Tumors dodge CAR T cells
“We expected two different tumors with exactly the same level of antigen [GRP78] Expression should be affected in the same way by CAR T-cell therapy, but they are not,” said first author Jorge Ibañez, Ph.D. st jude Department of Bone Marrow Transplantation and Cellular Therapy. “Instead, we found that certain tumor cell types had altered T-cell activation and T-cell GRP78 expression.”
Ibanez found that resistant tumor cell types were replacing the CAR T cells. Tumor cells induced GRP78-targeted CAR T cells to express GRP78 on the surface of CAR T cells. The more GRP78 there is on T cells, the less activated they become, reducing their cancer-killing activity. Furthermore, CAR T cells that remained activated targeted and killed their counterparts expressing GRP78 on their surface.
In fact, resistant tumors were affecting the CAR T cells. These tumors hoisted the GRP78 flag and said, “I’m here,” and then convinced incoming T cells to hoist their GRP78 flag. This caused the CAR T cells to kill each other or give up, leaving the tumor relatively unharmed.
through these experiments st jude The group unveiled the intriguing biology of GRP78. Given its presence on many difficult-to-treat tumor types, the protein remains an attractive target. The findings suggest that scientists will need to expand their understanding of this new interaction with T cells to create viable GRP78-targeted immunotherapy. Still, if they can, these CAR T cells could be broadly applicable across a wide range of tumor cell types.
“We always need to find new targets to improve cancer treatment,” Crenciut said. “What we found from a biological perspective is that GRP78 has potential but it is different from previous cancer-associated molecules. We show that as scientists develop the next generation of CAR T-cell therapies, we need to recognize that not all targets are the same.
Author and funding
Other authors of the study are Nikhil Hebbar, Unmesha Thanekar, Zhongzhen Yi, Haley Hawke, Meghan Ward, Chris Nevitt, Liqing Tian, Stephen Mack, Heather Shepard and Jason Chiang, all st jude,
The study was supported by grants from the National Institutes of Health (NIH) (P01CA096832 and R50CA211481), the National Cancer Institute (P30CA021765), the Chaddough Defeat DIPG Foundation (R01NS122859), the American Brain Tumor Association (ABTA) Basic Research Fellowship. Fight the Tumor and ALSAC, fundraising and awareness organizations st jude,