A group of researchers from San Raffaele-Telethon, also supported by Airc, of Milan, has developed a strategy capable of inhibiting the growth of glioblastoma in experimental models of the disease
Glioblastoma multiforme (GBM) is the most common and aggressive brain tumor in adults. Unfortunately to date, despite the improvement of surgical removal techniques, followed by radiotherapy and chemotherapy, the survival of patients with GBM is short. GBM is characterized by rapid cell proliferation, abnormal development of blood vessels that provide nutrition to the tumor and a particularly immunosuppressive tumor microenvironment that prevents the development of an adequate immune response. The possibility of reversing this latter feature by means of immunostimulating molecules is limited by the toxicity associated with their systemic administration. For these reasons, the development of effective immunotherapies is difficult. In a study published today in the scientific journal Science Translational Medicine, a group of researchers from the San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget) demonstrated the efficacy in the experimental model of glioblastoma multiforme of a gene therapy platform. which allows the release of immunostimulating molecules – in particular interferon alpha and interleukin 12 – to be conveyed into the tumor in a targeted, selective and adjustable manner. Researchers succeeded in preventing systemic toxicity and modulating the tumor microenvironment from immunosuppressive to activating the anti-tumor response thereby achieving inhibition of neoplastic growth. The research – coordinated by Luigi Naldini, director of SR-Tiget and professor at the Vita-Salute San Raffaele University, and by Nadia Coltella, researcher at SR-Tiget – was supported by the AIRC Foundation for cancer research, which has been contributing for years in search of Luigi Naldini’s group for the development of new anti-tumor gene therapies.
The method
The San Raffaele researchers have decided to exploit the characteristics of specific immunostimulating molecules (in particular, interferon alpha and interleukin 12), capable of acting at different levels at the same time. Interferon alpha, for example, can inhibit the growth of tumor blood vessels as well as activate and restore the function of the immune system. To prevent the onset of toxic effects in healthy tissues, it remains essential that these molecules, belonging to the cytokine family, are released in a selective and targeted manner at the tumor level, and that exposure to them occurs in the same way, specifies Nadia. Knife. For several years we have been working on the development of a gene immuno-therapy strategy aimed at tumors. We engineer in the laboratory with lentiviral vectors the hematopoietic stem cells, which give rise to all blood cells, including monocytes, which are distributed in the tissues becoming macrophages and contributing to the replacement of these cells and to the immune response. The vectors are designed to express therapeutic cytokines exclusively in monocytes derived from engineered stem cells that reach the tumor site explains Luigi Naldini. In fact, during the growth phase, the tumor spontaneously recalls monocytes and macrophages, which in this case are used as a sort of Trojan horse, releasing interferon alpha and interleukin 12 on site. In addition to the spatial specificity for the tumor, ensured by the design of the vector, the results of this new study added to the gene therapy platform the ability to temporally regulate the release of cytokines. This has been achieved by modifying the cytokine and making it unstable and ineffective until a drug is administered that stabilizes it and makes it work. The release of therapeutic cytokines by tumor macrophages therefore occurs only after the administration of the drug. This allows us to add an additional level of control to activate or inactivate the release of cytokines according to the therapeutic needs and growth of the glioblastoma, thus making the platform inducible and adjustable over time, adds Naldini.
The results
Having reproduced in the laboratory a very aggressive form of glioblastoma and similar to human disease, the results obtained are encouraging. In fact, we have shown that gene therapy with alpha interferon, both in the original version and in the inducible one, is able to reprogram the immune cells that infiltrate the glioblastoma in a pro-inflammatory and anti-tumor sense. There is also the disappearance of a population of pro-tumor macrophages, usually associated with a worse prognosis in patients with GBM, says Nadia Coltella. Adds Filippo Birocchi, first author of the article: The reduction in tumor mass and the increase in long-term survival in experimental models of the disease are significant. In some cases we have been able to observe the total disappearance of GBM and the development of an anti-tumor immune memory. SR-Tiget researchers are meanwhile continuing to develop the platform and investigating how to further enhance its efficacy by combining it with other immunotherapy strategies, such as CAR-T cells directed against specific target antigens expressed by cancer cells.
July 14, 2022 (change July 14, 2022 | 08:18)
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