Comparative Immunotherapeutic Strategies in Advanced Melanoma: A Systematic Review and Bayesian Meta-analysis of TIL and Engineered Viral Vector Therapies

Melanoma remains a treatment-refractory malignancy in a subset of patients despite major advances with immune checkpoint inhibitors. Tumor-infiltrating lymphocyte (TIL) therapy and engineered viral vector immunotherapies represent mechanistically distinct strategies for advanced melanoma, but their comparative clinical roles remain incompletely defined.

This systematic review and Bayesian meta-analysis evaluated clinical outcomes of TIL therapy and engineered viral vector immunotherapies in adults with unresectable stage III or IV melanoma. Searches of PubMed, Embase, Scopus, Web of Science, ClinicalTrials.gov, and grey literature sources identified 12 contemporary eligible studies published between 2015 and 2025. One additional pre-2015 pilot study was retained for qualitative historical context because it represented early clinical feasibility of viral vector-based immunotherapy in melanoma. Overall, 13 studies were included in the qualitative review, including four randomized controlled trials and nine single-arm studies, while eight studies were eligible for Bayesian quantitative synthesis of ORR.

TIL therapy demonstrated substantial standalone activity, particularly in checkpoint-exposed or PD-1-refractory populations, whereas viral vector therapies showed variable monotherapy activity and stronger responses when combined with immune checkpoint inhibition. The pooled Bayesian ORR estimate was 37.8% (95% highest density interval [HDI]: 30.6%-45.3%). Sensitivity analysis excluding the smallest included study yielded a similar pooled estimate of 38.3% (95% HDI: 30.4%-46.2%). Certainty of evidence was moderate for ORR and low for survival and safety outcomes due to heterogeneity, sparse reporting, and inconsistent endpoint definitions.

These findings support complementary rather than competing roles for TIL and engineered viral vector immunotherapies and highlight the need for biomarker-guided sequencing studies in advanced melanoma.