Stress-sensing cells hold promise as glioblastoma treatment

Treatments using gamma delta T-cells, a type of immune cell, hold promise for treating glioblastoma, scientists said, though they added that much more research is needed to determine whether these therapies are safe and effective in people with the disease.

They laid out the promises and hurdles of developing the treatments in a paper, “Challenges and Opportunities of γδ T Cell-Based Immunotherapy for Glioblastoma,” published in Biomedicines.

The work was led by scientists at Taipei Medical University in Taiwan. Several of the co-authors are employees of SL Science, a company that’s developing a gamma delta T-cell therapy for glioblastoma called SL-GD001. SL is developing another therapy, SL-GD002, which uses these same types of immune cells but is designed to treat pancreatic cancer.

“Glioblastoma has repeatedly defeated therapies that looked convincing in preclinical models,” William Wang, chairman and CEO of SL, and a study author, said in a company press release. “The clear lesson is that progress depends on rigorous evidence generation in humans, not further laboratory speculation.”

Wang said the paper “defines what we believe the next phase of development must look like: clinical trials designed from day one to show whether these cells reach the tumor, remain viable, and execute their therapeutic function. Translating this science into actionable clinical proof is our core focus, and our technology is advancing and evolving alongside new clinical discoveries. We intend our own programs to meet the exact standard we have set out here.”

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Targeting signs of cellular stress

Glioblastoma is an aggressive form of glioma that has proven very difficult to treat. Immune-modulating treatments, which have revolutionized care for many other types of cancer, have often fallen short in glioblastoma for a variety of reasons. Glioblastoma tumors have multiple mechanisms that help them evade the immune system, and they are highly heterogeneous (varied), making it hard to pin down a particular target for the immune system to go after.

T-cells are a broad group of immune cells that can fight cancer. There are many subtypes of T-cells; most of them work by recognizing specific molecular targets, known as antigens. The heterogeneity of glioblastomas means that these target-specific T-cells struggle to mount an effective attack against the entire tumor.

Gamma delta T-cells, however, are not target-specific. Instead, they look for general signs of cellular stress, which can arise when a cell turns cancerous or becomes infected with a virus. This feature makes them potentially well-suited to serve as foot soldiers to target highly heterogeneous glioblastomas.

Another advantage of gamma delta T-cells is that, due to their specific biology, it’s generally possible to take these cells from one person and infuse them into another person without causing major health issues. This isn’t the case for most target-specific T-cells, which can start problematic immune reactions.

Treatments using gamma delta T-cells have shown promising anticancer activity in multiple laboratory models of glioblastoma, and early clinical trials suggest that this type of immune cell therapy may be safe to use in people.

However, the researchers noted major challenges to effectively using these immune cells for glioblastoma treatment.

For one thing, therapeutic gamma delta T-cells would have to cope with the immune-suppressing environment within glioblastoma tumors. For another, if the cells are given into the bloodstream, they would need to be able to travel into the brain. There are also technical limitations in how these cells could be consistently manufactured for therapeutic use, along with considerations for clinical testing and for combining this type of immunotherapy with existing glioma treatments.

Gamma delta T-cells “are a biologically credible and mechanistically distinctive platform whose value in glioblastoma will be settled by further mechanistic study and, decisively, by adequately powered clinical trials with rigorous correlative endpoints,” the researchers said. “Until those data exist, the strategy should be advanced with disciplined optimism and described as what it is: promising, but unproven.”