Eye restoration, making whole and healing. That is what Immunocore, a UK-founded biotech company pioneering in T cell receptor (TCR) therapeutics, is working towards achieving. Tebentafusp (IMCgp100) was developed to treat patients with metastatic uveal melanoma (mUM), a rare eye disease but the most common primary intraocular malignancy in adults.
Uveal, or ocular, melanoma is often detected only after the disease has spread from the eye to other parts of the body, such as the liver. There is no standard treatment for metastatic uveal melanoma. Once the disease has spread, many patients do not survive for a year. Therefore, there is a real need for specifically approved treatments and dedicated management strategies to improve outcomes for patients affected by this difficult-to-manage disease. Given the limited activity of currently authorized agents for advanced melanoma in the treatment of metastatic uveal melanoma, efforts have been placed on conducting clinical trials that have been designed based on the increased understanding of the biology of this disease.
ImmTAC Technology Platform: the Magic Healing
On 8th September 2021, Immunocore announced that United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA) had accepted a Market Authorization Application (MAA) seeking approval of tebentafusp. Moreover, Tebentafusp is also being reviewed in the U.K. under the U.S. Food, and Drug Administration’s (FDA) Projects Orbis Initiative.
Tebentafusp is a novel TCR/Anti-CD3 bispecific fusion protein composed of a soluble T cell receptor fused to an anti-CD3 immune-effector function. It explicitly targets gp100, a lineage antigen expressed in melanocytes and melanoma. It is the first molecule developed using Immunocore’s ImmTAC technology platform to redirect and activate T cells to recognize and kill tumor cells.
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.
Building an Immune Synapse
Melanomas of the skin are treated with immune checkpoints inhibitors. However, such treatment is less effective against uveal melanoma. One of the reasons is that uveal melanomas have fewer genetic alterations than melanomas of the skin. Several studies suggested that immune checkpoints inhibitors are more effective against tumors with many genetic mutations. Therefore, investigations on new solutions to overcome the resistance that metastatic uveal melanomas have to existent immunotherapies drugs are very necessary.
Tebentafusp brings a different therapeutically approach based on the immune synapse. It binds to one molecule on melanoma cells and another on T cells, a type of immune cell. The drug brings the T cells close enough to the melanoma cells to kill them. Specifically, one end of tebentafusp recognizes a part of a protein called gp100 that tends to be produced in abundance in melanoma cells, including uveal melanoma cells. The other end of tebentafusp binds to and activates T cells to attack the nearby gp100-expressing melanoma cells.
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.
A significant limitation for Tebentafusp to recognize and bind to gp100-expressing cancer cells is that these cells must also express a specific type of human leukocyte antigen (HLA), known as HLA-A*02:01. HLAs, which are present on the surfaces of most cells in the body, play an essential part in the body’s immune response to foreign substances. More specifically, HLA-A*02:01 is present in approximately half of all Whites, which is the population most affected by uveal melanoma. In other words, patients would not be responsive to the treatment unless they present this HLA-A*02:01.
Very optimistic results were reported in the first clinical trials with tubentafusp for uveal melanoma and at least other three trials are going on. The overall survival rate showed promising results, especially as described before, this is a disease resistant to the classical melanoma therapies with checkpoints inhibitors. As a magic healing, tubentafusp can be a live saving alternative.
Bertil E. Damato, Joseph Dukes, Howard Goodall and richard D. Carvajal. Tebentafusp: T Cell Redirection for the Treatment of Metastaic Uveal Melanoma. Cancers 2019, 11, 971. https://pubmed.ncbi.nlm.nih.gov/31336704/
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