Tumor-infiltrating lymphocyte therapy in lung cancer: A systematic review

Abstract Background: Lung cancer remains the leading cause of cancer-related deaths, with over 124,000 deaths projected in the U.S. in 2025. Tumor-infiltrating lymphocyte (TIL) therapy, a form of adoptive cell therapy, has shown promise in melanoma and is now being explored in lung cancer. This review assesses the safety and efficacy of TIL therapy in non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), and other rare subtypes of lung cancer. Methods: A comprehensive literature search was conducted across PubMed, Embase, Scopus, and the Cochrane Library up to May 29, 2025, in accordance with PRISMA guidelines. Search terms included combinations of “tumor-infiltrating lymphocytes,” “TIL therapy,” “lung cancer,” “non-small cell lung cancer,” and “small cell lung cancer.” Eligible studies included adult patients receiving TIL therapy alone or in combination with standard therapies. Four studies (two single-arm and two comparative) were included. Due to heterogeneity in study design, interventions, and outcome reporting, results were synthesized descriptively. A random-effects meta-analysis was performed only for objective response rate (ORR), using Review Manager v5.4 and R v4.5.1. Heterogeneity was assessed using the I² statistic. Results: This analysis included four studies (Schoenfeld et al. 2024, Creelan et al. 2021, Chu et al. 2017, Ratto et al. 1996) involving 185 patients with advanced or metastatic NSCLC or malignant pleural effusion. The median age was 61.5 years, with approximately equal gender distribution. Most patients had stage III–IV disease and an ECOG performance status of 0–1. PD-L1 expression was low to moderate in the majority, and brain or liver metastases were reported in 46.4% of patients. TILs were sourced from lung or metastatic sites, expanded ex vivo, and administered following lymphodepletion (primarily cyclophosphamide/fludarabine). High-dose IL-2 and checkpoint inhibitors were used in some protocols. Objective response rates ranged from 21.4% to 46%, with a pooled ORR of 32% (95% CI: 13%–59%; p = 0.11; I² = 60.2%). Median OS was 22.4 months in the TIL group, compared to 14.1 months with cisplatin (Ratto et al.) and 371.8 days in another TIL cohort (Chu et al.). PFS ranged from 143.2 days (Chu et al.) to 1.5 years (Creelan et al.). The quality of life improved in 67% of TIL-treated patients compared to 33% of patients treated with cisplatin. Common toxicities included febrile neutropenia (28.5%), hypotension (64%), and cytopenias. Two treatment-related deaths were reported; most studies were open-label with variable attrition. Conclusion: TIL therapy shows encouraging clinical activity and manageable toxicity in lung cancer, with improvements in survival, response rates, and quality of life. However, small sample sizes and study variability limit definitive conclusions. Larger, standardized trials are needed to confirm its long-term benefits.