Background: Limitations with agents that activate endogenous T cell responses to cancer, particularly in the setting of solid tumors, supports the study of alternative mechanisms. STAR0602 is a bifunctional antibody—fusion molecule that selectively activates and expands a sub—set of human aβ T cells expressing the germline—encoded variable b6 and b10 regions of the T cell receptor (TCR). STAR0602 simultaneously engages a novel, direct TCR activation with a cis-binding cytokine co-stimulation through the fusion of IL-2 to an inactivated Fc domain bearing an anti-TCR Vb6/Vb10 Fab.
Methods: The effects of STAR0602 on healthy human and cancer patient T cells was assessed in vitro by flow cytometry and NanoString. A murine surrogate (mSTAR0602) was tested as a monotherapy in multiple murine syngeneic tumor models (including PD1-insensitive and refractory), with tumor re—challenge and cellular depletion studies to assess long-term protection and cell—specific activities, respectively. EMT6 tumors were excised for IHC staining and phenotyping of tumor-infiltrating lymphocytes (TILs) using flow cytometry and scRNAseq/TCRseq.
Results: STAR0602 induced expansion of Vb6/Vb10T cell subsets preferentially in CD8+ T cells over CD4+ T cells. Compared to controls and anti-CD3 mAbs, STAR0602—stimulated T cells adopted a novel, highly activated phenotype with markers of both effector and central memory T cells (TEM/TCM). STAR0602 also boosted the ex vivo expansion of antigen-specific T cells from HPV+ individuals (both healthy donor and cancer patient). Consistently across multiple syngeneic murine tumor models, mSTAR0602 monotherapy either eradicated tumors, or led to substantial tumor regressions. mSTAR0602-cured mice also demonstrated long-term protection from tumor re-challenge. In vivo anti-tumor activity was shown to be dependent on the accumulation of Vb6/Vb10T cells, and analysis of murine TILs showed expanded Vb6/Vb10 T cells were almost exclusively polyclonal TEM or TCM cells, with almost no exhausted or regulatory T cells.
Conclusions: STAR0602 is a first-in-class T cell activator that selectively targets subsets of the “germline TCR repertoire.” In vitro, STAR0602 promotes the expansion of a novel T cell phenotype with hallmarks of both effector and long-lived memory cells, and in vivo mSTAR0602 demonstrates potent and durable single-agent anti-tumor activity in PD1—insensitive solid tumor models, that is dependent on Vb6/Vb10 memory T cells. The modulation of the TME, striking increase in TCR diversity, and functional immune memory observed in murine models suggests that STAR0602 could promote a fundamental remodelling of adaptive immune responses to solid tumors via a PD1-independent mechanism, and thus represents a novel therapeutic strategy for patients. A phase 1/2 trial of STAR0602 in patients with advanced solid tumors is planned to commence in 2022.
Conflict of interest:
Ownership: Marengo Therapeutics.
Advisory Board: Marengo Therapeutics.
Board of Directors: Marengo Therapeutics.
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