1503 The BaseTIL trial: combination of adoptive cell therapy with tumor-infiltrating lymphocytes with nivolumab to treat melanoma

<h3>Background</h3> Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) is effective in patients with melanoma, although long-term responses seem restricted to patients with complete remission. Many patients develop secondary resistance to TIL-ACT; however, the underlying mechanisms remain unclear. We conducted the BaseTIL trial (NCT04165967), a single-center investigator-initiated phase I trial, to test the feasibility and safety of TIL-ACT followed by PD-1 blockade in patients with advanced cutaneous melanoma with disease progression after at least one line of anti-PD-1 therapy.^{1 2} <h3>Methods</h3> TIL-ACT included tumor collection, <i>ex vivo</i> TIL expansion, lymphodepletion with cyclophosphamide and fludarabine, TIL transfer, and <i>in vivo</i> TIL stimulation with interleukin-2 (125’000 IE/kg, 10 days). TIL-ACT was followed by nivolumab treatment for a maximum of two years. Nine patients received TILs after lymphodepletion and at least one dose of interleukin-2 (median: 10; range, 1–10), and seven started nivolumab (median: 5; range, 2–23) <h3>Results</h3> All patients experienced hematologic adverse events (AEs). The most common non-hematologic AEs were fever and cytokine-release syndrome. No nivolumab-associated AEs of ≥ grade 2 occurred. The objective response rate to TIL-ACT was 22% (2/9, 2 partial remission). We also describe the development of secondary resistance to TIL-ACT due to intratumoral heterogeneity and the selection of a resistant tumor cell clone by the transferred T cells in one patient. The translational data of this patient showed mechanisms involved in secondary resistance to TIL-ACT that can potentially change current clinical practice because it advocates for T-cell collection from multiple tumor sites and analysis of tumor heterogeneity before treatment with TIL-ACT. <h3>Conclusions</h3> Our clinical trial demonstrated the feasibility and safety of treating metastatic melanoma with TIL-ACT in combination with Nivolumab. However, larger-scale trials are required to further elucidate the efficacy of this combinatorial approach, as well as to understand the secondary resistance mechanisms to TIL therapy. <h3>Acknowledgements</h3> The patients and families who made this study possible. The clinical teams at the University Hospital Basel who participated in the TIL program. Werner Krenger and Anke Wixmerten for the support of the GMP productions. Julia Manzetti, and Dimitrios Tsakiris, and Astrid Tschan-Plessl for the initial help during the setup phase of the TIL program. Foundation ‘Fond’action contre le cancer’ for research funding. Bristol Myers Squibb Switzerland for research funding and drug supply of nivolumab. University Hospital Basel for institutional funding within the Innovation Focus Cell Therapy. <h3>References</h3> König David, <i>et al.</i> Adoptive cell therapy with tumor-infiltrating lymphocytes in combination with nivolumab in patients with advanced melanoma. <i>Immuno-Oncology and Technology</i>, 0(0):100728. König David, <i>et al.</i> Melanoma clonal heterogeneity leads to secondary resistance after adoptive cell therapy with tumor-infiltrating lymphocytes. <i>Cancer Immunol Res</i>. 2024 Jul 2;<b>12</b>(7):814–821. doi: 10.1158/2326-6066.CIR-23-0757. PMID: 38631025. <h3>Ethics Approval</h3> The protocol and amendments were reviewed and approved by the local ethics committee (EKNZ, Basel, Switzerland; EKNZ Nr. 2019-01908) and the Swiss Agency for Therapeutic Products (Swissmedic, Bern, Switzerland). The trial was conducted in accordance with the International Council for Harmonization Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. All patients provided Journal Pre-proof 6 written informed consent. The study was designed by the authors. Drug supply of nivolumab was granted by Bristol-Myers Squibb