Scientists at St. Jude Children’s Research Hospital in Memphis (United States) have shown that the 78-kDa glucose-regulated protein (GRP78) is a promising but complex target for CAR T-cell immunotherapy against brain – and solid tumors. By expressing GRP78, tumor cells in some cancers appear to be able to trick CAR T cells. This may explain why brain tumors in particular do not or hardly respond to immunotherapy.
The American researchers validated the cellular immunotherapy target GRP78 in proof-of-principle experiments. The group also discovered a resistance mechanism in which some tumors trick cancer-killing immune cells by expressing GRP78, which disables or kills the immune cells. The research, with implications for the development of immunotherapy for the wide range of difficult-to-treat brain and solid tumors expressing GRP78, was recently published in Cell Reports Medicine.
CAR T-cell therapy, which reprograms a patient’s immune cells to attack cancer, has proven successful against cancers such as leukemia, but not against brain or solid tumors. These reprogrammed immune cells target a specific protein that is expressed on cancer cells, but not on healthy cells. This targeted approach allows CAR T-cell immunotherapy to kill the tumor while leaving healthy tissue unharmed. One difficulty that has hampered the success of CAR T cells in brain and solid tumors is the challenge of identifying a good target for these tumors.
Complicated target
The researchers in Memphis discovered that GRP78 is a promising but complicated target for CAR T cells. High expression of GRP78 was seen in a variety of brain and solid tumor types, including adult glioblastoma, diffuse intrinsic pontine glioma (DIPG), osteosarcoma, triple-negative breast cancer and Ewing’s sarcoma, but therapeutic efficacy varied.
The researchers created GRP78-targeted CAR T cells that successfully killed many types of cancer in both cell and mouse models, albeit with significant variation. The researchers expected that higher levels of GRP78 would make it easier for the CAR T cells to locate and destroy the cancer, but that was not the case. The scientists found no relationship between the amount of GRP78 and the ability of the CAR T cells to kill cancer cells.
Cancer-killing activity
Two different tumors were expected to have exactly the same level of antigen [GRP78]expression would be similarly affected by CAR T-cell therapy, but this turned out not to be the case. Instead, the scientists found that certain tumor types altered T cell activation and T cell GRP78 expression. Resistant tumor types caused the GRP78-targeted CAR T cells to express GRP78 on the surface of the CAR T cells. The more GRP78 on the T cells, the less active they became, reducing their cancer-killing activity. In fact, the resistant tumors tricked the CAR T cells. These tumors essentially raised the flag of GRP78 and then convinced the approaching T cells to raise their own GRP78 flag. This tricked the CAR T cells into killing each other, leaving the tumor relatively unscathed.
Through these experiments, the St. Jude group revealed the complicated biology of GRP78. The protein remains a tempting target given its presence on many difficult-to-treat tumor types. The findings show that scientists must expand their understanding of this novel interaction with T cells to create viable GRP78-targeted immunotherapies. If successful, these CAR T cells could potentially be broadly applicable across a wider range of tumor types.
Reference
2023-11-22 11:34:10
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