esm.doi.bio/esm33/out1

Response: As of my knowledge cutoff in October 2023, tebentafusp is not approved or commonly used to treat IDH-wildtype glioblastoma. Tebentafusp is a bispecific T-cell receptor (TCR) fusion protein, also known as an ImmTAC (Immune-mobilizing Monoclonal T-cell Receptors Against Cancer), that specifically targets gp100—a melanocyte differentiation antigen presented by HLA-A02:01 molecules. It is approved for the treatment of HLA-A02:01-positive adults with unresectable or metastatic uveal melanoma, a rare cancer of the eye.

IDH-Wildtype Glioblastoma and Current Treatments:

IDH-wildtype glioblastoma is the most common and aggressive primary brain tumor in adults. Standard treatment typically includes:

• Maximal Safe Surgical Resection: Removal of as much of the tumor as possible without damaging critical brain function.
• Radiotherapy: Targeted radiation to kill remaining cancer cells.
• Chemotherapy with Temozolomide: An oral alkylating agent that crosses the blood-brain barrier.
• Tumor Treating Fields (TTF): A treatment modality using electric fields to disrupt cancer cell division (such as Optune).

Why Tebentafusp Is Not Used for Glioblastoma:

1. Target Antigen Expression: Glioblastoma cells generally do not express the gp100 antigen at levels sufficient for effective targeting by tebentafusp. Gp100 is primarily associated with melanocytic cells and is not a characteristic marker of glioblastoma.

2. HLA Restriction: Tebentafusp is specifically designed for patients who are HLA-A02:01 positive. While HLA-A02:01 is common, the lack of gp100 expression in glioblastoma makes this targeting strategy ineffective.

3. Blood-Brain Barrier (BBB): BiTE molecules and other large biologics face challenges crossing the BBB, which limits their effectiveness against central nervous system tumors like glioblastoma.

4. Clinical Evidence: There are no clinical trials or studies that have demonstrated the efficacy of tebentafusp in treating glioblastoma. Current research does not support its use in this context.

BiTE Platform and Glioblastoma:

While the BiTE (Bispecific T-cell Engager) platform holds promise in oncology by redirecting T cells to target tumor antigens, its application in glioblastoma is still under investigation. Challenges include:

• Identifying Suitable Targets: Finding antigens that are uniquely or overexpressed on glioblastoma cells but not on normal brain tissue to avoid off-target effects.
• Immunosuppressive Tumor Microenvironment: Glioblastoma creates an environment that suppresses immune responses, making immunotherapy less effective.
• Delivery to the Brain: Ensuring that therapeutic agents reach the tumor site in the brain in effective concentrations.

Conclusion:

Currently, there is no established method to treat IDH-wildtype glioblastoma with tebentafusp or the BiTE platform. Treatment remains focused on surgery, radiotherapy, chemotherapy, and exploring emerging therapies through clinical trials. If you or someone you know is dealing with glioblastoma, it's important to consult with a neuro-oncologist to discuss the most current and effective treatment options, including potential participation in clinical trials exploring new therapies.