Li et al. combined hematopoietic stem cell gene engineering and in vitro differentiation of iNKT cells to generate allogeneic iNKT (AlloHSC-iNKT) cells from multiple donors. These cells effectively target tumors through intrinsic NK functions and avoid the risk of graft-versus-host disease associated with recognition of host HLA by conventional allogeneic T cells. AlloHSC-iNKT were successfully engineered with CARs, HLA expression was ablated to reduce potential immunogenicity, and a “safety switch” suicide gene was inserted. The large yield from a single donor supports AlloHSC-iNKTs development for clinical testing.
Contributed by Margot O’Toole
ABSTRACT: Cell-based immunotherapy has become the new-generation cancer medicine, and “off-the-shelf” cell products that can be manufactured at large scale and distributed readily to treat patients are necessary. Invariant natural killer T (iNKT) cells are ideal cell carriers for developing allogeneic cell therapy because they are powerful immune cells targeting cancers without graft-versus-host disease (GvHD) risk. However, healthy donor blood contains extremely low numbers of endogenous iNKT cells. Here, by combining hematopoietic stem cell (HSC) gene engineering and in vitro differentiation, we generate human allogeneic HSC-engineered iNKT (AlloHSC-iNKT) cells at high yield and purity; these cells closely resemble endogenous iNKT cells, effectively target tumor cells using multiple mechanisms, and exhibit high safety and low immunogenicity. These cells can be further engineered with chimeric antigen receptor (CAR) to enhance tumor targeting or/and gene edited to ablate surface human leukocyte antigen (HLA) molecules and further reduce immunogenicity. Collectively, these preclinical studies demonstrate the feasibility and cancer therapy potential of AlloHSC-iNKT cell products and lay a foundation for their translational and clinical development.
Author Info: (1) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA (2) Department of Molecular, Cell and Development
Author Info: (1) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA (2) Department of Molecular, Cell and Developmental Biology, College of Letters and Sciences, University of California, Los Angeles, Los
Angeles, CA 90095, USA (3) Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA (4) Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA
90095, USA (5) Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA (6)Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA (7) Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA (8) Department of Pediatrics, University of California, Los Angeles, Los Angeles, CA 90095, USA (9) Department of Internal Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA (10) Division of Hematology/Oncology, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA (11) Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA (12) Parker Institute for Cancer Immunotherapy, University of California, Los Angeles, Los Angeles, CA 90095, USA (13) Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA (14) These authors contributed equally (15) Lead contact *Correspondence: liliyang@ucla.edu
