Hopeful news for cancer care
Two of the most exciting cancer care developments in recent years have been the development of checkpoint inhibitors and chimeric antigen receptor T cell therapy (CAR-T). These forms of treatment help T cells detect and destroy cancer cells that previously evaded the body’s natural defenses.
Several drugs based on CAR-T technology are approved for treating patents battling diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, mantle cell lymphoma, multiple myeloma, and B-cell acute lymphoblastic leukemia (ALL). Meanwhile. a number of checkpoint inhibitors are helping people with lung cancer, breast cancer and several other malignancies. These treatments include atezolizumab (Tecentriq), avelumab (Bavencio), cemiplimab (Libtayo), dostarlimab (Jemperli), durvalumab (Imfinzi), ipilimumab (Yervoy), nivolumab (Opdivo), and pembrolizumab (Keytruda).
However, for some patients, these treatments can allow swarms of rogue T-cells to attack healthy tissues as well as the cancer. In a series of mouse and laboratory experiments, the research team at Cincinnati Children’s reports tracking down the source of inflammation resulting from this T cell misbehavior and demonstrates a way to prevent it.
“We have identified a critical signaling node used by effector memory T cells (TEM) to mobilize a broad proinflammatory program in the innate immune system,” Pasare says. “We found that cytokine toxicity and autoimmune pathology could be completely rescued in multiple models of T cell-driven inflammation by disrupting these signals either through gene editing or with small molecule compounds.”
Without treatment, 100 percent of mice induced to experience a cytokine storm like those triggered by CAR-T therapy died within five days. But 80 percent of mice treated with antibodies to block signals emanating from activated T cells survived at least seven days.
Discovery not applicable to COVID-19
Many people with severe infections from the SARS-CoV-2 virus also have suffered cytokine storms. However, there are crucial differences between systemic inflammation triggered by a viral infection and this “sterile” form of runaway inflammation caused by activated T cells.
“We have identified a cluster of genes that are uniquely induced by TEM cells that are not involved in viral or bacterial infection response,” Pasare says. “This signifies a divergent evolution of these two mechanisms of innate activation.”
Next steps
In theory, an antibody treatment similar to that used in the mouse studies could be given to cancer patients before they receive CAR-T therapy. But more research is needed to determine if such an approach is safe enough to test in human clinical trials.
In addition to making a promising form of cancer care accessible to more people, controlling this sterile inflammation pathway might be helpful for children born with one of three very rare autoimmune diseases, including IPEX syndrome, which is caused by a mutation in the FOXP3 gene; CHAI disease, which results from malfunctions of the CTLA-4 gene; and LATIAE disease, caused by mutations in the LRBA gene.
About the study
Other Cincinnati Children’s co-authors for this study include: Hannah Meibers, BS, Irene Saha, PhD, Viral Jain, MD, Krishna Roskin, PhD, and Sing Sing Way, MD, PhD.
Funding sources for this study include the National Institutes of Health (AI123176 and AI155426) grants to Pasare and a National Science Foundation fellowship (2017220107) to McDaniel. Cincinnati Children’s has applied for a patent to cover methods for treating diseases by blocking TNF and CD40.