Immunotherapy is a form of cancer treatment that harnesses the immune system to recognize and target the tumor. In most cancers, the immune system fails to detect the rapid proliferation of tumor cells. Lack of immune cell detection is due to the tumor polarizing or reprogramming immune cells to promote cancer progression and suppress the immune system. This is done through variety of ways including the release of proteins or cytokines that direct immune cell development and function. Current immunotherapies target these polarized immune cells to switch them back toward an anti-tumor function. Although there are many ways to redirect immune cells to attack cancer, immunotherapies maintain limited efficacy due to the immunosuppressive mechanisms within the tumor microenvironment (TME). In addition, heightened toxicity associated with immunotherapy also pose challenges when prescribing treatments to patients.
One immunotherapy that has demonstrated significant promise in cancer patients is chimeric antigen receptor (CAR) T cells. T cells are immune cells within the body that are responsible for killing or lysing invading pathogens, including cancer. The immune system orchestrates a response by employing T cells to recognize an infection, in healthy individuals. In the context of cancer, T cells cannot recognize that the tumor is deleterious to the body. Therefore, CAR T cells are generated to reprogram the cell’s ability to recognize and lyse the tumor. CAR T cell therapy takes the patient’s T cells and engineers them to target specific surface markers on the tumor. They are then grown in a dish and expanded before being intravenously reinfused in the patient. CAR T cell therapy is commonly associated with lymphoma, but unfortunately neurotoxicity can be an adverse side effect which limits efficacy. Scientists are currently working to improve therapeutic benefit and reduce off target symptoms.
A recent article published in Nature Cancer, by Dr. Robert Zeiser and others, demonstrated that targeting a protein in brain cells could reduce lymphoma associated neurotoxicity. Zeiser is a professor and physician within the Department of Medicine at the University of Freiburg. His work focuses on blood malignancies, tumor immunology, and immune system mechanisms that exacerbate or suppress disease.
The underlying mechanism of how CAR T cell therapy generates neurotoxicity was previously unknown. Although it was known that many different proteins and cytokines were the direct cause, scientists were unsure which cells played an integral role. Researchers used mouse models and patients samples to analyze cells releasing neurotoxic associated cytokines. As a result, the team discovered that brain cells, known as microglia, significantly contributed to neurotoxicity. Additionally, they found that by depleting microglial cells, neurotoxicity was diminished. In an effort to understand the mechanism behind microglia generated toxicity, Zieser and others analyzed signaling pathways upregulated in these cells. They found that a pathway that activated the protein TAK1 was highly expressed in microglia after CAR T cell infusion. Therefore, the team depleted TAK1 and found significant reduction in toxicity. To translate their findings in humans, researchers used patient tissue to mimic the effects and found similar results. Overall, this is an exciting finding that provides a solution to CAR T cell associated neurotoxicity. As a result, therapeutic treatments can be paired to improve efficacy and prolong patient survival.
Article, Nature Cancer, Robert Zeiser, University of Freiburg