Currently, half of patients with non-hodgkin lymphoma and acute lymphoblastic leukemia-two cancer types that affect blood cells-not responding adequately to car-T cell treatment.
This therapy consists of collecting the defense cells of the person to be treated (T lymphocytes), modifying them in the laboratory to become capable of destroying tumor cells and reinject them in the body. These refractory cases usually recurred after conventional immunotherapy.
To circumvent the problem, Brazilian researchers developed a more powerful version of Car-T cells. The details of the research were released in the magazine Cancer Research
“Car-T cell immunotherapy is revolutionary and has saved the lives of many people in recent years. However, there is still a significant portion of patients who do not respond to this treatment. We tested a series of drugs in Car-T cells and one proved promising to inhibit epigenetic changes [relacionadas com o padrão de expressão dos genes] That made the cells unable against these two types of hematological tumor, ”says Maria Letícia Rodrigues Carvalho, the first author of the study conducted at AC Camargo Cancer Center with the support of FAPESP's master's scholarship, today in the doctorate.
As the authors explain, non-hodgkin lymphoma affects mostly middle-aged adults, while lymphoblastic leukemia patients are mostly children.
The studies were conducted in tumor cells (in vitro) and mice (in vivo) and represent the first step so that in the future there may be rehearsals in humans.
Among the drugs tested in Car-T cells, which showed the greatest potential was an inhibitor of the protein complex known by the acronym PRC2. In the healthy body, these proteins are necessary to induce the expression of genes that brake the action of defense cells, so that they do not attack healthy cells.
“However, in the context of cancer, it is important that there are no brakes like these, so that the complete elimination of the tumor occurs. Although the basis of car-T immunotherapy is precisely removing these brakes, some still remain. What we did was remove those that prevent a better response against non-Hodgkin lymphoma and acute lymphoblastic leukemia,” explains Tiago da Silva, a researcher at ACina Camargo Cancer Center supported by FAPESP and coordinator of the study.
Manufacture
First, the researchers produced Car-T cells from mononuclear peripheral blood cells of healthy people, obtained from blood banks at AC Camargo Cancer Center in Sao Paulo and the National Cancer Institute (Inca) in Rio de Janeiro.
In addition, they collected Car-T cells produced from the blood of patients with both tumor types and used in their own treatment at AC Camargo Cancer Center.
Car-T cells were modified with the PRC2 complex inhibitor and used to treat (in vitro) the two types of refractory tumor cells to immunotherapy. As a result, tumors have been eliminated faster and more efficiently than conventional Car-T samples (without inhibition of PRC2).
The researchers then left for mice testing that developed both types of tumor. After treatment with the PRC2 inhibitor, Car-T cells were washed before they were injected into the animals to ensure that there would be no remnants of the inhibitor and thus avoid the action of the compound in unwanted cells and mitigate the risk of eventual systemic toxicity. After 39 days, the animals that received modified Car-T cells had a higher improvement than the conventional treaties.
“The modification made in Car-T cells induced a more persistent response in the body and resulted in greater elimination of the tumor, both in vitro and in vivo. The epigenetic approach improves the quality of this immunotherapy and opens a very promising perspective,” says Medina.
Researchers now plan to test the possible side effects of mice therapy. This is because approved treatments are known to cause an exacerbated increase in inflammation in patients. The problem is softened with drugs approved for this purpose, which are part of the protocol of immunotherapy.
“If new studies point out that treatment is safe, PRC2 inhibition could be incorporated in the future of car-T cells, increasing the effectiveness of immunotherapy without increasing systemic risks,” says Carvalho.
The work was supported by FAPESP also through doctoral and postdoctoral scholarships granted to some of the co-authors.
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This content was originally published in a study enhances used immunotherapy against blood cancer on CNN Brazil.
Source: CNN Brasil