application in high-risk childhood brain tumours is ongoing.

Combination strategies to optimize the efficacy of chimeric antigen receptor T cell therapy in haematological malignancies

“…A clinical trial is currently ongoing to test the efficacy of NT-I7 administered 21 days after CD19 CAR T cell infusion in lymphoma patients (NCT05075603). Other immune stimulatory cytokines, such as IL-18 and IL-12, can also enhance the killing effects of CAR T cells (125,126). Their coupling with CAR T cells in haematological malignancies deserves future exploration.…”

Secretory co-factors in next-generation cellular therapies for cancer

“…Consequently, IL-12 was expected to improve CAR T-cell cytotoxicity; however, IL-12expressing CAR T cells have been reported to enhance monocyte(23) and T cell (16) recruitment, macrophage antigen presentation (14), and CAR T-cell persistence (19) rather than their cytotoxicity. Local recombinant IL-12 delivery can reshape the immunosuppressive TME(67,68) and several clinical trials for tumor therapies with recombinant IL-12 administration have been conducted in recent decades(69). Unfortunately, high-dose systemic IL-12 treatment can cause life-threatening adverse events(70,71) and milder regimens had no effect on advanced renal cell cancer as they delivered insufficient local concentrations of IL-12 to the TME(71).…”