Scientists Discover Key to Overcoming Cancer's Evasion Tactics

A cunning culprit that aids cancer cells in avoiding CAR T cell therapy has been identified by researchers at City of Hope^®, one of the biggest and most cutting-edge cancer research and treatment organizations in the United States, with a comprehensive cancer center in Los Angeles that is ranked among the top five cancer centers in the country by US News & World Report.

CAR T cell therapy uses the immune system to locate and eliminate tumor cells. This medication treats certain forms of leukemia and lymphoma, which are blood cancers.

However, some cancer cells have figured out how to evade the immune system to stay alive. The study published today in the journal Cell may result in more individualized treatments that increase cancer patients' survival.

Researchers discovered that a protein known as YTHDF2 is crucial in the progression of blood cancers. City of Hope then developed a novel drug called CCI-38 that inhibits and targets YTHDF2, slowing the spread of aggressive blood cancers. This strategy increases the chances of a successful cancer treatment.

We believe that using CCI-38 to target YTHDF2 will significantly enhance the effectiveness of CAR T cell therapy on blood cancer cells.”

Jianjun Chen, Ph.D., Study Co-Corresponding Author, Beckman Research Institute, City of Hope

Chen is a Simms/Mann Family Foundation Chair in Systems Biology and the Center for RNA Biology and Therapeutics director at Beckman Research Institute of City of Hope.

Chen said, “One of the challenges in treating blood cancers is a phenomenon called ‘antigen escape.’ A key target for these therapies is a protein called CD19 found in the cancer cells.”

Nevertheless, the cancer cells reduce or eliminate this CD19 marker in 28–68% of cases, which reduces the effectiveness of treatments. This problem still affects almost half of patients despite researchers developing ways to address several factors.

YTHDF2 activates genes that help cancer cells generate a steady supply of energy to support their growth and metastasis. By decreasing the presence of antigen biomarkers that typically cause the immune system to recognize and combat cancer, this protein helps cancer cells hide. Finally, in mouse studies, too much YTHDF2 turns healthy blood cells into cancerous ones, much like a werewolf's bite.

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.”

 Xiaolan Deng, Ph.D., Associate Research Professor and Study Co-Corresponding Author, Beckman Research Institute, City of Hope

Since its CAR T program began in the late 1990s, City of Hope, a known pioneer in CAR T cell therapies for glioblastoma and other cancers, has treated over 1,600 patients. The organization maintains one of the world's most extensive clinical research programs for CAR T cells.

Unraveling the biology underlying YTHDF2’s function will help us develop new strategies to prevent tumor cells from escaping immune surveillance. This could lead to personalized approaches for patients whose blood cancers do not respond to initial treatment or who relapse after initial response to T cell-based immunotherapy.”

Zhen-Hua Chen, Ph.D., Staff Scientist and Study First Author, Beckman Research Institute, City of Hope

A patent application submitted by the City of Hope team covers important facets of this work, which could improve treatment for patients with severe autoimmune diseases and other cancers.

The next research stage will concentrate on enhancing the efficacy and safety of CCI-38, investigating novel techniques to extract YTHDF2 from cancer cells, and creating clinical trials.