Immunotherapy has transformed the way physicians treat patients. In the context of cancer, immune cells are suppressed and become inert as a result of tumor-derived molecules and proteins. Specifically, immunotherapy is a form of treatment that activates and directs immune cells toward tumors that have previously evaded immune detection. Different forms of immunotherapy target specific immune cells to elicit robust antitumor immunity. In the last decade engineered immune cell therapy has become a promising tool for treatment of solid and hematological malignancies.
A form of research that has demonstrated strong efficacy in the clinic, includes chimeric antigen receptor (CAR)- T cell therapy. In CAR-T cell therapy, immune cells from donors or patients themselves are engineered to target specific biomarkers on the tumor and expanded. The cells are then infused into the patient to effectively target the tumor with minimal toxicity. Advancements in CAR-T cell therapy have enhanced standard-of-care therapy in lymphomas and leukemias. Scientists are currently working to improve CAR-T cell therapy in solid tumors and further improve safety and efficacy.
A recent article in Nature Chemical Biology, by Dr. Melita Irving and others, demonstrated that engineered CAR-T cells can be switched on and off. The work provides evidence that CAR-T cell activity can be controlled using a remote control using a cancer drug, known as venetoclax. The application of venetoclax allows CAR-T cells to reduce their interaction with cancer cells. As a result, this can help clinicians control delivery of therapy and enable therapeutic application in patients with different cancer types. Irving is a Principal Investigator at Ludwig Cancer Research in Lausanne, Switzerland. Her work focuses on the development of improved CAR-T cell therapies and tailoring immunotherapy to specific cancers under metabolic pressure.
Previous work by Irving and others generated a method to control CAR-T cell therapy through intracellular signaling with the use of venetoclax, which degraded the internal signaling component of the T cells to switch it off. The new remote-controlled therapy regulates the “off switch” from outside the cell instead of using internal signaling. In a living system CAR-T cell therapy is active until venetoclax is applied and transiently shuts off CAR-T cell function.
This work uses clinically approved protein components and a drug to directly disrupt therapeutic activity. Since the switch is on the surface of the cell, this new controlled therapy improves the safety profile and doesn’t destroy the CAR-T cells already in the patient. Consequently, the cells can become activated later on and elicit robust antitumor immunity. This therapeutic approach also avoids T cell exhaustion in which T cells become inert and unable to act on cancer cells. CAR-T cell therapy has been observed to have cycles of activity and exhaustion, making this new therapeutic strategy ideal.
Irving and others have demonstrated a unique way to regulate CAR-T cell therapy and make it more effective in patients with cancer. Since venetoclax is approved for cancer therapy, scientists hope to move this new treatment to the clinic. Overall, this new approach has the potential to improve standard-of-care therapy and provide insight on how to better control engineered cancer treatment.
Article, Nature Chemical Biology, Melita Irving, Ludwig Cancer Research
