T细胞
生物
抗体
化学
嵌合抗原受体
受体
细胞生物学
癌症研究
免疫学
免疫系统
生物化学
作者
Jonathan Hsu,Renee N. Donahue,Madan Katragadda,Jessica Lowry,Wei Huang,Karunya Srinivasan,Gurkan Guntas,J. Tang,Roya Servattalab,Jacques Moisan,Yo‐Ting Tsai,A. Allart Stoop,Sangeetha Palakurthi,Raj Chopra,Ke Liu,E. John Wherry,Zhen Su,James L. Gulley,Andrew Bayliffe,Jeffrey Schlom
出处
期刊:Science Translational Medicine
[American Association for the Advancement of Science (AAAS)]
日期:2023-11-29
卷期号:15 (724)
标识
DOI:10.1126/scitranslmed.adi0258
摘要
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.
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