Immunocore's Dar Says TCR Therapies Could Broaden Immunotherapy Beyond Checkpoint Resistance

Checkpoint inhibitors have transformed the treatment of melanoma and many other cancers, but a substantial proportion of patients either fail to respond or eventually develop resistance. According to Mohammed Dar, MD, chief medical officer and head of clinical development at Immunocore, addressing those patients will require therapies designed around entirely different mechanisms of immune activation.

Speaking with BioPharm International, Dar discussed updated data for the company's investigational PRAME-targeting T-cell receptor (TCR) bispecific therapy, brenetafusp, and explained why the platform could help extend the benefits of immunotherapy to patients who have exhausted current treatment options.

How could TCR bispecific therapies expand treatment beyond checkpoint inhibitors?

Dar said one of the most important findings from the latest brenetafusp data is that TCR bispecific therapies appear to function differently from checkpoint inhibitors, allowing them to remain active even when PD-1 therapies have failed.

"One of the most interesting insights from the brenetafusp data is that the mechanism of action for these TCR bispecifics is quite distinct from checkpoint inhibitors," Dar said. "They are likely to work in settings where checkpoints have historically not worked, including in patients who are resistant to checkpoint therapy."

Unlike conventional monoclonal antibodies that recognize proteins on the surface of tumor cells, TCR bispecifics can target intracellular proteins presented through the major histocompatibility complex. Dar said that capability dramatically expands the number of potential cancer targets.

"We're really excited about PRAME as a target," he said. "With these TCR bispecifics, we can unlock a whole new universe of targets, especially intracellular targets."

Because PRAME is expressed across numerous cancers—including ovarian, endometrial, lung cancer, and certain sarcomas—Dar believes the approach has the potential to reach a much broader patient population than therapies aimed at a single tumor type.

Lessons learned during the development of KIMMTRAK (tebentafusp), the first approved TCR therapy for solid tumors, continue to shape Immunocore's clinical strategy. Dar said the program demonstrated that overall survival may be a more meaningful endpoint for these therapies than traditional measures such as tumor shrinkage alone.

The company also observed that some patients whose initial imaging appeared to show disease progression ultimately experienced prolonged survival.

"We saw patients whose initial scans showed progression, but circulating tumor DNA declined dramatically, or whose tumors later stabilized," Dar said. "Those findings suggest conventional imaging may not fully capture how these therapies are working."

Looking ahead, Immunocore plans to present updated Phase I/II data for brenetafusp in ovarian cancer, including new survival results, along with initial clinical findings in lung cancer. The company is also advancing a half-life extended version of its PRAME-targeting molecule that is designed to remain in circulation longer.

For Dar, those milestones represent another step toward expanding immunotherapy for patients who have historically had limited treatment options.

"You have to understand the mechanisms driving resistance and then design therapies and clinical trials that specifically address those patients with the greatest unmet need," he said.