Abstract IA21: MUC16-directed immunotherapy for ovarian cancer

Abstract

Abstract Despite recent setbacks in the clinical development of immunotherapy for gynecologic malignancies, the promise of durable responses with this form of treatment has led to a redoubling of our efforts to understand and develop new immunotherapeutic modalities. Some of the reasons behind the relative lack of success of immunotherapy in ovarian cancer include low tumor antigenic burden; a hostile tumor microenvironment (TME) consisting of physical barriers to immune infiltration; suppressive ligands, cytokines, chemokines, and other immunosuppressive cellular elements. There are ongoing efforts to overcome many of these limitations simultaneously. For instance, several clinical trials are exploring the combination of immune checkpoint blockade with chemotherapy, poly (ADP-ribose) polymerase (PARP) inhibitors, or both in an attempt to increase tumor antigenic burden. Other approaches are centered around targeting known tumor-associated antigens such as MUC16. MUC16 is amplified in 5-10% of ovarian cancers. The predominant extracellular portion of MUC16 is cleaved and secreted (referred to as CA-125), although a significant portion of the antigen is retained on the surface of the tumor (referred to as MUC16ecto). We have developed a variety of MUC16ecto- directed therapies, including chimeric antigen receptor (CAR) T-cells and bispecific T-cell engager cells (BiTEs). Targeting MUC16ecto solves the problem of low tumor mutational burden in ovarian cancer, but further optimizations are required to overcome the immunosuppressive TME. For our CAR T-cell therapy, we devised and evaluated three separate approaches to overcome the TME in ovarian cancer. MUC16ecto-directed CAR T-cells modified to secrete interleukin-12 (IL-12) showed superior efficacy in advanced syngeneic and xenograft murine models of metastatic ovarian cancer. We found that autocrine and paracrine activity of IL-12 potentiated the activity of these CAR T-cells and mediated resistance to PD-L1 suppression. Furthermore, we found that secretion of IL-12 in the TME promoted differentiation of proinflammatory tumor-associated macrophages and led to the deletion of other suppressive macrophages in the TME. Similarly, MUC16ecto-directed CAR T-cells modified to secrete interleukin-18 (IL-18) significantly improved survival in low and high tumor burden syngeneic models of metastatic ovarian cancer. We also evaluated CAR T-cells engineered to secrete anti-PD-1 blocking single-chain variable fragments (scFv) and showed that this approach significantly improved efficacy in relevant preclinical models of metastatic ovarian cancer. Furthermore, this approach fostered CAR T-cell persistence leading to resistance to tumor rechallenge. Unsurprisingly, using CAR T-cells as a delivery vehicle for delivery of immune checkpoint blockade promoted bystander effects on endogenous immune cells and mitigated systemic anti-PD-1 leak. We next evaluated MUC16ecto-specific BITEs and found a significant reduction in tumor burden in xenogeneic models of metastatic ovarian cancer. Adjunctive therapies to augment our MUC16ecto-specific BiTEs are currently in testing, along with other MUC16-directed immunotherapeutic strategies. Citation Format: Oladapo O. Yeku, Sarwish Rafiq, Mythili Koneru, Terence J. Purdon, Mei Song, Pei Wang, Ronald Hendrickson, Renier J. Brentjens, David Spriggs. MUC16-directed immunotherapy for ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr IA21.