Gene therapy with blood stem cells, developed in Italy and now used for five rare diseases, could represent a new frontier against cancer. Research began many years ago at the San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget) in Milan (and that is exactly where these treatments have been developed). And today, from Science Translational Medicine, new encouraging data arrives. But let’s go in order.
Where does the idea come from
It is known that tumors during their growth attract some cells of our immune system – macrophages – which are “corrupted” and used by the tumor itself, for example to form new blood vessels that carry nutrients. Well, it is possible to exploit this mechanism and use the macrophages as Trojan horses, to bring molecules into the tumor that inhibit it. How? The intuition was to go “to the base”: directly modify the blood stem cells that give rise to the cells of the immune system. In this way, when the modified macrophages are recalled by the tumor, they can express within it an immunostimulating molecule, such as interferon alpha. This molecule is a well-known immunomodulator which, in addition to inhibiting the growth of tumor blood vessels, can also activate and restore the function of the immune system. In practice, the tumor micro-environment is reprogrammed, transforming it from immunosuppressive to immunostimulating.
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Using genes as if they were drugs
“We use genes as if they were drugs, this means gene therapy”, explains a Salute Luigi Naldini, director of the SR-Tiget, professor of the Vita-Salute San Raffaele University and co-founder of Genenta Science (spin off of San Raffaele, born in 2014 precisely to bring gene therapy in patients with cancer to the clinic, and first and only Italian biotech listed on Nasdaq, in December 2021): “We are certainly not the first to think about reprogramming the immune system to redirect it against cancer. Compared to what happens in CAR-T therapies, however, where the immune cells that lead to the final attack on the tumor are modified, we intervene first. Using viral vectors, we engineer in the laboratory the hematopoietic stem cells that give rise to all blood cells including monocytes, which are distributed in the tissues becoming macrophages and contributing to their turnover and immune response. A regulation system then ensures that interferon – or another immunostimulating molecule – is expressed only where the tumor is “.
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Because we talk about the platform
The one developed by Naldini and the SR-Tiget researchers is actually a gene immunotherapy platform. “The word ‘platform’ – explains the expert – means that it can be transversal to different types of cancer. For now we are focusing on glioblastoma, the most common and aggressive brain tumor in adults, both because there are no effective treatments for this disease apart from surgery and radiotherapy, and because it is a highly immunosuppressive tumor. But basically ours is a system of transport – selective, controlled and targeted – of molecules that can be tested on other solid tumors in the future ”.
Experimentation on 16 patients with glioblastoma
Since 2019, thanks to the support of Genenta Science, the first clinical study (phase 1 / 2a) is underway on 16 patients with glioblastoma multiforme, enrolled at the San Raffaele Hospital, the Carlo Besta Neurological Institute in Milan and coming from the Gemelli University Hospital in Rome. The goal of this trial is to demonstrate the safety of gene therapy and to validate the platform. The blood stem cells were taken from the patients, engineered and then reinfused. “In these three years – continues Naldini – patients have been administered the modified cells in increasing doses, and the first data indicate, in addition to the feasibility and tolerability of the treatment, that what we expected occurs: we are able to express interferon in the tumor and to at least partially activate the immune cells that infiltrate it “.
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The new study by SR-Tiget
Meanwhile, the SR-Tiget researchers are also continuing the development of the platform in their laboratories and are investigating how to enhance its effectiveness. Just today Science Translational Medicine publishes a new work of theirs conducted thanks to the support of the AIRC Foundation, which further validates the platform. The study was conducted on animal models and, in addition to interferon, interleukin 12, another molecule capable of activating the immune system, was used. The main novelty, however, consists in the introduction of an “on-off” system for the expression of the cytokine. The cytokine was in fact made unstable and inactive until a drug that stabilizes it is administered. “This allows us to add an additional level of control to activate or inactivate the release of cytokines, depending on the therapeutic needs and tumor growth, thus making the platform inducible and adjustable over time,” explains Naldini. The results show a significant reduction in tumor mass and a significant increase in the long-term survival of the animal models. In some cases, the disappearance of the tumor and the development of an anti-tumor immune memory have been observed. Very encouraging data, therefore: they give hope that gene therapy in the near future made in Italy may change the history of several cancers, as it has been for CAR-T therapies.