A TCR/anti-CD3 bispecific fusion protein targeting gp100 potently activated anti-tumor immune responses in metastatic melanoma

Tumor-specific cytotoxic T cells are required for effective immunotherapy. Here we introduce a bispecific fusion protein (tebentafusp) designed to target gp100 (a melanoma-associated antigen) through a high affinity T cell receptor binding domain, and through an anti-CD3 effector domain re-directs any cytotoxic T cell, regardless of its intrinsic specificity, to kill gp100-expressing tumor cells. In patients with metastatic melanoma, tebentafusp showed anti-tumor activity and manageable and predictable side effects. Notably, tebentafusp induced an increase in serum CXCL10 (a T cell attractant), and a reduction in circulating CXCR3+ CD8+ T cells together with an increase in cytotoxic T cells in the tumor microenvironment (TME). Furthermore, the appearance of rash, likely due to cytotoxic T cells targeting of gp100-expressing skin melanocytes, or an increase in serum CXCL10 showed a positive association with patient survival. Taken together, these results suggest that re-directing T cells using a gp100-targeting T cell receptor/anti-CD3 bispecific fusion protein may provide benefit to patients with metastatic melanoma. To assess the changes in the tumor immune micro-environment following tebentafusp more broadly, we analyzed gene expression from paired baseline and on-treatment biopsies. We compared within a subset of 9 patients (melanoma type: 1 uveal, 8 non-uveal), 2 responders (partial response) and 7 with progressive disease.