Engineering T cells to destroy cancer cells has been shown to be successful in treating certain types of cancer, such as leukemia and lymphoma. However, it didn’t work as well for solid tumors. One reason for this failure is that T cells only target an antigen (a target protein found on tumors); if some of the tumor cells do not express that antigen, they can escape attack by T cells. WITH have now found a way to overcome this obstacle, by using a Vaccine which enhances the response of engineered T cells, known as chimeric antigen receptor (CAR) T cells, and also helps the immune system generate new T cells that target other tumor antigens. The results are described in the journal Cell.
In studies involving mice, the researchers found that this approach made eradication of the tumors much more likely. “This vaccine enhancement appears to stimulate a process called antigen expansion, in which one’s own immune system works with engineered CAR T cells to fend off tumors in which not all cells express the antigen targeted by the CAR T cells.”, says Darrell Irvine, an Underwood-Prescott Professor with positions in MIT’s Departments of Biological Engineering and Materials Science and Engineering, and a fellow of MIT’s Koch Institute for Integrative Cancer Research and MGH’s Ragon Institute, of the MIT and Harvard. Irvine is the lead author of the study, which appears today in Cell.
The United States Food and Drug Administration has approved several types of T-cell treatments for blood cancers. These treatments are based on CAR-T cells, which are engineered to display receptors that can recognize a specific antigen found on cancer cells. To try to tailor this type of treatment to glioblastoma, a type of brain cancer, the researchers engineered CAR-T cells that target a mutated version of the EGFR receptor. However, not all glioblastoma cells express this antigen, and when attacked by CAR-T cells, some glioblastoma cells respond by stopping production of the target antigen.
The 2019 study
In a 2019 study, Irvine and his colleagues improved the efficacy of CAR-T cells against glioblastoma by administering a vaccine to mice shortly after administration of the engineered T cells. This vaccine, which carries the same antigen targeted by CAR-T cells, is taken up by immune cells in the lymph nodes, where the CAR-T cells are exposed to it. In that study, the researchers found that this vaccine boost not only helped engineered CAR-T cells attack tumors, but it had another unexpected effect: It helped generate host T cells that target other tumor antigens. . This phenomenon, known as “antigen diffusion,” is desirable because it creates populations of T cells that, working together, can completely eradicate tumors and prevent them from growing back.
The 2023 study
In their new study, the researchers wanted to explore how that additional T-cell response is triggered. They used the same type of CAR-T cells from their 2019 study, which are designed to target mutant EGFR, and the same vaccine. The mice in the study were given two doses of the vaccine, one week apart. The researchers found that in these boosted mice, metabolic changes occurred in CAR-T cells that increased their production of interferon-gamma, a cytokine that helps stimulate a strong immune response. This helps the T cells overcome the immunosuppressive environment of the tumor, which normally shuts down any nearby T cells.
Because the CAR-T cells killed the tumor cells expressing the target antigen, the host T cells (not the engineered CAR-T cells) encountered other antigens from those tumor cells, stimulating those host T cells to target those antigens and help destroy cancer cells. The researchers then tested their approach in mice with tumors that had different levels of the target antigen. They found that even in tumors in which only 50% of the tumor cells expressed the target antigen, about 25% of the tumors could still be eradicated, by a combination of CAR-T cells and host T cells. The success rate was higher for tumors with higher levels of the target antigen. When 80% of the tumor cells expressed the antigen targeted by the CAR-T cells, the tumors were eliminated in about 80% of the mice.
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