Background:
Modern melanoma therapies rely on T-cell function. Although immune checkpoint inhibitors (anti-PD1, -PD-L1, -CTLA4 and -LAG3) have revolutionised the treatment paradigm, suboptimal response rates and durability, and unpredictable toxicities are limitations in many patients. Tumour infiltrating lymphocytes (TILs) are effective but challenging to administer. Better therapies are needed. Newer therapies harness T-cells and the T-cell receptor (TCR) to augment antigen-directed cytotoxicity: T-cell engagers (TCEs) (eg. tebentafusp– the first TCE with survival benefit in uveal melanoma), engineered TILs (eTILs), chimeric antigen receptor T-cell therapies (CAR-T) and TCR-therapies (TCR-T). We review T-cell biology and summarise the status of emerging T-cell leveraging therapies in metastatic melanoma.
Methods:
Medline, Embase and PubMed databases were searched from 2000 to 20-03-2026, using keywords related to advanced/metastatic melanoma, clinical trials and T-cell therapies. The Clinical Trials Register (clinicaltrials.gov) was also searched with similar keywords to identify active, recruiting or completed trials. Identified trials were cross-checked for any published results (articles or conference abstracts), which were also included.
Results:
A total of 29 reports and 35 active or completed clinical trials were identified. The majority were on TCR-Ts (35.9%), followed by eTILs (31.3%), CAR-Ts (18.8%) and TCEs (14.1%). Common targets for TCR-Ts and CAR-T were NY-ESO-1, the MAGE-family, MART-1 and B7-H3. Most eTILs were transduced with cytokines (eg. IL-15, IL-7, IL-12, IL-2); chemokine regulators (CXCR2, SOCS1); PD-1 silenced; or directed to a particular neoantigen. Most therapies (62.5%) were restricted to patients with certain human leukocyte antigen (HLA) subtypes. HLA-A*02:01-restricted TCEs, tebentafusp and IMC-F106C (targeting gp100 and PRAME respectively), and PRAME-directed TCR-T, IMA203, are the only agents with phase 2/3 randomised trials. Most trials (60/64) are in early phase development. One study (PRISM-MEL-301) explored T-cell therapies in the first-line setting.
Conclusion:
T-cell leveraging therapies in metastatic melanoma are a growing frontier of innovation, evidenced by numerous active early phase trials. Whilst these therapies have the potential to improve the treatment paradigm of metastatic melanoma, further results and later phase trials are required to ascertain the clinical efficacy of TCEs, eTILs, TCR-Ts and CAR-Ts in this setting.