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Explore our cutting edge research, world-class patient care, career opportunities and more.
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Manipulating the immune system to treat cancer has generated phenomenal responses in some patients, including complete cures, but those responses are not the same for everyone. Chimeric antigen receptor (CAR) T–cell immunotherapy causes an initial response in 90% of B-cell acute lymphoblastic leukemia (B-ALL) patients, but there is a 50% chance a patient will experience a relapse after treatment.
A collaborative study led by co-corresponding authors Jiyang Yu, PhD, Department of Computational Biology interim chair, and Terrence Geiger, MD, PhD, Academic and Biomedical Operations senior vice president and deputy director, and Department of Pathology member, uncovered a reason why patients relapse after CAR T–cell therapy and reported a potential way to prevent it in Cancer Discovery.
They discovered that the gene for G protein–coupled receptor 65 (GPR65) is inactive in some tumors, and its reduced activity correlates with resistance to immunotherapy. Compensating for GPR65’s gene inactivation improved survival and tumor control in laboratory models.
“In the past, we haven’t had good biomarkers to predict immunotherapy response,” said Geiger. “We may now have a potential antigen-independent tumor biomarker in the GPR65 gene to identify which tumors will respond well to immunotherapy or if other treatments should be considered.”
(L to R) Co-first author Jayadev Mavuluri, PhD, Department of Pathology; senior co-corresponding author Terrence Geiger, MD, PhD, Academic and Biomedical Operations senior vice president and Academic and Biomedical Operations deputy director, Department of Immunology interim chair and Department of Pathology member; co-corresponding author Jiyang Yu, PhD, Department of Computational Biology interim chair; and co-first author Yogesh Dhungana, St. Jude Graduate School of Biomedical Sciences, leveraged findings about how cancer cells reduce the effectiveness of immunotherapy to suggest a combination treatment to reduce leukemia relapse.
After identifying GPR65’s importance, the scientists studied how it affected the microenvironment — the network of chemicals, signals, and structures surrounding the tumor. In a mouse model with an intact immune system, selectively removing the Gpr65 gene in tumors prevented CAR T cells from effectively treating B-ALL.
The researchers found that because GPR65 is a sensor protein, when it’s not present, the body becomes partly blind to what is happening around the tumor. Decreased activity of GPR65 allows the tumor to trigger pathways suppressing CAR T–cell activity. The researchers also found that one way these tumors modified their microenvironment was by recruiting immune cells called macrophages. Those macrophages sent out signals opposing other immune cells, effectively blocking the local activity of therapeutic T cells. When the researchers depleted macrophages, the mice treated with CAR T cells survived longer.
There are currently no approved treatment methods to deplete tumor-associated macrophages during immunotherapy clinically. Instead, the researchers looked at gene expression to identify potential therapeutic strategies. They found that when tumors decrease GPR65 gene expression, their vascular endothelial growth factor A (VEGFA) gene expression increases. When treating models with a drug inhibiting VEGFA, they saw a significant increase in CAR T cells’ ability to destroy the tumor.
“We’ve identified a proof-of-principle potential therapeutic opportunity using the combination of CAR T–cell immunotherapy and an anti-VEGF drug,” Yu said. “We hope this approach will help prolong the effectiveness of the treatment and prevent relapse for patients with B-ALL.”