Immunotherapy has transformed the field of medicine. In the context of cancer, immune cells become dysregulated and lose the ability to recognize and target the tumor. The tumor reshapes its environment to favor progression. This environment is referred to as the tumor microenvironment (TME) and creates a low oxygen or hypoxic landscape in which few immune cells can operate. Through tumor-derived signaling and other underlying cellular mechanisms, immune cells lose their function, become inert, and have the potential to promote tumor growth through molecule secretion. Immunotherapy works to redirect and activate immune cells toward the tumor. Reports have demonstrated how immunotherapy can elicit robust antitumor immunity and reshape the adaptive immune response. Different immunotherapies target various aspects of the immune system, but many focus on specialized immune cells known as T cells. These cells are responsible for targeting and lysing or killing tumor cells. They regulate infection and are activated to eradicate disease in the body.
One form of immunotherapy includes chimeric antigen receptor (CAR) T cell therapy. This form of treatment engineers T cells to directly target the tumor. Many cancers have specific and identifiable surface markers that differentiate them from healthy tissue. Scientists are able to use that information to engineer T cells and specifically target those identifiable surface markers. CAR T cells can be generated from donors’ or the patient’s own cells. The workflow of developing CAR T cells starts by intravenously extracting T cells from the donor or patient. The cells are then cultured in the lab and engineered to recognize tumor cells. The generated CAR T cells are then reinfused into the patient. This therapy has demonstrated clinical success with hematological or blood cancers; however, limited efficacy is still observed in solid tumors. The TME and nature of aggressive solid malignancies creates various obstacles for CAR T cells to have an effect. Therefore, scientists are working to understand these limitations and enhance therapeutic efficacy.
A recent article in Cancer Cell, from two groups led by Drs. Scott Abrams and Renier Brentjens, demonstrated that CAR T cell therapy designed to secrete a protein, known as IL-36g, reduced tumor growth and reprogrammed immune cells in the TME to be more antitumor-like. Both investigators are from Roswell Park Comprehensive Cancer Center in Buffalo, NY. Abrams is the Jacobs Family Endowed Chair of Immunology and Professor of Oncology, and Brentjens is the Deputy Director of Medicine and The Katherine Anne Gioia Endowed Chair in Cancer Medicine.
The research team applied different mouse models and patient samples to analyze the effect of the IL-36g armored CAR T cell therapy. Normally, to receive CAR T cell therapy, patients must undergo lymphodepletion in which cells are exposed to chemotherapy to reduce lymphocyte count. This ensures enhanced treatment efficacy but takes a toll on the patient’s body. Abrams, Brentjens, and others discovered that this CAR therapy can significantly reduce solid tumors in mice without the need for lymphodepletion. Further investigation indicated that other immune cells known as neutrophils were altered to promote antitumor immunity and activate other immune cells, which targeted cancer. Additionally, these neutrophils were able to present proteins that activated other T cells present in the TME.
Abrams, Brentjens and others discovered a novel therapeutic strategy that has the potential to improve standard-of-care therapy and enhance CAR T cell treatment. They discovered that lymphodepletion, a highly toxic process, can be eliminated and still obtain effective results. The team also highlighted the importance of neutrophils in therapeutic treatment. Overall, this groundbreaking discovery drives the field of CAR T cell therapy forward and provides insight into novel therapeutic strategies.
Article, Cancer Cell, Scott Abrams, Renier Brentjens, Roswell Park Comprehensive Cancer Center
