Abstract 974: Immune modulation following combination of TAK-164 with checkpoint inhibitors

TAK-164 is an antibody drug conjugate comprised of a full length, fully human IgG1 monoclonal antibody (mAb) directed towards the human extra-cellular domain of guanylyl cyclase C (GCC). The mAb is conjugated using ImmunoGen9s peptide-linked indolinobenzodiazepine DNA alkylator DGN549. Previously presented preclinical studies using TAK-164 have demonstrated single agent activity of TAK-164 in a panel of patient derived xenograft models of colorectal cancer grown in immunodeficient mice. With emerging evidence demonstrating the immunostimulatory activity of cytotoxic antibody drug conjugates we sought to explore the potential of TAK-164 in immune competent mice. A CT26 model was engineered to express human GCC, allowing us to test the ability of TAK-164 to modulate the tumor microenvironment, thereby potentiating the activity of checkpoint inhibitors. huGCC-CT26 tumor cells were implanted in the right flank of 6-8 week old BALB/c female mice and randomized when tumors were between 50-150mm3 and treated with a single intravenous administration of TAK-164 alone or in combination with checkpoint inhibition administered Intraperitoneally biweekly for 2 weeks and monitored for tumor growth. To understand if responses observed were driven by a response capable of inducing immunological memory we separated mice with complete responses and rechallenged with CT26 tumor cells on the opposite flank. While memory was observed in the mice that achieved complete response in the single agent groups, both frequency of complete response and tumor rejection was increased in groups treated with a combination of TAK-164 and immune checkpoint inhibition. We performed immunophenotyping studies which revealed broad immunomodulation of lymphoid and myeloid cells by TAK-164 and combination regimens. Collectively these data support further interrogation of immune checkpoint inhibition in combination with TAK-164. Citation Format: Victoria A. Appleman, Michael D. Smith, Michelle Ganno, Tiquella Hatten, Maria Borland, Adnan O. Abu-Yousif. Immune modulation following combination of TAK-164 with checkpoint inhibitors [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 974.