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.

Keywords: ImmTAC platform; T cell; T cell receptor; anti-CD3 bispecific; clinical data; immunotherapy; metastatic uveal melanoma; preclinical data; tebentafusp.

Figure 1

Immune-mobilising monoclonal T cell receptor against cancer (ImmTAC) molecule showing T cell receptor (TCR) targeting domain and effector anti-CD3 scFv. scFv—Single-chain variable fragment; TCR, T cell receptor.

Figure 2

ImmTAC molecules are designed to mimic the natural immune synapse formed by interaction of a TCR with a peptide-human-leukocyte-antigen (pHLA) complex. The anti-CD3 effector function attracts and binds to CD3 receptors (activating receptor) on T cell surfaces triggering T-cell mediated cancer cell lysis; HLA, Human leukocyte antigen; MHC, Major histocompatibility complex; TCR, T cell receptor.

Figure 3

Images from time-lapse video microscopy taken in dose-response experiments in vitro conducted over a range of successive time points from 0–20 h showing tebentafusp (80 pM)-mediated killing of gp100-positive HLA-A*02:01-positive uveal melanoma (UM) cells (92-1; red) by CD8+ T cells (dark blue). Melanoma cells that are gp100-negative, HLA-A*02:01-positive—an HLA-matched control—(A375; pale blue) are ignored by CD8+ T cells. The main image (left) represents t = 0 in the assay and is captured with a 63× oil immersion objective on Zeiss Axiovert 200M inverted microscope. The areas of green shown in the time-lapse images on the right-hand side are a dye activated by active caspase 3/7 to bind DNA and fluoresce, highlighting cellular apoptosis as a direct result of on-target tebentafusp-mediated T-cell redirection. The times where apoptosis of the highlighted target cells are first observed are denoted on the right and the border colours correspond to the same colour square in the main (left) image. Note the change in morphology of the cells on the right in line with the observed apoptosis as indicated by the green dye; UM, uveal melanoma.

Figure 4

Clinical studies with tebentafusp in UM; 1L, First line; 2L, Second line; CM, Cutaneous melanoma; ORR, Objective response rate; RP2D, Recommended phase II dose; UM, Uveal melanoma.

Figure 5

(A) OS in 19 patients with mUM receiving tebentafusp as part of the IMCgp100-102 trial [4]. (B) OS in 915 patients with mUM receiving immunotherapy, kinase inhibitors, anti-angiogenic therapy, chemotherapy or liver-directed therapy from 29 different trials [42]; KM, Kaplan–Meier; mUM, Metastatic uveal melanoma; OS, Overall survival.