Engineered immune cells reinvigorated CAR-T therapy in glioblastoma model

Targeted cytokine delivery reprogrammed tumour environment and enhanced immune response in preclinical brain cancer study

Researchers at the San Raffaele–Telethon Institute for Gene Therapy (SR-TIGET) in Milan have developed a targeted gene therapy strategy that revitalises the performance of chimeric antigen receptor T cell (CAR-T) therapy in preclinical models of glioblastoma, one of the most aggressive and treatment-resistant forms of brain cancer.

The study, led by Professor Nadia Coltella and Professor Luigi Naldini demonstrated that engineering a population of tumour-infiltrating immune cells to deliver immune-boosting cytokines directly into the tumour microenvironment could restore the cytotoxic activity of CAR-T cells and activate the host’s broader immune defences. In mouse models, this dual effect slowed tumour progression and improved survival outcomes.

The approach built on earlier work from Professor Naldini’s laboratory, which engineered haematopoietic progenitor cells to give rise to macrophages capable of releasing cytokines specifically within tumours. This strategy is already being clinically evaluated in the Temferon phase 1/2a trial for glioblastoma by NASDAQ-listed Genenta Science which is a spin-out from San Raffaele Institute.

“Our platform turns the tumour’s hostile environment into one that supports immune activation,” explained Dr Rossari, first author of the study.

“By reprogramming tumour-infiltrating macrophages to secrete cytokines locally, we improved CAR-T cell persistence and effectiveness.”

The study used two key cytokines: interferon-alpha (IFN-α), which stimulates antigen presentation and immune activity, and an engineered interleukin-2 (IL-2) mutant designed to act only on CAR-T cells carrying a matching receptor. This selective signalling ensured stimulation occurred solely within the tumour, reducing systemic side effects.

“This engineered cross-talk means immune activation is confined to the tumour site and focused on tumour-fighting cells, minimising collateral damage,” said Dr Alvisi, co–first author.

In animal models closely replicating the human disease, CAR-T cells alone were largely ineffective. However, when combined with the cytokine-delivering macrophages, the therapy significantly delayed tumour growth and prolonged survival. Notably, even tumours with limited expression of the CAR target antigen B7-H3 were controlled, suggesting a wider immune activation involving the host’s own T cells.

“This broader response, known as antigenic spreading, may be crucial to preventing immune evasion,” said Professor Coltella.

“It relied heavily on IFN-α activity and signals the potential for durable, systemic immunity,” she said.

Professor Naldini, Director of SR-TIGET and Professor at Università Vita-Salute San Raffaele, added: “This study represents another milestone in our long-term effort to translate gene and cell therapies into cancer treatments. Combining CAR-T cells with Temferon in future trials may offer broader and more lasting benefits to glioblastoma patients.”

The Temferon trial has so far demonstrated safety and initial signs of biological activity, though its therapeutic benefit remains to be confirmed in larger studies.

For further reading please visit: 10.1126/scitranslmed.ado9511