Chimeric antigen receptor (CAR)-T cells are a powerful, new form of cancer therapy that are being studied to treat blood cancers. Using a new approach, Yale Cancer Center researchers at Yale School of Medicine found a new way to substantially improve the effectiveness of CAR-T cell therapy.
The new study was published in Nature Immunology on July 27.
"We now have a promising way to engineer CAR-T cells, using synthetic CCT fusion,” said senior author Sidi Chen, PhD an associate professor of genetics at Yale School of Medicine and member of Yale Cancer Center. “This approach addresses key challenges in CAR-T therapy and may pave the way for more effective cancer treatments in the future."
The researchers focused on a part of the immune system called the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) cytoplasmic tail and fused it with CAR-T cells. They designed CAR-T cells with different numbers of CCTs (triplex CTLA-4 cytoplasmic tails) and tested their performance against cancer cells. The CAR-T cells equipped with CCTs had a progressive increase in toxicity to target cells.
Further investigation revealed that the CARs with increasing CCT fusion showed lower surface expression. With CCT fusion, the CAR-T cells' ability to persist and fight cancer improved significantly, particularly the CARs with monomeric and duplex CCTs, which exhibited superior antitumor efficacy in a relapsed leukemia model.
The researchers also observed enhanced survival in CAR-T cells with CCT fusion targeting a different cancer antigen, highlighting the potential to help treat various cancer types. These findings collectively demonstrate that CCT fusion improves survival by effectively increasing the number of CAR-T cells and preventing cell death (apoptosis). Researchers say this CCT fusion technology, in principle, is applicable to many types of cell therapies.
"This breakthrough has the potential to enhance cancer treatment and improve patient outcomes,” said Chen. “Enhancing CAR-T cells' durability and potency is an important step forward in the fight against cancer.”
Chen was joined by first author Xiaoyu Zhou from Yale School of Medicine, as well Yale co-authors Hanbing Cao, Shao-Yu Fang, Ryan Chow, Kaiyuan Tang , Medha Majesty, Meizhu Bai, Matthew Dong, Paul Renauer, Xingbo Shang, Kazushi Suzuki, and Andre Levchenko.
This research was funded by the National Institutes of Health and the U.S. Department of Defense.