CARTs effective for solid tumors, not just blood cancers

An American study indicates that these cells can fight breast, colon and lung cancer


A new study, led by researchers at UT Southwestern (UTSW) in Texas, United States, suggests that deleting a gene in immune cells used as therapy for blood cancers, known as CART cells, could make that these were also effective fighting solid tumors, such as breast, colon and lung.

In 2017, the Food and Drug Administration (FDA) approved chimeric antigen receptor T (CART) cell treatments, which consist of immune cells known as T cells that have been engineered to recognize specific proteins on the surface of cancer cells. When these cells are given by transfusion, they generate a specific immune response against cancer cells.

In this way, CART cells have been used successfully to treat blood cancers such as leukemia and lymphoma, often with “spectacular” results, as UTSW Associate Professor of Internal Medicine and Immunology says, Venuprasad Poojary. However, these treatments have had little success against solid tumors, such as those that develop in the colon, breast, and lung.

When CART cells enter these solid tumors, Poojary explains, they quickly become dysfunctional and lose their ability to fight cancer. “This state, called depletion, is accompanied by the addition of proteins, including PD1 and Tim3, on its surface, and the inability to produce their usual molecules that stimulate the immune system, such as interferon-gamma and tumor necrosis factor. ”, Argues the expert. “Finding a way to prevent CART cells from being depleted has become an important goal in cancer research,” Poojary adds.

To do this, the researcher and his team examined published studies comparing the genetic activity of active and depleted T cells. Specifically, the researchers quickly focused on a gene called Cbl-b, which is more active, or regulated, in depleted cells. In this way, the team confirmed that Cbl-b was activated in T cells that infiltrated tumors in a mouse model of colon cancer. These cells not only lost their ability to fight tumors, but also developed a distinctive set of cell surface proteins and the inability to produce, or express, immune molecules of depletion.

Introduction of Crispr genes
However, when the scientists used the Crispr gene-editing tool to remove Cbl-b in these cells, they regained their ability to fight cancer and lost other characteristics of so-called depletion. To add evidence to the key role of Cbl-b in T cell depletion, the researchers used genetically altered mice in which this gene was knocked out. When they transplanted cancer cells into these animals, the cells developed markedly smaller tumors than in the cancer cells of the active Cbl-b mice.

“Other experiments showed that Cbl-b removal also prevented depletion specifically in CART cells,” Poojary explains. Thus, when he and his team removed this gene from CART cells designed to recognize carcinoembryonic antigen, a cell surface protein normally overexpressed in colon cancer, the cells effectively fought cancer in mice bearing these tumors, significantly prolonging their survival.

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