Background: Immune checkpoint inhibitors have transformed the management of melanoma, yet many patients do not achieve durable benefit. Novel immunotherapeutic strategies are being developed in both cutaneous and uveal melanoma. Methods: This narrative review summarizes four classes of emerging immunotherapies: personalized cancer vaccines, intralesional immunotherapies, adoptive cell therapies, and bispecific T-cell engagers, focusing on mechanisms of action, clinical trial outcomes, limitations, and evidence maturity. Results: In the randomized phase IIb KEYNOTE-942 trial, adding the individualized mRNA vaccine mRNA-4157/V940 to adjuvant pembrolizumab prolonged recurrence-free survival (RFS; hazard ratio [HR] 0.561, 95% confidence interval [CI] 0.309-1.017), a hypothesis-generating result under phase III evaluation. In the phase III PIVOTAL trial, neoadjuvant intralesional daromun improved RFS compared with upfront surgery in resectable, mostly recurrent stage III melanoma (HR 0.55, 95% CI 0.38-0.78). The tumor-infiltrating lymphocyte therapy lifileucel and the oncolytic virus RP1 plus nivolumab received accelerated approval for anti-PD-1-refractory melanoma based on single-arm studies (objective response rates approximately 31-33%, with durable responses). In human leukocyte antigen HLA-A*02:01-positive metastatic uveal melanoma, the T-cell engager tebentafusp improved overall survival (OS) in a phase III trial. Preferentially expressed antigen in melanoma (PRAME)-directed T-cell receptor (TCR)-engineered T cells and T-cell engagers have shown activity in early-phase studies. Conclusions: These approaches expand therapeutic options for melanoma, but randomized evidence of improved outcomes is available only for some. HLA restriction, treatment burden, and manufacturing complexity remain key challenges, and ongoing phase III trials will define their clinical role.
Emerging immunotherapies in melanoma beyond immune checkpoint inhibitors: Vaccines, intralesional therapies, adoptive cell therapies, and T-cell engagers
Andrea Boutros;Alice Gatti;Alessandra Gennari
2026-01-01
Abstract
Background: Immune checkpoint inhibitors have transformed the management of melanoma, yet many patients do not achieve durable benefit. Novel immunotherapeutic strategies are being developed in both cutaneous and uveal melanoma. Methods: This narrative review summarizes four classes of emerging immunotherapies: personalized cancer vaccines, intralesional immunotherapies, adoptive cell therapies, and bispecific T-cell engagers, focusing on mechanisms of action, clinical trial outcomes, limitations, and evidence maturity. Results: In the randomized phase IIb KEYNOTE-942 trial, adding the individualized mRNA vaccine mRNA-4157/V940 to adjuvant pembrolizumab prolonged recurrence-free survival (RFS; hazard ratio [HR] 0.561, 95% confidence interval [CI] 0.309-1.017), a hypothesis-generating result under phase III evaluation. In the phase III PIVOTAL trial, neoadjuvant intralesional daromun improved RFS compared with upfront surgery in resectable, mostly recurrent stage III melanoma (HR 0.55, 95% CI 0.38-0.78). The tumor-infiltrating lymphocyte therapy lifileucel and the oncolytic virus RP1 plus nivolumab received accelerated approval for anti-PD-1-refractory melanoma based on single-arm studies (objective response rates approximately 31-33%, with durable responses). In human leukocyte antigen HLA-A*02:01-positive metastatic uveal melanoma, the T-cell engager tebentafusp improved overall survival (OS) in a phase III trial. Preferentially expressed antigen in melanoma (PRAME)-directed T-cell receptor (TCR)-engineered T cells and T-cell engagers have shown activity in early-phase studies. Conclusions: These approaches expand therapeutic options for melanoma, but randomized evidence of improved outcomes is available only for some. HLA restriction, treatment burden, and manufacturing complexity remain key challenges, and ongoing phase III trials will define their clinical role.
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