Building better CARs.
Yvonne Chen, MD
University of California Los Angeles
“It’s a privilege to work on research that is not just interesting, but has real potential to make life better for people,” says Yvonne Chen, PhD, of the Department of Microbiology, Immunology and Molecular Genetics, and the Department of Chemical Biomolecular Engineering at the University of California, Los Angeles.
Chimeric antigen receptor CAR-T cell therapy has been under investigation for about 30 years. It became well known to the public in 2011 when Alliance for Cancer Gene Therapy-funded Research Fellow and Scientific Advisory Council member Dr. Carl H. June and his team at the University of Pennsylvania successfully treated leukemia patients with T cells that had been genetically modified to express CARs that enable them to seek, find and destroy CD19 protein antigens on B-cell cancers. Since her time as a postdoctoral scholar at Seattle Children’s Research Institute and as a Junior Fellow in the Harvard Society of Fellows, Dr. Chen has made it her mission to better understand the mechanics and variables of CAR T-cell engineering. Simply stated by Chen, “we want to figure out exactly what makes a good CAR.”
Dr. Chen’s goal is to create new hope for cancer patients by empowering researchers with a more informed understanding of the factors required to successfully design new CARs to target different antigens. By developing a substantive frame of reference, expensive and time-consuming trial-and-error approaches could be abandoned in favor of more promising, pre-qualified strategies.
Dr. Chen’s search began at the molecular level. With a grant from Alliance for Cancer Gene Therapy, Dr. Chen began to organize an ambitious high-throughput screening (HTS) initiative to test thousands of CAR variants generated through random sequence mutations on specific residues within the CAR molecule. After discovering that results obtained from human T cells cultured in the lab are often not predictive of in vivo results observed in animals, her research methodology shifted to testing panels of rationally designed CAR constructs in animal models.
Five structural parameters for CAR design were explored to determine which have the most impact on CAR function. With systematic testing, three of the parameters clearly demonstrated substantial impact, and a promising new CAR that targets a B-cell lymphoma antigen (CD20) emerged.
Dr. Chen’s Alliance-funded achievements were presented at the 2018 Cell Therapies and Immunotherapy Conference. In 2019, a phase-1 clinical trial evaluating a CD19/CD20 bispecific CAR T-cell therapy previously developed by Dr. Chen’s laboratory began patient enrollment.
“Cell and gene therapies are very exciting,” says Dr. Chen, “because they clearly have application potential. Yet, a lot of the biology is still unknown and needs to be investigated. This puts researchers at a rare intersection – we get to work on scientific questions that are both fundamental and likely to directly impact patients.
“It’s important to acknowledge organizations like Alliance for Cancer Gene Therapy who invest trust and resources in research that is high-risk, high-reward. Critically, the organization distributes its support in a scientifically rigorous and financially responsible way, and we look forward to translating the research supported by Alliance for Cancer Gene Therapy into real benefits for patients.”
“It’s important to acknowledge organizations like Alliance for Cancer Gene Therapy who invest trust and resources in research that is high-risk, high-reward. Critically, Alliance for Cancer Gene Therapy distributes its support in a scientifically rigorous and financially responsible way, and we look forward to translating the research supported by the organization into real benefits for patients.”