Unexpected immune response may hold key to long-term cancer remission

In 2012, 7-year-old Emily Whitehead became the first pediatric patient to receive pioneering chimeric antigen receptor (CAR-T) therapy to fight the recurrence of acute lymphoblastic leukemia (ALL). Twelve years later, Emily is in remission and a student at the University of Pennsylvania, where the therapy was developed. But for many others, the fight continues: more than half of ALL patients experience a relapse within one year following CAR-T therapy.

Now, samples from the same pioneering clinical trials have been used in a new study, recently published in Nature in collaboration with EPFL, Yale University, University of Pennsylvania and Cleveland Clinic, that could again signal a paradigm shift in cancer treatment.

"For this study, the goal was to determine if the CAR-T cells of long-surviving ALL patients like Emily had a certain profile, or signature, that distinguished them from patients who relapsed," explains Li Tang, head of the Laboratory of Biomaterials for Immunoengineering in EPFL's School of Engineering.

In CAR-T therapy, white blood cells called T cells are extracted and engineered to express certain proteins that better target a patient's cancer. The modified CAR-T cells are then transferred back to the patient, with some retained for research. For the Nature study, scientists used nearly 700,000 CAR-T cells from 82 ALL patients, plus six healthy controls, and created a gene expression atlas to analyze each individual cell. This atlas showed that the cells of long-term ALL survivors indeed had something special: they contained certain proteins -- notably the cytokine IL-4, among others -- usually associated with something called a type 2 immune response.

Unlike a type 1 immune response, which has traditionally been the target of cancer therapies like CAR-T, type 2 responses are mobilized to fight parasitic immune threats like worms. Until now, researchers thought that type 2 immune factors were not useful in fighting cancer, and could even promote tumor growth. But the cell atlas data showed otherwise: the researchers notably observed a statistically significant correlation between the presence of type 2 immune factors and eight-year relapse-free remission from ALL.

An energy boost in the race against cancer

Tang emphasizes that the results of the cell atlas study, while significant, are correlational: "We did not show a causal relationship between type 2 immunity and cancer remission," he says. But a second study, led by Tang's lab and simultaneously published in Nature, suggests that IL-4 may alter the metabolism of T cells, "reinvigorating" them as they fight tumors.

For this second study, designed to investigate the mechanism of type 2 immunity, the researchers compared the effect of type 1 CAR-T immunotherapy alone with that of a combined type 1/type 2 immunotherapy on tumors in mice. This combined therapy included a modified, longer-lasting version of the IL-4 cytokine. The mice receiving the combined treatment not only had a greater curative response rate (86%), but also showed improved survival even after their immune systems were re-challenged with cancer cells, thanks to immune memory.

Closer analysis of these data revealed that the modified IL-4 appeared to be promoting glycolysis -- an essential metabolic pathway that provides energy to cells. Like a carbohydrate snack in the middle of a marathon, the researchers theorize that type 2 immunity factors like IL-4 give exhausted T cells an energy boost, revitalizing their ability to fight cancer.

"We wanted to see if we could harness type 2 immunity to enhance current immunotherapy, which is all type 1-centric. Our results show that type 1 and type 2 immunity can be thought of in terms of synergy, like yin and yang," Tang says.

"Our study not only sheds light on the synergy between these two types of immune response, but also unveils an innovative strategy for advancing next-generation cancer immunotherapy by integrating type 2 immune factors. Overall, I hope that these two studies -- one preclinical mechanistic and one clinical -- will inspire the field to challenge the type 1-centric paradigm in cancer immunotherapy, and re-examine the role of type 2 immunity."