Researchers at Mayo Clinic have developed two new strategies that can improve the efficiency of chimeric antigen receptor therapy (therapy CAR-T-cells) in the treatment of cancer. They presented the results of its preclinical research at the annual meeting of the American Society of Hematology in San Diego in 2018.
Reduction of toxicity in the treatment of CAR-T - cells
"Although the CAR-T-cells therapy has been successful in treating some types of cancer, severe toxicity has limited its widespread use," - says Rosalie Sterner, PhD. Sterner says that toxicity associated with therapy CAR-T-cells, including cytokine release syndrome, in which patients may experience fever, nausea, headache, rash, rapid heart rate, low blood pressure and shortness of breath, and neurotoxicity.
Sterner says that some patients undergoing CAR-T therapy sick during treatment and require a stay in the intensive care unit. It also notes that the reported death associated with the side effects of therapy CAR-T-cells. Sterner and her colleagues have developed a strategy to reduce severe toxicity associated with CAR-T-cell therapy.
Strategy includes GM-CSF blocking protein that is produced CAR-T-cells and other cells using a clinical grade antibody (lenzilumab).
"When we blocked the protein GM-CSF, we have found that we can reduce the toxicity in preclinical models, - says Sterner -. We were also able to demonstrate that the CAR-T-cells work better after blocking GM-CSF protein. "
The researchers then used gene editing technology called CRISPR, for the generation of CAR-T-cells, which are not isolated GM-CSF protein. Sterner says that these modified cells CAR-T were more effective than conventional CAR-T-cells.
Based on their findings, the research team continues to study the clinical phase II antibodies blocking GM-CSF, during therapy CAR-T-cells. If the results of the study are consistent with earlier results, the therapy may become the standard treatment during therapy CAR-T-cells.
"In the treatment of CAR-T -therapy doctors remove and modify the patient's T-cells to recognize and those struggling with cancer", - says Reon Sakemura, Ph.D., a hematologist and a doctoral student in the lab of Dr. Kenderiana. "After the modified T cells are re-infused into the patient, where they are looking for and eventually kill the cancer cells."
Dr. Sakemura said frequency response on CAR-T therapy depends on the disease. For example, in B-cellacute lymphoblastic leukemiaobserved response rates over 90% as compared with the response from 10 to 30% for the conventional treatment with chemotherapy. In other blood cancers such aslymphoma and chronic lymphocytic leukemia, response rate CAR-T-cell therapy remains low.
To increase the effectiveness of therapy CAR-T-cells at these cancers Dr. Sakemura and his colleagues have developed a strategy of combination therapy CAR-T -cells drug directed to a protein called «AXL». This protein is present on cancer and cancer in the surrounding environment. Drug called «TP-0903" not only kills cancer cells, but also enhances the CAR-T-cell activity when attacking cancer cells and potentially reduces the toxicity associated with the processing of CAR-T-cells.
Despite the fact that more research and clinical trials, Dr. Sakemura says: "We believe that the latter effect may eventually be used as an innovative approach to improve the effectiveness of therapy CAR-T-cells and to expand its use to other cancerous B-cells."