Tebentafusp: T Cell Redirection for the Treatment of Metastatic Uveal Melanoma

Abstract

Metastatic disease from uveal melanoma occurs in almost 50% of patients suffering from this ocular tumour, with median survival from development of symptoms being around 1 year. In contrast to cutaneous melanoma, kinase inhibitors and immune checkpoint inhibitors are usually ineffective in patients with metastatic uveal melanoma. Tebentafusp is a novel form of immunotherapy based on the immune-mobilising monoclonal T cell receptor against cancer (ImmTAC) platform, which comprises a soluble T cell receptor that is fused to an anti-CD3 single-chain variable fragment. The T cell receptor domain of tebentafusp targets cells present a human leukocyte antigen-A*02:01 complexed with a peptide derived from the melanoma-associated antigen gp100, which is expressed strongly by melanoma cells, weakly by normal melanocytes and minimally by other tissues. The anti-CD3 domain recruits CD3+ T cells (and, indirectly, other immune cells), redirecting these to the melanoma cells. The most common adverse events with tebentafusp are manageable and usually transient. Early survival data in patients with metastatic uveal melanoma are promising when considered alongside historical data. Based on these encouraging results, a randomised study comparing tebentafusp to investigator’s choice of therapy in metastatic uveal melanoma is ongoing.

Immune‐Mobilizing Monoclonal T Cell Receptors Mediate Specific and Rapid Elimination of Hepatitis B–Infected Cells

“…( 22,23 ) This is supported by previous clinical experience with tebentafusp, our lead ImmTAC molecule in oncology. ( 29,30 )…”

Molecular Insights and Emerging Strategies for Treatment of Metastatic Uveal Melanoma

“…It redirects the recruitment of CD8+ cytotoxic T lymphocytes against melanoma cells. This molecule has shown a favorable safety profile and durable responses in mUM, and it is currently under investigation in advanced UM in a single-arm, phase I/II dose-escalating clinical trial and in a randomized, controlled phase II trial versus the investigator’s choice of therapy [ 230 , 231 , 232 , 233 ]. As an additional promising strategy, CAR-T cells directed against human epidermal growth factor receptor 2 (HER2) were demonstrated to be able to kill uveal and cutaneous melanoma cells in vitro and in vivo settings [ 226 ].…”

Uveal Melanoma

“…Recent reports on a specific inhibitor of the mutated form of GNAQ [7,8] must be confirmed and translated into clinical applications. Immune checkpoint blockers that have met considerable success in the treatment of several cancers, including cutaneous melanoma [9], show very low response rates in uveal melanoma (but see [10][11][12][13][14]), likely due to the low number of neo-antigens, a consequence of a very low mutational burden [15][16][17].…”

“…In the present thematic issue, the authors of 44 articles (31 original research articles [10,13,, 11 reviews [4,11,12,14,[47][48][49][50][51][52][53], one position paper [54], and one network report [55]) give insight into the current state of our understanding of uveal melanoma biology and clinics. They also discuss opportunities for the development of new therapeutics that will hopefully soon improve the survival rates of metastatic uveal melanoma patients.…”

“…Fountain et al show that immune checkpoint blockers might be useful in the adjuvant setting and call for clinical trials [10]. Damato et al report on the promising T-cell receptor-gp100 fusion construct tebentafusp as a strategy for adaptive immunotherapy for metastatic uveal melanoma [14].…”