T-cell receptor (TCR)-engineered therapies represent an emerging approach in melanoma immunotherapy that fundamentally differs from current checkpoint inhibitors and cell surface-directed treatments.1 Unlike therapies targeting extracellular proteins, TCR-based approaches can access approximately 90% of cellular proteins, including intracellular targets, by recognizing peptide fragments presented on HLA molecules.2
PRAME (preferentially expressed antigen in melanoma), a cancer-testis antigen, has emerged as a promising target for TCR therapy.3 Frequently overexpressed in cutaneous melanomas with minimal expression in normal tissues, PRAME offers a favorable therapeutic window that may reduce toxicity risk.3 Early phase 1 trial data in HLA-A*02:01 positive patients demonstrate feasibility and preliminary responses in checkpoint inhibitor-refractory advanced solid tumors, including melanoma, though these findings remain investigational.1
TCR therapies work by redirecting immune recognition directly to tumor cells, potentially overcoming resistance mechanisms that limit checkpoint inhibitor efficacy.2 This mechanism targets tumor cells regardless of their PD-L1 expression status or other immune evasion strategies.2 In contrast to CAR-T therapies, which recognize surface antigens independent of MHC, TCR therapies can target intracellular tumor antigens presented via HLA, expanding the range of actionable targets in solid tumors. However, TCR cell therapy continues to face challenges including potential TCR mispairing, on-target off-tumor toxicity, and the need for refined manufacturing processes as these platforms advance toward broader clinical implementation.4
Patient selection for PRAME-targeted TCR trials requires both tumor PRAME expression and specific HLA typing (HLA-A*02:01 positivity), which occurs in about half of all patients with melanoma.1,5 Clinicians should consider incorporating these biomarker assessments during diagnostic workup or at progression, particularly for patients who may exhaust standard treatment options. Early identification of eligible patients expands access to emerging cellular therapy trials and ensures timely referral when appropriate. Understanding these targeted cellular approaches helps clinicians counsel patients on evolving treatment landscapes and research participation opportunities.
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