Researchers may have discovered a factor contributing to cancer cell evasion of chimeric antigen receptor (CAR) T-cell therapy, according to a recent study published by Chen et al in Cell. The findings could lead to more personalized therapies that improve survival among patients with cancer.
Background
CAR T-cell therapy—a treatment that harnesses the immune system in order to seek out and kill tumor cells—is used in certain types of leukemias and lymphomas. However, some cancer cells have learned how to escape from the immune system to avoid destruction.
“One of the challenges in treating [hematologic malignancies] is a phenomenon called antigen escape. A key target for these therapies is a protein called CD19 found on the cancer cells,” explained co–senior study author Jianjun Chen, PhD, the Simms/Mann Family Foundation Chair in Systems Biology and the Director of the Center for RNA Biology and Therapeutics at the Beckman Research Institute of City of Hope.
In 28% to 68% of cases, the cancer cells lower or lose this CD19 marker, making treatments less effective. Although researchers are working on strategies to target multiple components, nearly 50% of patients are still affected by this issue.
Study Methods and Results
In the recent study, the researchers identified a protein called YTHDF2 that may play a role in advancing the development of hematologic malignancies. YTHDF2 works by switching on genes that help cancer cells produce a stable energy source to fuel the cells’ ability to grow and spread. Additionally, this protein aids cancer cells in concealing themselves by reducing the presence of antigen biomarkers that normally trigger the immune system to detect and attack cancer. Excess YTHDF2 has previously been found to transform blood cells from healthy to cancerous in mouse studies.
The researchers developed a novel medicinal compound, CCI-38, which was designed to target and suppress YTHDF2—thereby reducing the growth of aggressive hematologic malignancies. The researchers found that the approach improved the likelihood of successful cancer therapy.
Conclusions
“We believe that using CCI-38 to target YTHDF2 will significantly enhance the effectiveness of CAR T-cell therapy on [hematologic malignancy] cells,” indicated Dr. Chen.
“Reducing the need for follow-up treatments could lead to better long-term survival and less relapse for our patients while lowering side effects and medical costs,” emphasized co–senior study author Xiaolan Deng, PhD, Associate Research Professor in Systems Biology at the Beckman Research Institute of City of Hope.
“Unraveling the biology underlying YTHDF2’s function will help us develop new strategies to prevent tumor cells from escaping immune surveillance,” underscored lead study author Zen-Hua Chen, PhD, a staff scientist in Systems Biology at the Beckman Research Institute of City of Hope. “This could lead to personalized approaches for patients whose [hematologic malignancies] don’t respond to initial treatment or who relapse after initial response to T-cell–based immunotherapy,” he concluded.
The researchers filed a patent application covering critical aspects of this work, which holds implications for improving care among patients with other cancer types and severe autoimmune diseases. The next phase of research will focus on improving CCI-38’s safety and effectiveness, exploring new methods to drive YTHDF2 out of cancer cells, and developing clinical trials.
Disclosure: The research in this study was supported by grants from the National Institutes of Health and the Simms/Mann Family Foundation. For full disclosures of the study authors, visit cell.com.
