Yvonne Chen's Research at UCLA: Engineering Cell-Based Immunotherapies for Cancer Treatment

Introduction

Dr. Yvonne Chen is a prominent figure in the field of biomolecular engineering, particularly known for her innovative work in developing cell-based therapies for cancer treatment. As an Associate Professor of Microbiology, Immunology, and Molecular Genetics at UCLA, and co-director of the Tumor Immunology program in the Jonsson Comprehensive Cancer Center, Dr. Chen's research focuses on engineering mammalian cells for clinical applications, with a significant emphasis on chimeric antigen receptor (CAR) T-cell therapy. Her work has been recognized with several prestigious awards, including the NIH Director’s Early Independence Award and the Cancer Research Institute Lloyd J. Old STAR Award.

Background and Education

Yvonne Chen's academic journey began with a B.S. in Chemical Engineering from Stanford University. She then pursued a Ph.D. in Chemical Engineering from the California Institute of Technology (Caltech) under the guidance of Christina D. Smolke, Ph.D. Following her doctoral studies, Dr. Chen gained postdoctoral experience at the Seattle Children’s Research Institute and the Department of Systems Biology at Harvard Medical School. Before joining UCLA in 2013, she was a Junior Fellow in the Harvard Society of Fellows.

The Chen Laboratory at UCLA

The Chen Laboratory at UCLA is dedicated to applying biomolecular engineering techniques to develop novel mammalian-cell systems for clinical use. The lab is composed of a diverse group of researchers, including:

Mobina K.: Assistant Project Scientist and Lab Manager, with a Ph.D. in Molecular Genetics from the University of Leicester, UK.
Justin: Ph.D. Student in Chemical & Biomolecular Engineering, with a background in metabolic engineering and biopharmaceutical process development.
Nayoung: Postdoctoral Fellow with a Ph.D. in Cell Biology from Yale University, specializing in genetic regulatory mechanisms of hematopoietic progenitors.
Kenny: Pediatric Hematology/Oncology Fellow, interested in developing cellular therapies for pediatric sarcomas.
Tora: Ph.D. Student in Chemical & Biomolecular Engineering, focusing on analytical chromatography, mass spectrometry, and immunotherapy development.
Savannah Kim: Ph.D. student in Bioengineering, interested in utilizing cell immunotherapy and biomaterials to bridge the gap in cancer therapy.
Ryan: M.D. & Ph.D. Student in the Molecular Biology Interdepartmental Program (MBIDP), with expertise in micro-electro-mechanical systems (MEMS) and microfluidic cell-sorting applications.
Melanie Ayala Ceja: Staff Research Associate, with a background in optimizing the production of neural progenitor cells.
Jimmy: Staff Research Associate with experience in topological superconductivity and CAR-T cell activation patterns.
Caitlin: Staff Research Associate, specializing in the reactive oxygen species response in Drosophila macrophages.
Vy (Sunny) Tran: Staff Research Associate, with a background in photovoltaic cells and distributed Bragg reflectors.

Former members of the lab have included Laurence Chen, Amy Hong, Andrew Hou, Eunwoo (Chris) Nam, Ximin Chen, Meng-Yin Lin, Patrick Ho, Eugenia Zah, and ZeNan Chang.

Research Focus: CAR T-Cell Therapy

Dr. Chen's primary research focus is on engineering cell-based immunotherapies, particularly CAR T-cell therapy, to target and eliminate cancer cells. CAR T-cells are created by genetically modifying a patient's own T cells to express a synthetic receptor, known as a chimeric antigen receptor (CAR), that enables them to recognize and bind to specific antigens on the surface of tumor cells. This technology has shown remarkable success in treating certain blood cancers, but its application to solid tumors has been more challenging.

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Overcoming Antigen Escape

One of the major challenges in CAR T-cell therapy is antigen escape, where cancer cells lose the target antigen, rendering them invisible to the CAR T-cells. To address this issue, Dr. Chen's lab is developing bispecific CAR T-cells that can simultaneously target two different antigens on the tumor cell surface. This approach makes it more difficult for the tumor to escape therapy, as it would need to lose both antigens to evade the T-cells. A bispecific CAR targeting CD19 and CD20, both antigens found on B cells, has shown promising results in preclinical studies.

Targeting Solid Tumors

Solid tumors present additional hurdles for CAR T-cell therapy, including the physical tumor microenvironment, which can prevent immune cells from infiltrating the tumor. The tumor microenvironment often contains immunosuppressive molecules, such as TGF-β, that can inhibit T-cell proliferation and function.

To overcome this challenge, Dr. Chen's lab has engineered CAR T-cells that can respond to TGF-β by becoming more active rather than shutting down. These TGF-β-targeting CAR T-cells proliferate and produce immune-stimulating cytokines in response to TGF-β, enhancing their ability to attack tumor cells.

Improving CAR T-Cell Design

Dr. Chen's lab is also focused on systematically improving the design of CARs to enhance their efficacy and safety. This involves studying the molecular and receptor-level sequences and structures that make a good CAR and understanding the mechanisms behind their function. The goal is to move beyond trial-and-error approaches and develop a rational design process for novel CARs that can target a variety of antigens.

Clinical Trials and Impact

The Chen Lab led the first investigator-sponsored clinical trial on CAR-T cell therapy at UCLA. Chen and Sarah Larson, M.D. co-led a first-in-human clinical trial evaluating a next-generation CAR-T cell therapy approach for patients with relapsed or treatment-resistant non-Hodgkin’s B-cell lymphoma. The CARs were engineered to recognize two different antigens found on the surface of cancer cells. Early results from this trial found that the new approach minimized treatment resistance and resulted in long-lasting remission.

Addressing Glioblastoma Multiforme (GBM)

Dr. Chen is also engineering a novel cell-based therapy to treat glioblastoma multiforme (GBM), the most common and malignant type of brain cancer. GBM is uniformly fatal and lacks effective treatment options. To address this, Dr. Chen and her team are developing a more robust CAR T-cell therapy for GBM by engineering cells to simultaneously latch on to two distinct GBM proteins, while also expressing factors that prevent immune suppression in the area surrounding the tumor.

Key Publications

Dr. Chen's research has been published in numerous high-impact journals, including:

Journal of Experimental Medicine (CAR-T cell manufacturing: Major process parameters and next-generation strategies, 2024)
Gene Therapy (Successes and challenges in clinical gene therapy, 2023)
Cancer Discovery (CD19/CD20 bispecific chimeric antigen receptor (CAR) in naïve/memory T cells for the treatment of relapsed or refractory non-Hodgkin lymphoma, 2023)
Cell Systems (The sound of silence: Transgene silencing in mammalian cell engineering, 2022)
Nature Reviews Drug Discovery (Navigating CAR-T cells through the solid-tumour microenvironment, 2021)
Nature Communications (Systematically optimized BCMA/CS1 bispecific CAR-T cells robustly control heterogeneous multiple myeloma, 2020)
Cancer Cell (Engineering CAR-T cells for next-generation cancer therapy, 2020)
EBioMedicine (CAR-T design: Elements and their synergistic function, 2020)
Journal of Industrial Microbiology and Biotechnology (Synthetic biology advances and applications in the biotechnology industry: a perspective, 2018)
Nature Chemical Biology (Rewiring T-cell responses to soluble factors with chimeric antigen receptors, 2018)
Bioengineering & Translational Medicine (TGF‐β-responsive CAR‐T cells promote anti‐tumor immune function, 2018)
Trends in Molecular Medicine (CARs: synthetic immunoreceptors for cancer therapy and beyond, 2017)
ACS Synthetic Biology (Modularly Constructed Synthetic Granzyme B Molecule Enables Interrogation of Intracellular Proteases for Targeted Cytotoxicity, 2017)
Cancer Immunology Research (T Cells Expressing CD19/CD20 Bispecific Chimeric Antigen Receptors Prevent Antigen Escape by Malignant B Cells, 2016)
ACS Synthetic Biology (Quantitative Analyses of Core Promoters Enable Precise Engineering of Regulated Gene Expression in Mammalian Cells, 2016)
Journal of Translational Medicine (Identification and selective expansion of functionally superior T cells expressing chimeric antigen receptors, 2015)
Nucleic Acids Research (Design of small molecule-responsive microRNAs based on structural requirements for Drosha processing, 2011)
Proceedings of the National Academy of Sciences (Genetic control of mammalian T-cell proliferation with synthetic RNA regulatory systems, 2010)

These publications highlight Dr. Chen's significant contributions to the field of cancer immunotherapy and synthetic biology.

Vision for the Future

Dr. Chen's vision for the future of T-cell therapies includes a deeper understanding of the molecular mechanisms that make a good CAR, the key parameters that influence T-cell product effectiveness, and the potential for engineering T-cells to communicate with the natural immune system. Her goal is to increase the consistency, clinical benefit, and safety of T-cell products while reducing their cost.

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