Abstract PL05-04: TIL therapy of solid cancers: T cell features of clinical activity

Abstract Although treatment with tumor-infiltrating lymphocytes has received accelerated FDA approval, a major question remains which features of the infused TIL product correlate with clinical benefit. Recently, the results from our large randomized controlled phase III trial confirmed the unprecedented clinical activity of TIL therapy for patients with anti-PD-1 refractory metastatic melanoma. A marketing authorization application for TM001, the TIL product coming from the RCT, is under review by EMA. In the past 3 years, patients have been treated with TM001 under hospital exemption in the Netherlands. Real-world data from TM001 demonstrate ORR and PFS rates similar to what has been found in the RCT, indicating the consistency in benefit coming from TIL therapy. One major challenge with TIL is the lack of predictive biomarkers. Tumor-reactive T cells in the TME are in general rare. During aspecific expansion of TIL for therapy, there is no control over these rare tumor-reactive T cells, hence leading to a highly variable product between patients. In order to study the tumor-recognizing potential of TIL products and its relation to clinical response, we sought to develop technologies that enable to rapidly assess the antigens being recognized by expanded patient TIL. Using functional antigen recognition screens, we show that TIL in responder patients more often contain TIL with specificities for neoantigens and C/T antigens, compared to non responders’ TIL products. In addition, we found that the in situ? cell states of these tumor-reactive T cells at the start of TIL culture are predictive of clinical response by defining which T cells will expand into the infusion product. Features associated with clinical response include the capacity of tumor-reactive TIL to proliferate during ex vivo expansion, and involved expression of CD25 and markers of early T cell exhaustion. In contrast, lack of response was associated with either a lack of tumor-reactivity among patient TIL, or a lack of ex vivo expansion of tumor-reactive cells due to a late dysfunctional phenotypic state. In moving TIL to other indications, we show that TIL can be grown from epithelial cancers and sarcomas. Using the functional antigen drop-out screens, we show that many of these TIL from patients with either endometrial cancer or penile cancer harbour tumor-reactive clones and therefore could lead to an efficacious TIL product. Clinical trials are in preparation. Citation Format: John B. A. G. Haanen. TIL therapy of solid cancers: T cell features of clinical activity abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr PL05-04.