Intratumoral IL12 mRNA Therapy Promotes TH1 Transformation of the Tumor Microenvironment
| Autor: | Kristen Arnold, Chris Morehouse, Eleanor Clancy-Thompson, Katharina Deschler, Susannah Hewitt, Russell Karp, Ameya Apte, Chris Bagnall, Faith Musenge, Darren Potz, David A. Leinster, Kathy Mulgrew, Ankita Mishra, Gordon Moody, Maja Sedic, Joshua Frederick, John Zielinski, Fabien Garcon, Sushma Gurumurthy, Nadia Luheshi, Michal Sulikowski, Steve Novick, Han Si, Philip Martin, Grace Adjei, James Moynihan, Jean-Martin Lapointe, Amanda Watkins, Shannon Burke, Ronald Herbst, Dyane Bailey, Robert W. Wilkinson |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Mice Nude Apoptosis Mice SCID CD8-Positive T-Lymphocytes B7-H1 Antigen Mice 03 medical and health sciences Lymphocytes Tumor-Infiltrating 0302 clinical medicine Immune system Immunity Gene expression Tumor Cells Cultured Tumor Microenvironment Animals Humans Medicine RNA Messenger Melanoma Cell Proliferation Mice Inbred BALB C Tumor microenvironment business.industry Antibodies Monoclonal Th1 Cells Natural killer T cell Interleukin-12 Xenograft Model Antitumor Assays Mice Inbred C57BL 030104 developmental biology Oncology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer research Interleukin 12 Female Colorectal Neoplasms business Ex vivo CD8 |
| Zdroj: | Clinical Cancer Research. 26:6284-6298 |
| ISSN: | 1557-3265 1078-0432 |
| Popis: | Purpose: While immune checkpoint inhibitors such as anti–PD-L1 are rapidly becoming the standard of care in the treatment of many cancers, only a subset of treated patients have long-term responses. IL12 promotes antitumor immunity in mouse models; however, systemic recombinant IL12 had significant toxicity and limited efficacy in early clinical trials. Experimental Design: We therefore designed a novel intratumoral IL12 mRNA therapy to promote local IL12 tumor production while mitigating systemic effects. Results: A single intratumoral dose of mouse (m)IL12 mRNA induced IFNγ and CD8+ T-cell–dependent tumor regression in multiple syngeneic mouse models, and animals with a complete response demonstrated immunity to rechallenge. Antitumor activity of mIL12 mRNA did not require NK and NKT cells. mIL12 mRNA antitumor activity correlated with TH1 tumor microenvironment (TME) transformation. In a PD-L1 blockade monotherapy-resistant model, antitumor immunity induced by mIL12 mRNA was enhanced by anti–PD-L1. mIL12 mRNA also drove regression of uninjected distal lesions, and anti–PD-L1 potentiated this response. Importantly, intratumoral delivery of mRNA encoding membrane-tethered mIL12 also drove rejection of uninjected lesions with very limited circulating IL12p70, supporting the hypothesis that local IL12 could induce a systemic antitumor immune response against distal lesions. Furthermore, in ex vivo patient tumor slice cultures, human IL12 mRNA (MEDI1191) induced dose-dependent IL12 production, downstream IFNγ expression and TH1 gene expression. Conclusions: These data demonstrate the potential for intratumorally delivered IL12 mRNA to promote TH1 TME transformation and robust antitumor immunity. See related commentary by Cirella et al., p. 6080 |
| Databáze: | OpenAIRE |
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