Scientists at City of Hope®one of the largest and most advanced cancer research and treatment organizations in the United States, with its National Medical Center named among the nation’s top 5 for cancer by U.S. News & World Report, have identified a delicate culprit. which helps cancer cells escape CAR T cell therapy.
CAR T cell therapy harnesses the immune system to seek out and kill tumor cells. This treatment is used in certain types of leukemia and lymphoma –; blood cancers. However, some clever cancer cells have learned to hide from the immune system to avoid destruction. The study published today in the journal Cell could lead to more personalized therapies that improve the survival of cancer patients.
Researchers have identified a protein called YTHDF2 that plays a leading role in the development of blood cancers. City of Hope then created a new medicinal compound called CCI-38, which targets and suppresses YTHDF2, thereby reducing the growth of aggressive blood cancers. This approach improves the chances of successful cancer treatment.
We believe that using CCI-38 to target YTHDF2 will significantly improve the effectiveness of CAR T cell therapy on blood cancer cells. »
Jianjun Chen, Ph.D., Simms/Mann Family Foundation Chair in Systems Biology and Director of the Center for RNA Biology and Therapeutics at the Beckman Research Institute at City of Hope
“One of the challenges in treating blood cancers is a phenomenon called “antigen leak.” A key target of these therapies is a protein called CD19 found on cancer cells,” added Dr. Chen, corresponding author of the new study.
However, in 28 to 68% of cases, cancer cells decrease or lose this CD19 marker, making treatments less effective. Although researchers are working on strategies to target multiple components, almost half of patients still experience this problem.
YTHDF2 activates genes that help cancer cells produce a stable energy source to fuel their ability to grow and spread. Additionally, this protein helps cancer cells hide by reducing the presence of antigenic biomarkers that normally trigger the immune system to detect and attack them. Finally, excess YTHDF2 works like a werewolf bite to turn healthy blood cells into cancer cells in mouse studies.
“Reducing the need for follow-up treatments could lead to better long-term survival and fewer relapses for our patients while reducing side effects and medical costs,” said Xiaolan Deng, Ph.D., research professor. Associate in Systems Biology at Beckman. City of Hope Research Institute and co-corresponding author of the study.
City of Hope, a recognized leader in CAR T cell therapies for glioblastoma and other cancers, has treated more than 1,600 patients since launching its CAR T program in the late 1990s. The institution continues to have of one of the most comprehensive CAR T cell clinical research programs in the world.
“Unraveling the biology underlying YTHDF2 function will help us develop new strategies to prevent tumor cells from escaping immune surveillance,” said systems biology researcher Zhen-Hua Chen, Ph.D. at the Beckman Research Institute at City of Hope and first author of the study. “This could lead to personalized approaches for patients whose blood cancers do not respond to initial treatment or who relapse after an initial response to T-cell immunotherapy.”
The City of Hope team has filed a patent application covering critical aspects of this work, which has implications for improving the care of patients with other cancers and serious autoimmune diseases. The next phase of research will focus on improving the safety and efficacy of CCI-38, exploring new methods to eliminate YTHDF2 from cancer cells, and developing clinical trials.
