CAR T cells attached to renal cell carcinoma. (Illustration: iStock.com)
Researchers at Winship Cancer Institute of Emory University have developed an “armored” form of CAR T-cell therapy designed to remain active longer and recruit additional immune cells to help attack cancer.
The findings, published July 22 in Science Translational Medicine, could provide a new strategy for overcoming some of the most persistent barriers limiting CAR T-cell therapy, particularly for solid tumors.
CAR T-cell therapy is a type of immunotherapy that uses a patient’s own T cells, a type of immune cell, to recognize and attack cancer. Sometimes described as a “living drug,” CAR T cells have transformed treatment for certain blood cancers. However, the cells can become exhausted after they are infused into a patient, reducing their ability to control cancer over time. CAR T cells have also been far less successful against solid tumors, which can be difficult for immune cells to enter and contain signals that suppress their activity.
Targeting a key source of CAR T-cell suppression
Sarwish Rafiq, PhD
The Winship-led research focused on vasoactive intestinal peptide, or VIP, a naturally occurring molecule that can suppress immune activity by binding to receptors on T cells. To examine whether this pathway could affect CAR T-cell function in patients, the researchers analyzed blood samples from patients with large B-cell lymphoma who had received CAR T-cell therapy. Higher VIP expression shortly after treatment was associated with poorer treatment response and overall survival. Because the findings came from a small group of patients treated at a single institution, the authors note that the association will need to be validated in a larger and more diverse patient population. Researchers then engineered CAR T cells to secrete a short peptide drug that blocks VIP from activating its receptors. The modified cells, called CAR/VIPRa T cells, are designed to deliver the VIP receptor antagonist where it is needed while also protecting themselves from suppressive signals.
“Our study identifies the VIP/VIP receptor axis as a functionally relevant immune checkpoint in CAR T cells,” says corresponding author Sarwish Rafiq, PhD, program leader for CAR T Basic/Translational Research in the Winship Center for Cancer Immunology, and associate professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine. “By engineering CAR T cells to produce a drug that blocks this pathway, we can improve the fitness of the CAR T cells themselves while also supporting the tumor-fighting activity of nearby immune cells.”
During laboratory manufacturing, the engineered CAR/VIPRa T cells maintained a less differentiated, memory-like state and remained metabolically quiet until they encountered tumor cells. Those characteristics are associated with the ability of CAR T cells to persist and continue responding to cancer.
Once stimulated by tumor cells, however, the engineered cells mounted a strong metabolic and functional response.
“One exciting finding was that the engineered CAR T cells were healthier and less exhausted at baseline, yet they still responded strongly when they encountered tumor cells,” Rafiq says. “We were also encouraged to see that they enhanced the recruitment of the body’s own T cells.”
Engineered cells show greater fitness and tumor-fighting potential
Edmund K. Waller, MD, PhD, FACP
In mouse models of blood and solid tumors, the CAR/VIPRa T cells infiltrated tumors more effectively, retained a less exhausted, memory-like phenotype and demonstrated better tumor control than conventional CAR T cells. The treatment improved survival in preclinical models of pancreatic cancer and melanoma, among others.
The benefit was particularly pronounced in mice with intact immune systems. Because the antagonist secreted by the engineered cells could also act on the animals’ unmodified T cells, the treatment helped draw more of those immune cells into the tumor. This suggests the approach may generate a broader immune response rather than relying exclusively on the infused CAR T cells.
The researchers also manufactured CAR/VIPRa T cells using blood samples from patients with pancreatic ductal adenocarcinoma. Compared with conventional CAR T cells made from the same patient samples, the engineered cells were more viable and had more of the characteristics associated with immune memory.
The research builds on years of work by co-author Edmund K. Waller, MD, PhD, FACP, a researcher at Winship and professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine, whose laboratory has studied how VIP signaling suppresses immune activity and has developed drugs targeting VIP receptors.
“Our work shows that the suppressive effects of VIP also extend to CAR T cells,” Rafiq says. “The novelty of this approach is that the engineered cells produce a peptide drug that improves their own condition while also reshaping the immune environment around the tumor.”
Advancing toward clinical testing
Heather K. Lin, MD, PhD
The findings are preclinical and do not yet have immediate implications for patient care. Rafiq and her colleagues are working toward clinical testing of CAR/VIPRa T cells in patients with solid tumors at Winship.
“While this work is still in the laboratory, it points toward future ways to make CAR T-cell therapy more effective and available to more patients, including those with solid tumors,” Rafiq says. “If the approach translates successfully, it could help produce deeper and more durable antitumor responses.”
The Winship-led study was conducted by a multidisciplinary team led by corresponding author Sarwish Rafiq, PhD, and first author Heather K. Lin, MD, PhD, with significant contributions from Dejah A. Blake, Susan N. Thomas, PhD, and Edmund K. Waller, MD, PhD. The research also involved investigators from Emory University School of Medicine, Georgia Institute of Technology and Children’s Healthcare of Atlanta.
The research was funded with support from Winship Cancer Institute and grants from the National Institutes of Health (award numbers UL1TR002378, 1R44CA298704-01, R41CA247165, R01NS133344 and P30CA138292). Additional funding provided via Georgia Center for Oncology Research and Education, Emory University Research Committee, Mary Kay Ash Foundation, Melanoma Research Foundation, Samuel and Nancy Gordon GCRC Research Program, American Society of Hematology, Abraham J. & Phyllis Katz Foundation and Biolocity, among other sources.