Abstract 1573: Combinatorial antitumor effects of CD3-based trispecific T cell activating constructs (TriTACs) and checkpoint inhibitors in preclinical models

Abstract

Abstract Tri-specific T Cell-Activating Constructs (TriTACs) are T-cell engagers that have been developed to redirect T cells to kill tumor cells. TriTAC molecules are currently being investigated in multiple phase 1/2 clinical trials in solid tumors, including HPN424 targeting prostate-specific membrane antigen (PSMA) in prostate cancer (NCT03577028), HPN536 targeting mesothelin (MSLN) in multiple malignancies (NCT03872206) and HPN328 targeting Delta Like Canonical Notch Ligand 3 (DLL3) in small cell lung cancer (SCLC) (NCT04471727). TriTAC molecules consist of a single domain antibody (sdAb) specific for a tumor antigen, a sdAb specific for serum albumin for half-life extension, and a single chain Fv (scFv) specific for the CD3ϵ subunit of the T cell receptor (TCR) complex for T cell engagement. In the presence of antigen expressing tumor cells, TriTAC treatment leads to potent T cell activation, production of proinflammatory cytokines, and re-directed tumor cell killing. Upregulation of co-stimulatory and/or inhibitory receptors during activation can potentially affect the cytolytic functions of TriTAC-activated T cells. We demonstrate that PD-1 can be readily detected on T cells subsequent to the engagement of the TCR by the TriTAC molecules HPN424, HPN536, and HPN328 in the presence of tumor cells expressing the target antigens PSMA, MSLN, and DLL3, respectively. We also demonstrate that TriTAC molecules upregulate PD-L1 on T cells in a dose-dependent manner. While induction of PD-1 on T cells suggests that cytolytic activity of TriTAC-activated T cells may be down-modulated by PD-L1-expressed by target tumor cells, simultaneous upregulation of PD-L1 on T cells suggests a second mechanism through which the functions of TriTAC-activated T cells could be further regulated by the PD1/PD-L1 axis in the tumor microenvironment through T cell-T cell interactions. In addition, in the MSLN-expressing NCI-H292 lung cancer model that co-expresses constitutive, high levels of PD-L1, both anti-PD1 and anti-PDL1 antibodies significantly enhanced the antitumor effects of the MSLN-targeting TriTAC HPN536 in vivo. Together these results demonstrate the potential utility of PD1/PDL1 blockade to enhance the potency of TriTAC-mediated tumor cell killing, supporting further investigation of these combinatorial approaches in patients. Citation Format: Mary Ellen Molloy, Laura B. Valenzuela, Priyanka E. Basak, Che-Leung Law. Combinatorial antitumor effects of CD3-based trispecific T cell activating constructs (TriTACs) and checkpoint inhibitors in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1573.