Combination Of Local Mrna Immunotherapy With Systemic Immune Checkpoint Blockade Demonstrates Antitumor Activity Across A Diverse Range Of Preclinical Syngeneic Tumor Models

Cancer immunotherapies with anti-PD-1/PD-L1 checkpoint blockade antibodies have revolutionized the treatment of a wide variety of malignancies. However, immunotherapy is ineffective in a significant subset of patients, or eventually results in the development of resistance with relapsed disease. Therefore, the future of immuno-oncology is identification of new agents that can be combined to increase the depth and breadth of anti-PD-1/PD-L1 therapies. Local intratumoral delivery of messenger RNA (mRNA)-based immunotherapies provides an opportunity to stimulate innate and adaptive immune responses against tumors and modulate tumor microenvironment, while limiting the side-effects related to systemic administration of immuno-modulatory therapeutics. We examined the local immunotherapy of synthetic mRNAs encoding immunomodulatory cytokines (single chain interleukin-12 (IL-12), interferon alpha (IFN-α), granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-15 sushi(IL-15)) alone and in combination with anti-PD-1 antibodies across 12 syngeneic mouse tumor models representing a diverse range of murine tumor types. Single agent treatment with cytokine mRNAs resulted in a significant anti-tumor response in 8 out of 12 tumor models. Combining cytokine mRNA with systemic anti-PD-1 immunotherapy further improved the anti-tumor response and resulted in tumor growth inhibition in two additional models otherwise unresponsive to single agent treatments. Transcriptome and cytokine analyses have been performed to understand factors which determine sensitivity to single agent and combination treatments with cytokine mRNA and anti-PD-1 antibodies. In summary, the combination of local cytokine mRNA immunotherapy with immune checkpoint blockade demonstrated improvement in the anti-tumor activity in a range of preclinical cancer models representing different murine tumor types. Based on these and other data, clinical testing of cytokine encoding mRNA mixture has recently been initiated (NCT03871348). Citation Format: Natalia V. Malkova, Tatiana Tolstykh, Mikhail Levit, Joachim Theilhaber, Andrew Hebert, Kevin Atchison, Adalis Maisonet, Christian Hotz, Ugur Sahin, Alexei Protopopov, Jack Pollard, Sukhvinder Sidhu, Dmitri Wiederschain, Timothy R. Wagenaar. Combination of local mRNA immunotherapy with systemic immune checkpoint blockade demonstrates anti-tumor activity across a diverse range of preclinical syngeneic tumor models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4451.