Abstract 5640: Targeting tumor-promoting inflammation (TPI) via the IL-1βpathway for cancer immunotherapy
Authors: Pushpa Jayaraman, Vanessa Rodrik-Outmezguine, John Millholland, Neil O'Brien, Connie Wong, Rohan Diwanji, Muchun Wang, Elizabeth Choi, Ronald Linnartz, Kristine Rose, Marc Pelletier, Alexander Savchenko, Tong Luo, Valerie Rezek, Scott Kitchen, Jason Baum, Catherine Sabatos-Peyton, Anne-Marie Martin, Glenn Dranoff
Journal: Cancer Research (2020)

Abstract Introduction: TPI is a hallmark of cancer and plays a pivotal role in tumor initiation, development, progression, and invasiveness. High levels of tumor-promoting inflammatory cytokines e.g. IL-1β and IL-6 are associated with advanced malignancies and reduced survival. Selective IL-1β inhibitors like canakinumab (CAN) and gevokizumab (GEV) aim to target TPI within the tumor microenvironment (TME) by reducing tumor-associated immune suppression. In phase III CANTOS study, CAN significantly reduced lung cancer (LC) incidences and LC related mortalities in atherosclerosis patients, providing the first clinical evidence for the role of IL-1β inhibition in LC. We have utilized preclinical models to gain further insights into the mechanistic role of CAN and GEV in cancer development and progression. Methods: Preclinical efficacy of anti-human IL-1β antibodies, CAN and GEV was assessed using humanized mouse models of non-small cell lung cancer (NSCLC, H358), triple-negative breast cancer (TNBC, MDA-MB-231) and colorectal cancer (CRC, SW480) either as single agents or in combination with other immunomodulatory agents including PD-1 inhibitor pembrolizumab (PEM) and anti-VEGF therapy. A murine surrogate IL-1β blocking antibody clone 01BSUR was used to evaluate efficacy in murine syngeneic models of breast (4T1) and lung (LL-2) cancer either as single agent or with PD-1 inhibitor and docetaxel (DOC). Tumor infiltrating lymphocytes (TIL) characterization was carried out by flow cytometry and IHC in syngeneic and humanized models, respectively. Results: The IL-1β inhibitors showed anti-tumor activity in both murine syngeneic and humanized models as single agents or with other agents. In the H358 NSCLC mouse model, CAN + PEM significantly inhibited tumor growth and was associated with &amp;gt;50% regression vs control. Decreased tumor growth was also observed with GEV treatment in the SW480 CRC mouse model, both alone and with anti-VEGF therapy. In GEV+anti-VEGF arm, a decrease in tolerogenic DC-10 immune populations and an increase in CD45+ immune cells and CD68+ myeloid cells were also observed. In the MDA-MB-231 TNBC mouse model, CAN single-agent showed a decrease in tumor growth vs control. In murine syngeneic 4T1 and LL-2 models, anti-IL-1β alone and anti-IL-1β + anti-PD-1 resulted in increased presence of CD8+ T cells and reduction of immunosuppressive myeloid-derived suppressor cells, neutrophils, and regulatory T cells in the tumor, suggesting that the TME may be shifting to a less suppressive phenotype after IL-1β blockade. Similar changes were observed with combination of anti-IL-1β with DOC and anti-VEGF in murine syngeneic models. Conclusions: These data provide key insights into the biology behind IL-1β blockade currently being pursued in clinical trials with CAN and GEV. Additional preclinical studies to investigate mechanism of action of these agents and other novel combinations are planned. Citation Format: Pushpa Jayaraman, Vanessa Rodrik-Outmezguine, John Millholland, Neil O'Brien, Connie Wong, Rohan Diwanji, Muchun Wang, Elizabeth Choi, Ronald Linnartz, Kristine Rose, Marc Pelletier, Alexander Savchenko, Tong Luo, Valerie Rezek, Scott Kitchen, Jason Baum, Catherine Sabatos-Peyton, Anne-Marie Martin, Glenn Dranoff. Targeting tumor-promoting inflammation (TPI) via the IL-1βpathway for cancer immunotherapy [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 5640.