Veatch and colleagues will conduct preclinical testing of their approach on MISTRG humanized mouse model to identify targets with greatest potential
Seattle, WA – October 21, 2024
Washington Research Foundation (WRF) has approved a $250,000 technology commercialization grant to support groundbreaking research led by Joshua Veatch, MD, Ph.D., at Fred Hutch Cancer Center (Fred Hutch). The team is testing CD4 T-cell therapy for a wide range of cancers including melanoma, lung cancer and Merkel cell carcinoma, providing new hope for patients with these devastating illnesses. Veatch’s collaborators on this project include McGarry Houghton, MD, and Anthony Rongvaux, Ph.D., of Fred Hutch, along with Paul Nghiem, MD, Ph.D., of the University of Washington’s Department of Dermatology.
Adoptive T-cell therapies, in which a patient’s immune cells are extracted from the blood, genetically engineered to target cancer cells, and reinfused into the patient, show great promise in the treatment of cancers. Chimeric Antigen Receptor (CAR) T-cell therapies have been effective treatments for leukemia and lymphoma but have shown limited efficacy in treating solid tumor cancers.
One reason for this has been difficulty finding ways for T cells to specifically target cancer cells and not normal cells. Leukemia and lymphoma have targets on the cell surface that are not found on normal cells, but many solid tumors do not. T cells can also recognize targets that are brought to the surface of cells by membrane proteins designed to communicate with the immune system, but tumors often shut these down so that they can hide from T cells. Solid tumors present an additional complication, as they create a microenvironment in their immediate vicinity that promotes cancer growth and hinders immune response.
Veatch and his colleagues are testing a new adoptive T-cell therapy capable of targeting cancers that does not depend on the tumor cells cooperating. Instead of engineering T cells that search for antigens on the surface of cancer cells, the team is transforming T cells that search for antigens on the surface of other immune cells in the tumor. A class of immune cells called antigen presenting cells (APCs) engulf protein fragments they find in the body and present them on their surface. A specific type of T cell called CD4 T cells check these APCs and, upon recognizing an antigen, recruit other immune cells to coordinate an immune response targeting the cell that produced the antigen. By engineering CD4 T cells to identify cancer antigens presented by APCs, Veatch and his team aim to create an adoptive T-cell therapy capable of targeting cancers that hide from T cells that directly recognize them. Healthy cells are untouched, reducing potential side effects from the treatment.
There are several reasons why this approach has not yet been pursued. Due to the indirect way CD4 T cells target cancer cells, developing CD4 T-cell receptors that can detect cancerous antigens without mistakenly attacking normal tissue has been challenging. However, Veatch’s team has identified T-cell receptors from patient-derived T cells that enable CD4 T-cell targeting of a significant portion of melanoma cancers, lung cancers and Merkel cell carcinomas.
Another key barrier to developing this technology is the lack of an animal model system. Since CD4 T cells rely on the recruitment and coordination of immune cells, a suitable animal model would need to possess a significant portion of the human immune system. To overcome this hurdle, Veatch’s team is using an immunodeficient (MISTRG) mouse model developed largely by Rongvaux. By expressing multiple human immune genes, this new mouse line can support the survival of engrafted human immune cells.
“Targeting the other immune cells in the tumor rather than the tumor cells themselves is a different approach than other T-cell therapies that has the potential to overcome the way tumors evade the immune system,” said Veatch, an assistant professor in Fred Hutch’s Translational Sciences and Therapeutics Division. “We know this strategy can work with mouse immune cells, and being able to show it can work with human immune cells attacking targets in human cancer cells is a critical step in bringing this to patients.”
Meher Anita, Ph.D., WRF’s director of grant programs, said, “Our technology commercialization grants are intended to de-risk innovative new approaches so that they can continue to successfully develop, and in this case, eventually be tested in patients. This project will help uncover whether targeting CD4 T cells can improve on existing cell therapies, particularly for solid tumors.”
Armed with these building blocks and promising preliminary studies, the Veatch team is ready to complete preclinical testing of these therapies over the next two years. They will identify the receptors with the greatest potential for this approach, with their longer-term sights set on clinical trials.
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About Washington Research Foundation
Washington Research Foundation (WRF) supports research and scholarship in Washington state, with a focus on life sciences and enabling technologies.
WRF was founded in 1981 to assist universities and other nonprofit research institutions in Washington with the commercialization and licensing of their technologies. WRF is one of the foremost technology transfer and grantmaking organizations in the nation, having earned more than $445 million in licensing revenue for the University of Washington and providing over $160 million in grants to the state’s research institutions to date.
WRF Capital, the investment vehicle for Washington Research Foundation, has backed 132 local startups since 1996. Returns support the Foundation’s investment and grantmaking programs.
For additional information, please visit wrfseattle.org.
