Rishabh Gaur - Oncology Department Senior Editor
Published 16 December, 2022
According to “Synthetic cytokine circuits that drive T cell infiltration into immune-excluded tumors,” by Greg Allen et. al, a group of scientists researched a mechanism to improve the effectiveness of CAR T-cell therapies against solid tumors, particularly those found in pancreatic cancer and melanoma. CAR T-cell therapies are a rapidly developing line of treatment for blood cancers. Humans have immune cells called T-cells that attack foreign cells by recognizing specific proteins, called antigens, that are on their surface. In CAR T-cell therapy, these T cells are engineered to produce chimeric antigen receptors, or CARs, on their surface that can recognize antigens on the surface of cancer cells (Allen et. al, 2023). Certain CAR T-cell therapies have been approved for blood cancers, but they are not used to treat solid tumors because the tumor provides competition for scarce nutrients, blocks or disarms T-cells, and causes T-cells to gradually lose their ability to kill other cells in a phenomenon called exhaustion. Activated T-cells produce a cytokine called Interleukin-2 (IL-2) that helps T-cells grow and survive (cytokine - a type of protein produced by immune cells to generate a response). IL-2 therapeutic use is currently limited, as it can be toxic if in excess and it can also be taken up by other immune cells before it gets to the ones needed to kill tumor cells. To overcome this, the researchers created a CAR T-cell with two receptors: a receptor for a protein present on cancer cells, and another receptor called synNotch that induces IL-2 production when it is bound to a different protein on the same cancer cells. Therefore, IL-2 is delivered more precisely to the tumor, reducing the chance of toxicity, and improving the efficacy of the CAR T-cell.
This article describes a possible breakthrough in CAR T-cell immunotherapy that will be very interesting to follow over the next few years. One limitation of CAR T-cell therapy that was not fully addressed in the article was T-cell exhaustion. T-cells become less effective at killing cells over time, and some studies have shown that they can be re-energized following a short break. If I could improve the study, I would attempt to methodically turn the T-cells on and off in shifts that allow some to re-energize while the others attack the tumor. CAR T-cell therapy is currently especially ineffective against pancreatic cancer and melanoma due to the reasons listed above, so these breakthroughs could be very valuable. Pancreatic cancer can be caused by many factors including smoking, diabetes, obesity, and family history, and it is extremely lethal because it often doesn’t show symptoms until it has spread, so it is detected quite late. It can be treated by radiation therapy, chemotherapy, or surgery depending on the type and extent of cancer. Scientists believe the leading cause of melanoma is exposure to UV rays from the sun. It is most commonly treated through surgery to remove the tumor. This treatment is normally successful as long as it is done early, but melanoma is prone to spread throughout the body, making it quite deadly undetected. This study could lead the way for new treatments that give us a way to fight these especially deadly diseases and save the lives of so many.
References
Allen, G. M., Frankel, N. W., Reddy, N. R., Bhargava, H. K., Yoshida, M. A., Stark, S. R., Purl, M., Lee, J., Yee, J. L., Yu, W., Li, A. W., Garcia, K. C., El-Samad, H., Roybal, K. T., Spitzer, M. H., & Lim, W. A. (2022). Synthetic cytokine circuits that drive T cells into immune-excluded tumors. Science, 378(6625). https://doi.org/10.1126/science.aba1624
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