In a new study, researchers from the Mayo Clinic in the United States have developed a new strategy that may improve the performance of chimeric antigen receptor T (CAR-T) cell therapy in the treatment of cancer. They presented their preclinical findings at the 2018 American Society of Hematology Annual Meeting in San Diego, USA. The results of the related study were recently published in Blood, entitled “GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts”. The author is Saad Kenderian, a blood scientist at the Mayo Clinic, and the first author is Rosalie Sterner, a doctoral student at Kenderian Laboratories.
Sterner said, “Although CAR-T cell therapy has succeeded in certain cancers, severe toxicity limits its widespread use.” Cytokine release syndrome is a toxicity associated with CAR-T cell therapy in which patients develop symptoms such as fever, nausea, headache, rash, rapid heartbeat, hypotension, dyspnea, and neurotoxicity.
Sterner said that some patients who received CAR-T cell therapy got sick during treatment and needed to stay in the intensive care unit (ICU) for a while. She also noted that deaths related to side effects of CAR-T cell therapy have been reported. Sterner and her colleagues have developed a strategy to reduce the side effects associated with CAR-T cell therapy, which involves the use of clinical grade antibodies lenzilumab to block granulocyte macrophage colony stimulating factor (GM-CSF) released by CAR-T cells and other cells.
“We found that toxicity was reduced in preclinical models when the GM-CSF protein was blocked. We also confirm that CAR-T cells work better after GM-CSF protein is blocked,” Sterner said.
Next, these researchers used CRISPR/Cas9 gene editing technology to generate CAR-T cells that did not secrete GM-CSF protein. According to Sterner, these genetically modified CAR-T cells work more efficiently than normal CAR-T cells.
Based on these findings, these researchers are using Phase II clinical trials of this GM-CSF blocking antibody during CAR-T cell therapy. If the results of this clinical trial are consistent with earlier findings, this therapy may become the standard treatment for the Mayo Clinic during CAR-T cell therapy.