Research from St. Judd Children’s Research Hospital is moving the field of cancer immunotherapy one step closer to treating brain and solid tumors. Scientists at St. Judd have validated a cellular immunotherapy target called the 78-kDa glucose-regulated protein (GRP78) in a proof-of-principle trial. The group also discovered a resistance mechanism in which some tumors trick cancer-killing immune cells into expressing GRP78, thereby turning off the immune cells or even causing them to be killed. The study, which has implications for immunotherapy for a wide range of hard-to-treat brains and solid tumors expressing GRP78, was published today. Cell Report Medicine.
Reprogramming a patient’s immune cells to target cancer has been successful against leukemia but not brain or solid tumors. These reprogrammed cells, known as chimeric antigen receptor (CAR) T cells, target a specific protein expressed on cancer cells but not healthy ones. This targeting CAR enables T-cell immunotherapy to kill tumors while selectively leaving healthy tissues intact. One difficulty that has hindered the success of CAR T cells in brain and solid tumors is the challenge of identifying a good target for these cancers.
We found GRP78 to be an excellent CAR T-cell target. “We observed high GRP78 expression in many brain and solid types, including adult glioblastoma, diffuse intrinsic pontine glioma (DIPG), osteosarcoma, triple-negative breast cancer, and Ewing sarcoma, but our therapeutic efficacy was variable.”
Giedre Krenciute, Ph.D., senior co-corresponding author, St. Jude Department of Bone Marrow Transplantation and Cellular Therapy
The researchers developed GRP78-targeted CAR T cells that successfully killed many cancers in both cell types and mouse models, although there were significant variations. The researchers hoped that high levels of GRP78 (more protein to target) would make it easier for CAR T cells to detect and destroy cancer; However, that was not the case. The scientists found no correlation between the amount of GRP78 and the ability of CAR T cells to kill cancer.
“We showed that conventional methods of targeting expression do not equal response,” co-corresponding author Paulina Velasquez, MD, St. Jude Department of Bone Marrow Transplantation and Cellular Therapy. “GRP78 appears to be a particular target that did not respond as we expected, making it a promising but complex candidate.”
Tumors manipulate CAR T cells
“We expected two different tumors to have exactly the same level of antigen [GRP78] CAR expression would be similarly affected by T-cell therapy, but they are not,” said first author Jorge Ibáñez, PhD, St. Jude Department of Bone Marrow Transplantation and Cellular Therapy. “Instead, we looked at certain tumor cell types with T-cell activation and T -modulating cell GRP78 expression.”
Ibanez found that resistant tumor cell types were modifying the CAR T cells. Tumor cells allow GRP78-targeted CAR T cells to express GRP78 on the CAR T cell surface. The more GRP78 the T cells have, the less activated they become, reducing their cancer-killing activity. Also, CAR T cells that were activated targeted and killed their antagonists by expressing GRP78 on their surface.
In effect, the resistant tumors blocked the CAR T cells. These tumors picked up the GRP78 flag, said “here I am,” and then persuaded approaching T cells to pick up their own GRP78 flag. This tricked the CAR T cells into killing each other or leaving, leaving the tumor relatively intact.
Through these tests, St. Judd’s group has uncovered the complex biology of GRP78. The protein remains a tantalizing target, given its presence in many difficult-to-treat tumor types. The findings show that scientists need to expand their understanding of this newfound interaction with T cells to develop effective GRP78-targeted immunotherapies. Still, if they can, these CAR T cells could be widely applicable to a wide range of tumor cells.
“We always need to find new targets to improve cancer treatment,” Krenciute said. “What we found from a biological perspective is that GRP78 has potential but is different from previous cancer-related molecules. We have shown that as scientists develop the next generation of CAR T-cell therapies, we need to recognize that not all targets are equal.”
Authors and Funders
Other authors of the study are Nikhil Hebbar, Unmesha Thanekar, Zhongzhen Yi, Haley Hauke, Megan Ward, Chris Nevitt, Liqing Tian, Stephen Mack, Heather Sheppard and Jason Chiang, all of St. Petersburg. Jude.
The research was supported by grants from the National Institutes of Health (NIH) (P01CA096832 and R50CA211481), National Cancer Institute (P30CA021765), ChadTough Defeat DIPG Foundation (R01NS122859), American Brain Tumor Association (ABTA). Fight the Tumor and ALSAC, St. Jude.