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Background Tebentafusp, a gp100-directed ImmTAC bispecific (gp100 x CD3), is the first TCR therapeutic to demonstrate survival benefit and is approved for the treatment of HLA-A*02:01+ adults with unresectable or metastatic uveal melanoma (mUM). 1 A baseline blood T cell fitness (TCF) signature, which captures levels of naïve/stem cell memory T cells, was strongly associated with clinical benefit from ImmTAC therapy.2 We explored how mUM patients with high TCF derive greater benefit from tebentafusp treatment.Methods The impact of different T cell:tumor cell ratios (E:T) on ImmTAC-mediated killing was assessed in vitro over 72 hours using the UM cell line MP41. Baseline and on-treatment tumor biopsies from a Phase 2 trial of tebentafusp-treated HLA-A*02:01+ mUM patients ( NCT02570308) were used to quantify CD3+ cells by immunohistochemistry (n=117) and to measure gene expression by bulk RNAseq (n=85). TCF was determined from baseline blood bulk RNAseq based on mean expression of TESPA1, CD28 and GPR183. TCF high/low patients were cut at median TCF.Results In vitro, MP41 cell numbers increased by 253% over 72h. In the presence of ImmTAC, their growth was stabilized at low E:T ratios (50% increase at 1:3 E:T) and reduced at high E:T ratios (38% decrease from baseline at 5:1 E:T). ImmTAC-mediated caspase 3/7 activity, a marker of tumor apoptosis, was only evident at E:T ratio ≥ 2:1. Treatment of MP41 with ImmTAC supernatants resulted in a 25-fold reduction in tumor cell growth, decreased expression of melanogenesis and proliferation genes by 1.7-2.4-fold, and increased acute inflammation genes >1000-fold. In mUM tumor biopsies, infiltrating CD3 + T cells increased after 3 doses of tebentafusp, more so in TCF high patients (3.4 fold change [FC]) compared to TCF low patients (1.5 FC, table 1). In TCF high but not TCF low patients, acute inflammation genes were significantly increased, while tumor proliferation and melanogenesis genes were reduced. (table 1). Both TCF high and low patients showed similar induction of T cell cytotoxic genes, and PDL1 and PDL2 but not CTLA4 or LAG3 genes were significantly upregulated only in TCF low patients (table 1). Expression of the cancer testis antigen PRAME and normal hepatocyte genes (GGT1, CEPT1) remained unchanged in both groups.Conclusions In TCF high patients, tebentafusp increases the E:T ratio in tumors, modifies the tumor microenvironment to an inflammatory state (turning cold tumors hot) and slows tumor proliferation, resulting in greater disease control and longer survival.Trial Registration NCT02570308References Nathan, et al. NEJM 2021.Sacco, et al. ESMO 2024.Ethics Approval Patient samples used in this study were collected as part of clinical trial NCT02570308. The trial was carried out in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines, and the study protocol was approved by the relevant ethics bodies at each participating site. Patients provided written informed consent before being screened for enrollment. Further details can be found in Carvajal R.D. et al. Clinical and molecular response to tebentafusp in previously treated patients with metastatic uveal melanoma: a phase 2 trial. Nat. Med. 2022;28:2364–2373.Abstract 959 Table 1Mean fold changes of T cell counts and gene signatures in patient biopsies from tebentafusp-treated mUM patients