Cell Therapy: New cancer therapy may effectively control fungal infections

Cell Therapy: New cancer therapy may effectively control fungal infections.  Redirecting GXMR-CAR T cells can induce cytotoxic activity against fungi that express GXM in the cell wall.

A new cell-based cancer therapy has been found to be expected to control infections caused by fungi. A study published in the journal Cell Therapy showed that the use of CAR (chimeric antigen receptor) T cells programmed to “recognize” Cryptococcus spp. can effectively fight infection in vitro and in vivo in mice.

C. gattii and C. neoformans are found in soils containing dead organic matter, and in places contaminated by pigeons and other bird feces. They cause systemic fungal diseases in human tissues, which can infect the lungs and central nervous system, and further lead to meningitis or meningoencephalitis. Different parts of the infection have different symptoms, and they can be fatal. The infection can be spread after inhaling the fungus.

According to the US Centers for Disease Control and Prevention (CDC), there are approximately 1 million cases of cryptococcal infections worldwide each year, with a mortality rate between 20% and 70%. There are 220,000 cases of cryptococcal meningitis infections every year, and the main people infected are AIDS patients with HIV.

In order to evade the host’s immune response, Cryptococcus encapsulates itself in a capsule with acidic polysaccharide (GXM) as the main component, which is considered to be its main pathogenic factor. The human immune system (especially CD4+ T cells and CD8+ T cells) is difficult to recognize and prevent infections.

In this study, the team redirected CD8+ T cells to the GXM target in the capsule by expressing GXM-specific CAR, with the goal of allowing cells to directly recognize pathogens and inhibit their growth. The results of the study show that GXMR-CAR T cells can be redirected to recognize Cryptococcus neoformans. In the future, the focus will be on the therapeutic effect of this cell in an animal model of cryptococcosis.

The first author Silva explained that the infusion of GXMR-CAR-T cells not only inhibited the growth of fungi, but also reduced the number of titan cells (making infections more toxic). Titan cells are very large yeast cells with a diameter of more than 45um. The decrease of titan cells indicates a good prognosis for cryptococcosis treatment. CAR-T cells can be used to treat other fungal infections, and can be used in combination with conventional drugs to reduce their side effects, and can also establish immune memory to protect patients from invasive fungal infections.

With the support of FAPESP, Silva is currently investigating ways to optimize the protective response of CAR T cells to fungal diseases, including infections caused by Candida albicans and Histoplasma capsulatus.

Direct death of fungi

Researchers from the MD Anderson Cancer Center in Texas, USA, in collaboration with Silva, used a CAR that was found to target carbohydrates in the cell wall of Aspergillus fumigatus to explore fungi that died directly from redirecting CD8+ cells for the first time.

Some countries have increased interest in the use of CAR T cells to treat cancer and other diseases. Since 2017, the U.S. Food and Drug Administration (FDA) has approved various forms of CAR T cell therapies, especially for the treatment of leukemia and other diseases. Lymphoma.

In Brazil, the Cell Therapy Center (CTC) research team, led by the Ribere Preto School of Medicine (FMRP-USP) of the University of São Paulo in Brazil, tested this new cancer therapy for the first time in 2019 using reprogrammed cells from patients. For the treatment of advanced diffuse large b-cell lymphoma.

Target Recognition

Silva and other authors hypothesized that redirecting GXMR-CAR T cells can induce cytotoxic activity against fungi that express GXM in the cell wall. Studies have shown that human T cells expressing GXMR-CAR modification can bind to GXM in vitro and interact with the yeast form of Clostridium neoformans.

Silva believes that the most critical part of constructing CAR is the target recognition part. In this part, we use monoclonal antibodies that interact with Cryptococcus, and also use DNA sequences to encode the part of the antibody that recognizes fungi, and combine it with other parts that encode CAR. Combine DNA sequences.

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