Extended monitoring and biomarker analysis in metastatic melanoma patients treated with TIL therapy and conditioning-replacing igrelimogene litadenorepvec virotherapy: Pre-infusion immune cell and cytokine profiles associated with survival.

2538 Background: Adoptive transfer of tumor-infiltrating lymphocytes (TILs) can be effective in metastatic melanoma, but its routine use is limited by the need for lymphodepleting chemotherapy and systemic high-dose IL-2. To reduce toxicity while preserving antitumor activity, a strategy pairing TIL therapy with the oncolytic adenovirus igrelimogene litadenorepvec (TILT-123) was assessed. This virus selectively replicates in malignant tissue and drives local expression of TNF and IL-2 within tumors, functionally replacing the need for pre-infusion chemotherapy and post-infusion IL-2 administration. Methods: Seventeen patients with advanced melanoma resistant to immune checkpoint inhibitors were treated and sampled (NCT04217473). Treatment with igrelimogene litadenorepvec started upon tumor biopsy collection for TIL manufacturing took place and eventually followed by autologous TIL infusion around 36 days after. Hypotheses generated during data analysis were validated using additional patient datasets (NCT04695327, NCT05271318). Results: The regimen was well tolerated, with no dose-limiting toxicities. Objective response rate was 11.7%, with disease control in 35% by RECIST 1.1 and 47% by PET; metabolic responses were seen in 27%. Among those patients, higher baseline expression of epidermal and hepatocyte growth factors (EGF and HGF respectively) was associated with poorer prognosis. Higher than median HGF was negatively correlated with survival (p=0.032). Additionally, patients that achieved disease stabilization or better had a lower presence of circulating MDSCs (p=0.017). The link between growth hormones, MDSCs and disease progression was extrapolated to a larger dataset including other patients treated with igrelimogene litadenorepvec to find out the same trend for survival (HGF; p = 0.003, EGF; p = 0.029). In parallel, baseline circulating young memory T cells (CD27+CD28+CD8+) and an early expansion of NK cells (CD45+CD56+CD3-) correlated with a lower chance of progressing (T cells p=0.005, NK cells p=0.003). Conclusions: Combining TILT-123 with TIL therapy was safe and produced meaningful clinical activity in checkpoint inhibitor-refractory melanoma, especially in patients with lower HGF and EGF at baseline and a higher presence of young memory T cells and NK cells. In this clinical set-up, adapting the inclusion exclusion criteria to select patients with those defined immune system features, could help improve efficacy beyond. This approach may substantially broaden the feasibility and accessibility of TIL-based immunotherapy, especially due to the omission of the toxic conditioning regimens. Clinical trial information: NCT04217473 .