UCLA researchers in the Department of Molecular Immunology & Molecular Genetics have developed gamma delta (gd) T cell receptor gene-modified immune cells derived from stem and progenitor cells that enable scalable, off-the-shelf allogeneic cell therapies with broad therapeutic potential.
BACKGROUND: Cell-based immunotherapies have demonstrated immense clinical impact but remain limited by complex, patient-specific manufacturing, high cost, and varying product quality. Conventional autologous T cell therapies require individualized production and are constrained by long manufacturing timelines and inconsistent starting material. On the other hand, gamma delta (gd) T cells represent a unique subset of T cells that recognize targets independently of classical HLA restriction, making them well suited for allogeneic applications. gd T cells exhibit innate-like cytotoxicity, broad target recognition, and reduced risk of graft versus host disease. Thus, they are attractive candidates for off-the-shelf immune therapies across oncology, autoimmunity, and infectious disease.
INNOVATION: UCLA researchers led by Dr. Lili Yang have developed a platform for generating engineered gd T cells through TCR gene engineering of stem and progenitor cell populations, including hematopoietic stem cells (HSCs), induced pluripotent stem cells (iPSCs), and embryonic stem cells (ESCs). Researchers have shown that gene-engineered stem or progenitor cells can be differentiated into invariant gd T cells either in vitro or in vivo, yielding highly uniform and scalable cell products. The engineered gd T cells can further be modified to co-express additional disease-targeting or immune-regulatory molecules, such as chimeric antigen receptors (CARs), cytokines, or engineered receptors and ligands, enabling enhanced persistence, efficacy, and safety. This approach eliminates the need for patient-specific manufacturing and supports large-scale production of consistent, cryopreservable cell therapy suitable for immediate clinical use.
POTENTIAL APPLICATIONS:
- Allogenic off-the-shelf cell therapy
- Cancer
- Autoimmune disease
- Inflammatory & infectious disease
- Combination therapy incorporating CARs or other immune modulators
ADVANTAGES:
- HLA-independent gd TCR recognition allows for universal donor use
- Scalable manufacturing
- Uniform, invariant cell products
- Cheaper and faster than autologous therapies
- Flexible platform allows for co-expression of CARs and other molecules
DEVELOPMENT-TO-DATE: The inventors have established methods for gd TCR gene engineering of stem and progenitor cells and demonstrated efficient differentiation into functional gd T cells in vitro and in vivo. These cells exhibit potent cytotoxic activity and support scalable manufacturing suitable for allogeneic therapy.
Related Papers (from the inventors only):
- Lee, D., Dunn, Z.S., Guo, W. et al. Unlocking the potential of allogeneic Vδ2 T cells for ovarian cancer therapy through CD16 biomarker selection and CAR/IL-15 engineering. Nat Commun 14, 6942 (2023). https://doi.org/10.1038/s41467-023-42619-2
- Lee D, Rosenthal CJ, Penn NE, Dunn ZS, Zhou Y, Yang L. Human γδ T Cell Subsets and Their Clinical Applications for Cancer Immunotherapy. Cancers (Basel). 2022 Jun 18;14(12):3005. doi: 10.3390/cancers14123005. PMID: 35740670; PMCID: PMC9221220.
Keywords: gd T cells, gamma delta T cells, T cell receptor engineering, TCR gene therapy, stem cell-derived T cells, iPSCs, HSCs, allogeneic cell therapy, immunotherapy, cancer, autoimmune disease, off-the-shelf, infectious disease