Immunologic Determinants of Infusion Products and the Tumor Microenvironment Govern Response to TIL Therapy in Advanced Melanoma

Durable responses to tumor-infiltrating lymphocyte (TIL) therapy in advanced melanoma tracked with infusion products enriched for stem-like and LAG-3-expressing CD8+ T cells, and with tumors containing tertiary lymphoid structures (TLS), according to a pooled analysis published in Med. Investigators at H. Lee Moffitt Cancer Center profiled both the infused product and the source tumor microenvironment across four early-phase trials, with a median follow-up of 102 months.

TIL therapy is now approved for advanced melanoma, but many patients derive limited benefit and the contribution of the procured tumor tissue to product quality remains poorly defined. Sixty patients enrolled between 2009 and 2018 received TIL alone (n = 19) or combined with ipilimumab (n = 13), nivolumab (n = 11), or vemurafenib (n = 17), and 50 proceeded to infusion. Products were characterized by flow cytometry and TCRβ sequencing; tumors were assessed by H&E review, multiplex immunofluorescence for TLS, and GeoMx whole-transcriptome spatial profiling of tumor, immune, and TLS regions.

Durable (≥12 months) responses occurred in 36% of infused patients, with complete responses in 14%, a median progression-free survival (PFS) of 8.4 months and a median overall survival of 46 months. Responders received products with a higher CD8+ fraction (89% vs 54%, p = 0.003), more stem cell memory CD8+ T cells (p = 0.04), and greater peripheral persistence (overlap coefficient 0.83 vs 0.72, p = 0.013). LAG-3+CD3+ frequency was 71% versus 40% (p = 0.001), and higher infused LAG-3+ TIL numbers predicted longer PFS (41 vs 2.9 months, p = 0.002). Prior checkpoint inhibitor exposure was associated with fewer stem-like cells and reduced OX40 and 4-1BB expression, clonality, and diversity. TLS were present in 56% of tumors and associated with response (56% vs 20%, p = 0.014) and PFS (HR, 0.40; 95% CI, 0.19–0.86). A 25-gene immune activation score derived from responder immune regions stratified PFS (p < 0.0001) and validated in an external cohort (p = 0.048). The authors conclude that integrated profiling of product and microenvironment may guide patient selection and combination strategies.

Reference:

Karapetyan L, Xu J, Ward K, et al. Immunologic determinants of infusion products and the tumor microenvironment govern response to TIL therapy in advanced melanoma. Med. 2026;7(8):101231. https:doi.org/10.1016/j.medj.2026.101231