The combination of an immunotherapy, PD-1 blockade, and biologic therapy, IL-2 therapy, generate higher quality effector CD8+ T cells—cells that play central roles in eliminating infected or malignant cells—which resemble the highly functional effector CD8+ T cells seen after acute viral infection that help the immune system control or clear the virus. Reported in Nature, the study ("PD-1 combination therapy with IL-2 modifies CD8+ T cell exhaustion program") was led by researchers at Winship Cancer Institute of Emory University, the Emory Vaccine Center and Department of Microbiology and Immunology at Emory University School of Medicine.
CD8 T cells are critical components of adaptive immunity to control cancer pathogens (viruses, bacteria or other microorganisms that cause disease), but are generally observed to be exhausted and/or dysfunctional in cancer and chronic viral infections.
"Our study shows that PD-1 blockade plus IL-2 combination therapy, overcomes this limitation," says lead author Masao Hashimoto, MD, PhD. He explains that the combination therapy "dramatically changes" the process by which T cells, a type of immune cell, mature into T cells "that resemble highly functional effector CD8+ T cells seen after an acute viral infection."
PD-1/PD-L1 blockade is a breakthrough cancer immunotherapy, which uses the immune system to fight cancer. PD-1 inhibitors are a class of drugs referred to as immune checkpoint inhibitors; they work by turning off PD-1, a protein on T cells that helps keep them from acting against cancer cells. PD-1inhibitors have been tested in a broad range of preclinical or clinical-stage malignancies, including melanoma, Hodgkin's lymphoma, breast cancer, non-small cell lung cancer (NSCLC) and hepatocellular carcinoma. IL-2 (interleukin-2) therapy is a type of biologic therapy, which modifies the body's response to cancer cells. IL-2 therapy is used to treat kidney cancer and melanoma.
Hashimoto says the ability of the combination therapy to effect qualitative changes in the CD8+ T cells could play an important role in determining the "striking synergy" between IL-2 therapy and PD-1 blockade. Hashimoto says this synergy "has special relevance to cancer immunotherapy."
The study, says Hashimoto, "defines the underlying mechanisms of how IL-2 synergizes with PD-1 blockade and provides an immunological rationale for the advantage of using PD-1 therapy in combination over PD-1 therapy alone in human studies to improve clinical outcomes in patients with cancer."
Hashimoto says an important question going forward from the basic research perspective is "how long these functional effector CD8+ T cells generated by the PD-1 plus IL-2 combination therapy are maintained in terms of number, location and phenotype (observable traits)."
As for translating this science into application, he says, "We are keen to test how our findings in preclinical models are reproduced in patients with cancer, and we hope to start a clinical study evaluating if PD-1 blockade plus low dose IL-2 therapy results in generating more functional effector CD8+ T cells than historical PD-1 therapy alone—and if this strategy improves the clinical outcomes of patients with cancer."
This work was supported by National Institutes of Health (NIH) grants R01AI030048, P01AI0526299, P50CA101942, P01CA236749, P50CA101942, P01CA236749, R01AI129191, P50CA217691, and the Roche pRED ROADS programme (ROADS grant 55440 funded by Roche, ID ROADS-034).