A Feasibility Study of Tumor-Infiltrating Lymphocytes (TIL) in Patients with Cutaneous Squamous Cell Carcinoma and Merkel Cell Carcinoma after Anti-Pd-1 Therapy.

TPS9616 Background: Tumor infiltrating lymphocyte (TIL) therapy is an autologous cellular therapy isolated from a patient's tumor. Clinical data demonstrated that TIL therapy in heavily pretreated melanoma patients yielded an objective response rate (ORR) in 30% of patients with 5-year overall survival (OS) of approximately 20%. TILs were approved by the FDA in February 2024 for the treatment of metastatic or unresectable melanoma that have progressed on anti-PD-1 therapy and BRAF+MEK inhibitors (in patients with BRAFV600 mutation). Non-melanoma skin cancers, including cutaneous squamous cell cancer (CSCC) and Merkel cell cancer (MCC), share biologic features with melanoma, including an “inflamed” tumor microenvironment and high responsiveness to anti-PD-1 therapy. However, approximately, a third of patients will experience disease progression after anti-PD-1 therapy or will discontinue treatment due to toxicity and subsequently experience disease progression. Given the overlap between melanoma and CSCC/MCC, we hypothesize that TIL therapy may induce immune response against non-melanoma skin cancers. Because some of these tumors are superficial and are often ulcerated and can contain polymicrobial contamination, this trial will also assess the feasibility of TIL production in this unique patient population, alongside its safety and efficacy. Methods: Ten patients with CSCC (Cohort A) and 4 patients with MCC (Cohort B) adults will be eligible for TIL if they have disease progression after anti-PD-1 therapy. Eligible patients should have adequate organ function and be able to receive dose-reduced non-myeloablative lymphodepletion (NMA-LD) and interlukin-2 (IL-2). Following tumor harvest and TIL manufacturing, patients will receive NMA-LD including cyclophosphamide (30 mg/kg on days –5 and –4), and fludarabine (25 mg/m2 on days –5 to –1). Subsequently, patients will receive TIL on day 0 followed by IL-2 (600,000 IU/kg) for up to 6 doses. The primary objective is to evaluate feasibility and safety of TIL production and administration in cohorts A and B (defined by successful tumor harvest that leads to a TIL product that contains ≥ 1 x 10^9 cells, administration of NMA-LD, infusion of TIL therapy and complete at least 1 dose administered of IL-2). Secondary objectives include ORR, progression-free survival, duration of response, OS and correlative studies. Within Cohort A, efforts will be made to achieve an approximately equal distribution of ulcerated and non-ulcerated lesions. To maintain this balance, ulceration status will be monitored throughout the enrollment process, and eligibility criteria may be modified as necessary to ensure proportional representation of each subtype. Clinical trial information: NCT07288073 .