CAR T cell are engineered immune cells that have been proven to be effective against blood cancers. However, they are less effective against solid tumors due to T-cell exhaustion. Now researchers at Penn Medicine have illuminated key molecular details of this exhaustion process , which point to a specific strategy to combat it.
In the study, which was published Dec. 2 in Cell, the researchers developed an in-lab dish model that allowed researchers to study in depth the process of exhaustion in the chimeric antigen receptor (CAR) T cells designed to fight pancreatic tumors. The model’s process of exhaustion of T cells closely resembled the process seen in the T cells of patients. The model also revealed novel facets of the exhaustion process, which included the role played by two genetic regulators of exhaustion, ID3 and SOX4, which were silenced, allowing CAR T cells to retain much of their effectiveness against the tumor cells.
“This will help us get closer to the next-generation CAR-T therapies that are far more efficient against solid tumors,” said Carl June, MD, co-author and senior author, and the Richard W. Vague professor in Immunotherapy at Penn’s Perelman school of Medicine. He is also the director of the Center for Cellular Immunotherapies in Penn’s Abramson Cancer Center.
Shelley L. Berger PhD, the Daniel S. Och University Professor at Penn, is the co-senior researcher in the study.
CAR T cells, also referred to as natural infection- or cancer-fighting immune cells, also known as T cells, were taken from blood of a patient and genetically reprogrammed. The T cells of the patient have been reprogrammed to recognize an “antigen” on cancerous cells. The T cells that have been reprogrammed are then multiplied by methods of cell culture and infused into the patient in order to fight the cancer. June was the pioneer of this method of treatment. It has been approved by the U.S. Food and Drug Administration (FDA) since 2017. It is used to treat certain lymphomas and leukemias. In some instances, it has successfully treated these cancers.
CAR T cells aren’t as effective in fighting solid tumor-forming carcinomas. This is due to a distinct feature of T-cell biology. T-cell exhaustion is thought to have evolved to protect these powerful immune cells to avoid causing collateral damage to the body. Exhaustion occurs by T cells when they are exposed too long-;on the order of weeks-;to their target antigen as they usually are in the case of tumors that are solid.
In the new study, the researchers developed a lab-dish model of T-cell exhaustion to study it more closely, in the hope of revealing ways to reverse it They engineered CAR T cells against a cell marker called mesothelin, found on the surface of pancreatic and some other tumors, and kept the T cells exposed to mesothelin-expressing pancreatic tumor cells for four weeks.
The T cells responded by showing typical signs of exhaustion but also signs that were not evident in previous studies. These novel exhaustion phenomena included an identity change among some of the T cells, such that they partly reverted to an immune cell type known as the NK cell, which has been considered an ancestor of T cells. Researchers found evidence of this same T-cell to change to NK-cells among exhausted CAR T cells from cancer patients.
In addition, researchers discovered that CAR T cells exhaustion was accompanied by a surge in the levels of two proteins, ID3 & SOX4, which serve as master switches for a large number of immune cell genes. The suppression of these apparent switches on T-cell exhaustion allowed the exhausted CAR T cells to retain much of their effectiveness in killing tumors after prolonged exposure to tumor cells.
The study suggests an approach to inhibiting ID3 and/or SOX4 that could aid CAR T cells to work more effectively against solid tumors.
These findings are exciting because of their potential clinical implications, but also because they essentially confirm our model’s cell-based potential for exploring CAR T cell biology and continuously improving the effectiveness of this immunotherapy to the benefit of patients.”
Regina Young, PhD, co-author director of research operations, Center for Cellular Immunotherapies, Penn Medicine
Good, C.R. et. as. (2021). A NK-like CART cell transition in CAR cell dysfunction. Cell. doi.org/10.1016/j.cell.2021.11.016.
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