Abstract LB101: Cell-generated IL12 combined with PD-1 inhibition produces local and abscopal immune activation to eradicate metastatic melanoma and pancreatic cancer

Abstract

Background: Cytokines have been FDA approved for cancer immunotherapy for treatment of metastatic melanoma and renal carcinoma for over 30 years (1, 2). To overcome stability and toxicity limitations seen with high dose cytokine immunotherapy, we developed a delivery platform, called cytokine factories, composed of genetically engineered epithelial cells encapsulated in biocompatible polymers. These clinically translatable cytokine factories are able to safely deliver high local doses of pro-inflammatory cytokines, such as interleukin-12 (IL12), and allow for controlled and predictable dosing in vivo. Results: Tumor-adjacent administration of IL12-based cytokine factories in vivo created a high local cytokine concentration (IP space) without substantial leakage into the systemic circulation. In addition, administration of cytokine factories in combination with anti-PD1 checkpoint inhibitors caused reduction of tumor burden by over 60% when delivered as a monotherapeutic to mice with metastatic melanoma (3). Further, when administered in combination with local anti-PD1 checkpoint inhibitors, these cytokine factories led to reduction of intraperitoneal tumor burden by over 80% after only 10 days of treatment. Finally, we evaluated the ability of this therapy to treat pancreatic tumors which are notoriously known to be resistant to immunotherapy. We found that the median survival for control animals was 45 days. However, 8/8 of animals treated with IL12 cytokine factories survived throughout the duration of the study (110 days), demonstrating a significant extension of overall survival time. Conclusions: Our findings demonstrate efficacy of cytokine factories as single agent and combination therapeutics in preclinical animal models and provide rationale for future clinical testing for the treatment of metastatic peritoneal cancers in humans. References: (1) H. Choudhry, N. Helmi, W.H. Abdulaal, M. Zeyadi, M.A. Zamzami, W. Wu, M.M. Mahmoud, M.K. Warsi, M. Rasool, M.S. Jamal, Prospects of IL-2 in Cancer Immunotherapy, Biomed Res Int, 2018 (2018) 9056173. (2) D.F. McDermott, M.B. Atkins, Interleukin-2 therapy of metastatic renal cell carcinoma–predictors of response, Semin Oncol, 33 (2006) 583-587. (3) N.E. Reticker-Flynn, W. Zhang, J.A. Belk, P.A. Basto, N.K. Escalante, G.O.W. Pilarowski, A. Bejnood, M.M. Martins, J.A. Kenkel, I.L. Linde, S. Bagchi, R. Yuan, S. Chang, M.H. Spitzer, Y. Carmi, J. Cheng, L.L. Tolentino, O. Choi, N. Wu, C.S. Kong, A.J. Gentles, J.B. Sunwoo, A.T. Satpathy, S.K. Plevritis, E.G. Engleman, Lymph node colonization induces tumor-immune tolerance to promote distant metastasis, Cell, 185 (2022) 1924-1942 e1923. <![endif]→ Citation Format: Amanda Nash, Bertha Castillo, Danna Murungi, Nathan Reticker-Flynn, Omid Veiseh. Cell-generated IL12 combined with PD-1 inhibition produces local and abscopal immune activation to eradicate metastatic melanoma and pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB101.