Poster - #UCLA-5 - Keywords: Hematopoietic stem cell (HSC), Invariant natural killer T (iNKT) cell, Coronavirus disease 2019 (COVID‐19), Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), Allogeneic adoptive cell transfer, Off‐the‐shelf cellular product

Development of off-the-shelf hematopoietic stem cell-engineered invariant natural killer T cells for COVID-19 therapeutic intervention

Yan‐Ruide Li, Zachary Spencer Dunn, Gustavo Garcia Jr., Camille Carmona, Yang Zhou, Derek Lee, Jiaji Yu, Jie Huang, Jocelyn T. Kim, Vaithilingaraja Arumugaswami, Pin Wang and Lili Yang
1. Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles. 2. Department of Molecular, Cell and Developmental Biology, College of Letters and Sciences, University of California, Los Angeles. 3. Mork Family Department of Chemical Engineering and Materials Science, University of Southern California. 4. Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles.

ABSTRACT:
New COVID‐19 treatments are desperately needed as case numbers continue to rise and emergent strains threaten vaccine efficacy. Cell therapy has revolutionized cancer treatment and holds much promise in combatting infectious disease, including COVID‐19. Invariant natural killer T (iNKT) cells are a rare subset of T cells with potent antiviral and immunoregulatory functions and an excellent safety profile. Current iNKT cell strategies are hindered by the extremely low presence of iNKT cells, and we have developed a platform to overcome this critical limitation. We produced allogeneic HSC‐engineered iNKT (AlloHSC‐iNKT) cells through TCR engineering of human cord blood CD34+ hematopoietic stem cells (HSCs) and differentiation of these HSCs into iNKT cells in an Ex Vivo HSC‐Derived iNKT Cell Culture. We reliably generated AlloHSC‐iNKT cells at high‐yield and of high‐purity; these resulting cells closely resem‐ bled endogenous human iNKT cells in phenotypes and functionalities. In cell culture, AlloHSC‐iNKT cells directly killed SARS‐CoV‐2 infected cells and also selectively eliminated SARS‐CoV‐2 infection‐stimulated inflammatory monocytes. In an in vitro mixed lymphocyte reaction (MLR) assay and an NSG mouse xenograft model, AlloHSC‐iNKT cells were resistant to T cell‐mediated alloreaction and did not cause GvHD.