A T cell receptor β chain-directed antibody fusion molecule activates and expands subsets of T cells to promote antitumor activity

• Published in: Science translational medicine Vol. 15; no. 724; p. eadi0258
• Main Authors: Hsu, Jonathan, Donahue, Renee N, Katragadda, Madan, Lowry, Jessica, Huang, Wei, Srinivasan, Karunya, Guntas, Gurkan, Tang, Jian, Servattalab, Roya, Moisan, Jacques, Tsai, Yo-Ting, Stoop, Allart, Palakurthi, Sangeetha, Chopra, Raj, Liu, Ke, Wherry, E John, Su, Zhen, Gulley, James L, Bayliffe, Andrew, Schlom, Jeffrey
• Format: Journal Article
• Language: English
• Published: United States 29.11.2023
• Subjects: Animals; Antibodies - pharmacology; CD8-Positive T-Lymphocytes; Humans; Mice; Neoplasms - drug therapy; Neoplasms - metabolism; Programmed Cell Death 1 Receptor - metabolism; Receptors, Antigen, T-Cell - metabolism; Receptors, Antigen, T-Cell, alpha-beta - metabolism
• ISSN: 1946-6242
• DOI: 10.1126/scitranslmed.adi0258

Despite the success of programmed cell death-1 (PD-1) and PD-1 ligand (PD-L1) inhibitors in treating solid tumors, only a proportion of patients respond. Here, we describe a first-in-class bifunctional therapeutic molecule, STAR0602, that comprises an antibody targeting germline Vβ6 and Vβ10 T cell receptors (TCRs) fused to human interleukin-2 (IL-2) and simultaneously engages a nonclonal mode of TCR activation with costimulation to promote activation and expansion of αβ T cell subsets expressing distinct variable β (Vβ) TCR chains. In solution, STAR0602 binds IL-2 receptors in cis with Vβ6/Vβ10 TCRs on the same T cell, promoting expansion of human Vβ6 and Vβ10 CD4 and CD8 T cells that acquire an atypical central memory phenotype. Monotherapy with a mouse surrogate molecule induced durable tumor regression across six murine solid tumor models, including several refractory to anti-PD-1. Analysis of murine tumor-infiltrating lymphocyte (TIL) transcriptomes revealed that expanded Vβ T cells acquired a distinct effector memory phenotype with suppression of genes associated with T cell exhaustion and TCR signaling repression. Sequencing of TIL TCRs also revealed an increased T cell repertoire diversity within targeted Vβ T cell subsets, suggesting clonal revival of tumor T cell responses. These immunological and antitumor effects in mice were recapitulated in studies of STAR0602 in nonhuman primates and human ex vivo models, wherein STAR0602 boosted human antigen-specific T cell responses and killing of tumor organoids. Thus, STAR0602 represents a distinct class of T cell-activating molecules with the potential to deliver enhanced antitumor activity in checkpoint inhibitor-refractory settings.