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Abstract
Intratumoral electroporation-mediated IL-12 gene therapy (IT-pIL12/EP) has been shown to be safe and effective in clinical trials, demonstrating systemic antitumor effects with local delivery of this potent cytokine. We recently optimized our IL-12 gene delivery platform to increase transgene expression and efficacy in preclinical models. Here we analyze the immunological changes induced with the new IT-pIL12/EP platform in both electroporated and distant, non-electroporated lesions. IT-pIL12/EP-treated tumors demonstrated rapid induction of IL-12-regulated pathways, as well as other cytokines and chemokines pathways, and upregulation of antigen presentation machinery. The distant tumors showed an increase in infiltrating lymphocytes and gene expression changes indicative of a de novo immune response in these untreated lesions. Flow cytometric analyses revealed a KLRG1hi CD8+ effector T-cell population uniquely present in mice treated with IT-pIL12/EP. Despite being highly activated, this population expressed diminished levels of PD-1 when re-exposed to antigen in the PD-L1-rich tumor. Other T-cell exhaustion markers appeared to be downregulated in concert, suggesting an orchestrated “armoring” of these effector T cells against T-cell checkpoints when primed in the presence of IL-12 in situ. These cells may represent an important mechanism by which local IL-12 gene therapy can induce a systemic antitumor immune response without the associated toxicity of systemic IL-12 exposure.
Highlights
Interleukin 12 (IL-12) is pleotropic inflammatory cytokine, which links innate and adaptive immunity and drives Th1/ Tc1 cell-mediated immune responses
Our results suggest that CD8 T cells primed in the IL-12-treated tumor microenvironment (TME) may be, at least transiently, “armored” against multiple T-cell checkpoints, contributing to their fitness as antitumor cytotoxic T lymphocyte (CTL) and may represent a prominent mechanism by which local IT IL-12 gene therapy can deliver a safe and effective abscopal response
In a Phase 1 clinical trial in advanced melanoma, EPmediated transfection of plasmid-encoded IL-12 was safe and led to local necrosis and inflammation in the electroporated tumor, as well as regression of distant untreated cells are shown in red
Summary
Interleukin 12 (IL-12) is pleotropic inflammatory cytokine, which links innate and adaptive immunity and drives Th1/ Tc1 cell-mediated immune responses. Systemic administration of recombinant IL-12 protein [1,2,3] or IL-12-expressing adoptive cell. These authors contributed : Anandaroop Mukhopadhyay, Jocelyn Wright, Shawna Shirley. Therapies [4] have led to severe immune-related toxicities in patients. Intratumoral (IT) gene therapy with plasmids expressing IL-12 has been tested both in experimental mouse models and in the clinic. As a monotherapy in advanced melanoma, IT electroporationmediated transfection of a plasmid encoding human IL-12 yielded a 33% best overall response rate, with 50% of patients showing regression of untreated lesions, without any reported systemic drug-related toxicity [5, 6]
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