Abstract LB338: A novel class of T cell-activators targeting germline encoded TCRβ chains promotes antitumor activity in PD1-refractory models through expansion of a clonally enriched effector memory T cell subset

Abstract

Abstract Background: Here we describe a new class of selective T cell activator molecule that combines antibody targeting of the variable (V) β regions of the T cell receptor (TCR) with a costimulatory cytokine. STAR0602, a molecule that selectively targets T cells expressing Vβ6 and Vβ10 TCRs and delivers IL-2R co-stimulation, activates and expands human Vβ6 and Vβ10 T cells that are enriched in tumor infiltrating lymphocytes (TIL) relative to other Vβ subsets. Using this molecular design, STAR0602 and molecules targeting other Vβ T cell subsets simultaneously engage a novel, non-clonal mode of TCR activation with cytokine co-stimulation. Methods: The effects of STAR0602 on activation and expansion of primary human T cells were assessed in vitro by flow cytometry, homogeneous time-resolved fluorescence, TCRseq, and NanoString. Several murine surrogate molecules targeting different Vβ T cell subsets with a range of baseline frequencies were tested in murine syngeneic tumor models. Tumors were excised for phenotyping of TILs including tetramer staining of antigen specific T cells using flow cytometry, and scRNAseq/TCRseq. Results: In vitro, STAR0602 induced TCR signaling and IL-2R pathway activation in human T cells that preceded expansion of Vβ6/Vβ10 T cells that acquired an atypical central memory T cell (TCM) phenotype. Across PD1-refractory syngeneic murine tumor models, monotherapy with fusion molecules targeting different Vβ TCR and delivering IL-2R co-stimulation induced potent anti-tumor activity that was associated with expansion and accumulation of targeted Vβ T cell subsets in blood and tumors. In vivo anti-tumor activity was dependent on the accumulation of effector memory T or TCM Vβ T cells expressing a novel effector gene signature. Additional analysis of TILs showed increased clonality in de novo expanded Vβ T cells compared to controls in addition to increased numbers of tumor-specific T cells. Conclusions: To our knowledge, the use of therapeutic antibodies to selectively target and expand Vβ T cell subsets and thereby modulate the germline TCR repertoire for therapeutic benefit is novel. Here we show that STAR0602 selectively binds and activates human Vβ6/Vβ10 T cells and promotes a novel TCM phenotype. Murine surrogate molecules targeting different Vβ T cell subsets demonstrated potent and durable single-agent anti-tumor activity even when targeting low frequency Vβ subsets. These expanded Vβ T cells appear to drive enhanced anti-tumor activity due to their increased effector potentials, novel memory phenotype, and a striking enrichment in clonal diversity. In summary, STAR0602 and similar Vβ TCR-targeting constructs have the potential to remodel the adaptive immune response to solid tumors that are refractory to anti-PD1 therapy. A Phase 1/2 clinical trial of STAR0602 is ongoing in patients with advanced metastatic cancers. Citation Format: Jacques Moisan, Madan Katraggada, Jonathan Hsu, Jessica Lowry, Wei Huang, Jian Tang, Roya Servattalab, Gurkan Guntas, Raj Chopra, Zhen Su, Andrew Bayliffe. A novel class of T cell-activators targeting germline encoded TCRβ chains promotes antitumor activity in PD1-refractory models through expansion of a clonally enriched effector memory T cell subset [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 LB338.