Results from a preclinical study in mice and a joint clinical study in patients reveal that the type 2 immune response, commonly linked to parasitic infections and previously thought to hinder cancer immunity, actually shows a positive correlation with prolonged cancer remission.
Results from a preclinical study in mice, conducted by EPFL, along with a collaborative clinical study involving patients, indicate that the type 2 immune response — which is typically connected to parasitic infections and assumed to negatively impact cancer immunity — has a positive relationship with long-term cancer remission.
In 2012, 7-year-old Emily Whitehead became the first child to undergo groundbreaking chimeric antigen receptor (CAR-T) therapy to combat the recurrence of acute lymphoblastic leukemia (ALL). Twelve years later, Emily is in remission and is now a student at the University of Pennsylvania, where this therapy was developed. However, for many others, the struggle continues: over half of ALL patients face a relapse within a year after receiving CAR-T therapy.
Recently, samples from these early clinical trials have been utilized in a new study published in Nature, in collaboration with EPFL, Yale University, the University of Pennsylvania, and the Cleveland Clinic, which might again shift paradigms in cancer treatment.
“The purpose of this study was to identify whether the CAR-T cells from long-surviving ALL patients, like Emily, exhibited a specific profile or signature that set them apart from those who experienced a relapse,” explains Li Tang, who leads the Laboratory of Biomaterials for Immunoengineering at EPFL’s School of Engineering.
During CAR-T therapy, T cells, a type of white blood cell, are removed and modified to express proteins that target the patient’s cancer more effectively. The enhanced CAR-T cells are then reintroduced into the patient, with some reserved for research purposes. In the Nature study, researchers examined nearly 700,000 CAR-T cells from 82 ALL patients as well as six healthy controls to create a gene expression atlas for analyzing each cell. This atlas demonstrated that the cells of long-term ALL survivors had unique characteristics, featuring specific proteins such as the cytokine IL-4, commonly related to a type 2 immune response.
In contrast to a type 1 immune response, which has historically been the focus of cancer therapies like CAR-T, type 2 responses are activated to combat parasitic threats such as worms. Until this point, scientists believed that type 2 immune factors provided no benefit against cancer and might even assist tumor growth. However, the data from the cell atlas indicated otherwise, revealing a notable statistical link between the presence of type 2 immune factors and an eight-year relapse-free remission from ALL.
An energy boost in the race against cancer
Tang notes that while the findings of the cell atlas study are significant, they are correlational: “We did not establish a causal link between type 2 immunity and cancer remission,” he states. However, a second study led by Tang’s lab, which was published simultaneously in Nature, suggests that IL-4 might influence T cell metabolism, effectively “reinvigorating” them in their fight against tumors.
This second study, aimed at examining the mechanism of type 2 immunity, compared the effects of type 1 CAR-T immunotherapy alone to a combined type 1/type 2 immunotherapy on tumors in mice. This combined approach included a modified, longer-lasting version of the IL-4 cytokine. Mice receiving the combined treatment not only exhibited a higher rate of successful responses (86%) but also showed improved survival rates after their immune systems faced a renewed challenge from cancer cells, thanks to their immune memory.
Further analysis revealed that the modified IL-4 appeared to enhance glycolysis, a crucial metabolic pathway responsible for providing energy to cells. The researchers likened this to a carbohydrate snack during a marathon, theorizing that type 2 immunity factors, like IL-4, provide exhausted T cells with an energy boost, renewing their capacity to combat cancer.
“We aimed to explore whether we could leverage type 2 immunity to improve existing immunotherapy, which has primarily been focused on type 1. Our findings indicate that type 1 and type 2 immunity can work synergistically, akin to yin and yang,” Tang adds.
“Our research not only illuminates the interplay between these two immune response types but also introduces an innovative approach for advancing next-generation cancer immunotherapy by incorporating type 2 immune factors. Overall, I hope these two studies — one investigating mechanisms and the other clinical — will encourage the field to question the type 1-centric focus in cancer immunotherapy and rethink the role of type 2 immunity.”
