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A research effort aimed at developing new cancer immunotherapies using nanobody delivery and targeted heating of tumors has received funding from the Waddell Walker Hancock Cancer Discovery Fund.
Researchers aim to develop new treatments that reprogram regulatory T cells, which normally suppress immune responses, into killer T cells with antitumor activity. The key to this reprogramming is the STING signaling pathway, and the force required to unlock it is body temperature associated with fever. This hypothesis is based on the group’s recent findings about how fever affects the immune response.
The overriding goal is to develop immunotherapies that benefit more patients. Only about 15% of cancer patients respond to current immunotherapies.
The project was led by Dr. Jeffrey Rathmell, Cornelius Vanderbilt Professor of Immunobiology, Director of the Vanderbilt Immunobiology Center, and Professor of Pathology, Microbiology, and Immunology, and John Tanner, Associate Professor of Chemistry and Biomolecules. Collaborate and lead with Dr. Wilson. Engineering, biomedical engineering, pathology, microbiology, immunology.
This is the first grant from the Waddell Walker Hancock Cancer Discovery Fund, which was created in 2022 to commemorate its 50th anniversary.th Anniversary of the AB Hancock Jr. Memorial Cancer Research Institute.
“This project is unlikely to receive standard federal funding at this stage,” Rathmell said. “It’s high risk, high return, and it’s also very multidisciplinary. There are so many different components that it’s hard to put money into one bucket like you would normally use for traditional fundraising. Otherwise, I don’t know if we would be able to easily raise this funding.”
Waddell Walker Hancock Cancer Discovery Fund supports basic science research projects based on innovative ideas that have the potential for high rewards but are considered high risk. Many donors have contributed to this endowment fund, which will provide critical seed funding for Hancock Scholars in perpetuity.
““This fund honors the pioneering spirit of my mother, Waddell Walker Hancock,” said Del Hancock, whose family has supported cancer research at Vanderbilt-Ingram University for more than 50 years. “She was dedicated to the Hancock Laboratory and determined to support those striving to understand the causes of cancer. We have been part of the Cancer Center since the beginning. I am proud and look forward to seeing where these Hancock Scholars take us in the future.”
The project, led by Wilson and Rathmell, was chosen from a large pool of applicants, said Dr. Larry Marnett, Distinguished Professor of Biochemistry and Chemistry at Vanderbilt University and director of the Hancock Institute.
“We received many excellent applications, but Jeff and John’s application stood out because it provides important information about the regulation of immune responses in cancer and is currently being used to We are pleased to support the collaboration of these two talented researchers. Waddell Walker Hancock’s commitment to the fight against cancer We are extremely grateful to the many donors who have generously shared their dedication with us,” said Marnett, the Mary Geddes Stahlman Professor of Cancer Research.
Researchers in the Rathmell lab will profile changes in gene expression in mouse models and human regulatory T cells in response to fever-related temperature and STING activation. They plan to better understand these changes in order to define the mechanisms between STING signaling and temperature-induced changes in regulatory T cell function associated with fever.
Wilson’s lab is pioneering nanobody-drug conjugates for targeted delivery of STING agonists. Because the STING signaling pathway is a mediator of inflammation and immune responses, the lab’s next step is to target these complexes to CTLA-4, a protein receptor highly expressed on regulatory T cells. is to further develop.
Instead of inducing whole-body temperature, researchers envision using focused ultrasound or focused magnetic resonance imaging to heat specific tumor sites.
“We’re doing some basic hypothesis-based science, and at the same time using what we’ve learned, we’re trying to manipulate the molecules that selectively activate STING in these specific types of T cells. “There are,” Wilson said. “This primes the pump for regulatory T cells to be reprogrammed from anti-tumor progenitor cells, and further heat can push regulatory T cells to their highest levels for even greater anti-tumor efficacy. I’m thinking, at that point, the T cells will become the drug.”
The professors and Rachel Smith, a graduate student working in both labs, collaborated with Darren Heintzman in Rathmell’s lab to understand how fever changes immune system metabolism. Koto admitted that he was the originator of this project. This study revealed that regulatory T cells are less able to suppress the immune system when temperatures rise, and that higher temperatures activate the STING pathway.
“Fever is something very basic, but we actually don’t know much about it,” Rathmell said.
To make a gift to support the Waddell Walker Hancock Cancer Discovery Fund, please visit: give.vanderbilthealth.org/WaddellWalkerHancock.
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