HLA-A*02:01

Tebentafusp for patients with HLA-A*02:01-positive mUM is associated with improved survival outcomes and manageable toxicity. These findings support tebentafusp as the standard of care for this patient population.

Dermatological involvement is common and manageable, highlighting the need for early dermatological input in patients receiving tebentafusp. Emerging data suggest a possible association between rash and response, which warrants further investigation.

Anti-PD-1 monotherapy demonstrated limited clinical activity, providing little benefit beyond conventional chemotherapy. Dual checkpoint blockade with ipilimumab and nivolumab achieved higher response and disease control rates, albeit with increased toxicity, suggesting a potential benefit for selected patients. Tebentafusp has emerged as an effective option and a new standard of care for a molecularly defined subgroup of HLA-A*02:01-positive patients. However, for the majority of individuals with metastatic uveal melanoma, effective systemic therapies remain an unmet need.

Additionally, circulating tumor DNA (ctDNA) may serve as a more sensitive efficacy biomarker than radiological responses, warranting further investigation. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD420251084090.

For patients with metastatic uveal melanoma (UM), tebentafusp is currently the only systemic therapy approved by the EMA and FDA, but its use is limited to HLA-A*02:01-positive individuals...These findings indicate that patients responding to ICB display tumors with enhanced immune activation. CD28 and CCL8 emerged as promising candidates and should be validated in prospective studies to determine their clinical utility.

T cells engineered with each αβTCR selectively recognized and killed HLA-A*02:01-positive AML targets endogenously expressing corresponding mutations. Overall, our findings support the clinical translation of adoptive neoantigen-specific TCR-engineered T cells as a novel therapeutic strategy for treating AML.

Administration of the surrogate immunotherapeutic prolonged median survival time of B16.F10 tumour-bearing mice relative to controls. Based on these results, a Phase I clinical trial with CVGBM was started in HLA-A*02:01-positive patients with surgically resected MGMT-unmethylated GBM (NCT05938387).

Patients enrolled in the phase 1 part of CD-TCR-001 displayed signs of potential clinical and biological activity of MDG1011 among the small number of patients studied. Advanced disease stage and rapid progression in the r/r AML patients limited clinical impact. The acceptable safety profile of MDG1011 merits further investigation of this TCR-T therapy, potentially in patients at an earlier stage of their disease and with lower tumor burden.

Cutaneous toxicity occurred in 89% of patients, but reactions were manageable with no patients permanently discontinuing treatment. To our knowledge, we also report the first case of bullous pemphigoid associated with tebentafusp.

TRAEs were consistent with tebentafusp's mechanism of action, mostly occurred during dose escalation, and were predictable, reversible, and manageable with appropriate surveillance and intervention.

Tebentafusp therapy can lead to diffuse fundus hypopigmentation and choroidal thinning, similar to what has been reported after immune checkpoint inhibition. The progressive choroidal hypopigmentation, without evidence of associated intraocular inflammation, indicates that glycoprotein 100, the target antigen of tebentafusp, is also expressed by normal choroidal melanocytes.

Our analysis indicates that the triple combination of Ipilimumab, anti-PD-1 agents, and tebentafusp significantly enhances objective response rates, disease control rates, 1-year overall survival rates, and median overall survival (mOS) compared to ICI monotherapy alone. Additionally, early-phase studies involving dendritic cell-based immunotherapies and peptide vaccines has shown encouraging signs of tumor-specific immune activation, along with improved tolerability. Collectively, this review underscores the urgent need for more precise and effective immunotherapeutic approaches tailored to the unique biology of mUM.