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The field of melanoma research continues to advance rapidly and have ripple effects across oncology. Immune checkpoint inhibitors (ICIs) that stimulate the body’s immune system to recognize and destroy cancer cells have transformed the treatment landscape for advanced melanoma. Yet roughly half of patients still do not respond or develop resistance to currently approved therapies.
To overcome these challenges, researchers are exploring new ways to harness the immune system – from innovative bispecific protein therapies that “bridge” tumor and immune cells to next-generation engineered T-cell therapies. This October edition of Melanoma Clinical Trials to Watch highlights several ongoing clinical trials and recent updates at scientific meetings evaluating novel immunotherapy approaches for patients with advanced melanoma.
Immunocore has developed a unique class of bispecific drugs known as ImmTAC (immune-mobilizing monoclonal T-cell receptor against cancer) therapies. These drugs act as molecular “bridges” that bring a patient’s immune cells into close contact with melanoma cells, helping trigger an immune attack. This approach offers a new strategy for patients whose disease has progressed after ICIs.
Two ImmTAC drugs – brenetafusp and tebentafusp – are currently in Phase 3 testing for patients with advanced melanoma.
The Phase 3 PRISM-MEL-301 trial (NCT06112314) is comparing the combination of brenetafusp (IMC-F106C) plus nivolumab to standard nivolumab regimens as first-line treatment (the first treatment for advanced melanoma). This trial is for patients with Stage 3-4 advanced melanoma who have not yet received treatment.
Brenetafusp is designed to work with a certain human leukocyte antigen (HLA) – proteins which are involved in disease and immune defense. Participants must test positive for HLA-A*02:01, present in about half of melanoma patients, as brenetafusp specifically targets this protein in combination with PRAME (preferentially expressed antigen in melanoma), a tumor-associated protein found on the surface of nearly all melanoma cells.
The trial is being conducted in two stages to identify the optimal brenetafusp dose. The Phase 3 PRISM-MEL-301 trial is being conducted based off previous clinical data1 from a Phase 1/2 study which showed encouraging signs of activity – 35% of patients previously treated with ICIs experienced tumor reduction, and the therapy was well tolerated.
The Phase 3 TEBE-AM trial (NCT05549297) is testing another ImmTAC drug called tebentafusp – a therapy currently FDA-approved as KIMMTRAK for uveal melanoma – in patients with Stage 3 unresectable or Stage 4 non-uveal melanoma who have previously received ICIs.
Like brenetafusp, tebentafusp is designed to activate T cells against HLA-A*02:01–positive melanoma cells, but it targets a different protein called gp100, which is expressed at high levels in most melanoma cells and at much lower levels in normal cells.
Patients in the study are randomly assigned to receive tebentafusp alone, tebentafusp plus pembrolizumab, or a physician’s choice of standard treatment. Earlier studies2 combining tebentafusp with other immune checkpoint inhibitors showed that 14% of patients responded and tumor shrinkage rate was 41%, with a manageable safety profile.
ImmTAC drugs are generally administered as weekly IV infusions. As mono-therapies, these drugs have shown they were fairly well tolerated and have reduced side effects by allowing immune cells to attack just the cancer cells without attacking healthy cells. It is important to note that ImmTAC drugs are new, so some aspects of these drugs are not yet fully understood.
Uveal melanoma, also called ocular melanoma, develops in the eye and accounts for only about 5% of all melanoma cases. Though rare, it can be difficult to treat, especially once it spreads beyond the eye. In 2022, the FDA approved tebentafusp (KIMMTRAK) for advanced or metastatic uveal melanoma. This therapy works by linking immune T cells and tumors, helping the immune system recognize and destroy the cancer cells.
Despite this progress, up to half of patients either do not respond to available treatments or experience disease progression and metastasis, most often to the liver. To address this unmet need, researchers are now turning to PRAME (Preferentially Expressed Antigen in Melanoma) – a protein found in roughly 90% of uveal melanomas that is associated with poorer outcomes – as a promising new target for cellular immunotherapy.
At the 2025 European Society for Medical Oncology (ESMO) Congress and Society for Melanoma Research (SMR) Annual Meeting, leading clinician-scientist Dr. Sapna Patel of the University of Colorado Anschutz presented results from Immatics’ ongoing Phase 1b IMA203/IMA203CD8 trial (NCT03686124). The study is evaluating anzutresgene autoleucel (anzu-cel, formerly IMA203), a PRAME-directed T-cell receptor (TCR) T-cell therapy in patients with advanced solid tumors, including a dedicated uveal melanoma (UM) cohort who previously received treatment.
Immatics’ TCR T-cell approach involves engineering a patient’s own T cells to recognize and enable a precise immune attack on tumor cells while sparing healthy tissue. Study participants were adults whose tumors tested positive for both the HLA-A*02:01 and PRAME proteins and who no longer had effective standard treatment options. Patients undergo leukapheresis (the collection of white blood cells), followed by lymphodepleting chemotherapy, and then receive a single infusion of anzu-cel supported by low-dose IL-2.
As Dr. Patel reported, in the uveal melanoma cohort of 16 patients, anzu-cel demonstrated strong anti-tumor activity and durability in this heavily pretreated population:
Importantly, several patients who had previously received tebentafusp or other TCR-based therapies also responded, suggesting the potential of PRAME-directed therapy to overcome prior resistance – even in those with large-volume disease.
Treatment related adverse events were largely consistent with lymphodepletion and T-cell therapy and were considered manageable. The most common adverse event was lymphodepletion-related cytopenias (low blood cell counts).
Given these encouraging results, Immatics is launching a Phase 2 expansion trial3 aimed at further validating these findings in a larger uveal cohort, refining the patient selection process, and exploring potential predictive biomarkers.
CAR-T therapy is a type of cell-based immunotherapy that uses a patient’s own genetically modified T cells to recognize and kill cancer cells. Unlike standard ICIs, CAR-T cells directly target specific proteins on the surface of cancer cells, which may overcome resistance to existing treatments.
One promising target in melanoma is IL13Rα2, a protein found on approximately 25% of tumors. Patients with high IL13Rα2 expression may be eligible for certain clinical trials.
Stanford Medicine is leading a phase I clinical trial to evaluate the safety and potential effectiveness of IL13Rα2-targeting CAR-T cells in patients with advanced melanoma and other solid tumors. The trial is led by Dr. Anusha Kalbasi (Stanford), with collaborators including Dr. Antoni Ribas (UCLA) and Dr. Christine Brown (City of Hope). The study is now open for enrollment at Stanford, City of Hope, and UCLA.
A patient’s individual expression of IL13Rα2 is measured by immunohistochemistry (IHA H-score). The trial specifically includes patients whose tumors have an IHA H-score of 50 or higher. Roughly 10–15% of melanoma patients have extremely high expression of IL13Ra2.
Participants undergo a chemotherapy conditioning regimen followed by an infusion of their own genetically modified T cells. The trial is designed to determine the safety and maximum tolerated dose of this treatment as well as clinical response.
The trial builds on prior success of CAR-T therapies in blood cancers and preliminary studies in glioblastoma. It also benefits from early support of a Melanoma Research Alliance Team Science Award, which helped researchers secure further funding to expand this work.
If successful, this trial could provide a new treatment option for patients who do not benefit from existing therapies and pave the way for additional CAR-T studies in melanoma and other solid tumors.
The melanoma research landscape continues to evolve as researchers test new ways to activate the immune system and expand the benefits of immunotherapy to more patients. From ImmTAC to engineered TCR-T and CAR-T cell therapies, these approaches represent the next generation of immune-based treatments that may help overcome resistance and extend long-term survival.
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