cells Review Development of Stem Cell-Derived Immune Cells for Off-the-Shelf Cancer Immunotherapies Yan-Ruide Li 1,† , Zachary Spencer Dunn 2,† , Yang Zhou 1 , Derek Lee 1 and Lili Yang 1,3,4,5, *   Citation: Li, Y.-R.; Dunn, Z.S.; Zhou, Y.; Lee, D.; Yang, L. Development of Stem Cell-Derived Immune Cells for Off-the-Shelf Cancer Immunotherapies. Cells 2021, 10, 3497. https://doi.org/ 10.3390/cells10123497 Academic Editor: Umberto Galderisi Received: 8 October 2021 Accepted: 8 December 2021 Published: 10 December 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA 90095, USA; charlie.li@ucla.edu (Y.-R.L.); zzydcat@g.ucla.edu (Y.Z.); ylee932@ucla.edu (D.L.) 2 Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA 90089, USA; zacharsd@usc.edu 3 Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095, USA 4 Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA 5 Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA * Correspondence: liliyang@ucla.edu † These authors contributed equally to this work. Abstract: Cell-based cancer immunotherapy has revolutionized the treatment of hematological malignancies. Specifically, autologous chimeric antigen receptor-engineered T (CAR-T) cell therapies have received approvals for treating leukemias, lymphomas, and multiple myeloma following unprecedented clinical response rates. A critical barrier to the widespread usage of current CAR-T cell products is their autologous nature, which renders these cellular products patient-selective, costly, and challenging to manufacture. Allogeneic cell products can be scalable and readily administrable but face critical concerns of graft-versus-host disease (GvHD), a life-threatening adverse event in which therapeutic cells attack host tissues, and allorejection, in which host immune cells eliminate therapeutic cells, thereby limiting their antitumor efficacy. In this review, we discuss recent advances in developing stem cell-engineered allogeneic cell therapies that aim to overcome the limitations of current autologous and allogeneic cell therapies, with a special focus on stem cell-engineered conventional αβ T cells, unconventional T (iNKT, MAIT, and γδ T) cells, and natural killer (NK) cells. Keywords: stem cell engineering; allogeneic cancer therapy; off-the-shelf cell therapy; chimeric antigen receptor (CAR); T cell receptor (TCR); graft-versus-host disease (GvHD) 1. Introduction After decades of fervent research, tumor-targeting adoptive T cell therapy has entered mainstream oncology [1]. In the 1980s, Rosenberg and others conducted numerous trials testing autologous tumor infiltrating lymphocyte (TIL) therapy and witnessed notable although rare clinical responses in certain chemotherapy refractory cancers [2–4]. Advances in molecular engineering ushered in a new era of adoptive therapy in which tailor-made T cells are genetically modified with the machinery to both target and kill cancer cells [5]. Chimeric antigen receptors, or CARs, link the single chain variable fragment of an antibody to T cell intracellular activation and stimulatory domains, allowing T cells to recognize cancer cells independently of major histocompatibility complex (MHC) restriction and perform cytotoxic functions [6]. CAR-T cells have transformed the treatment of blood cancers, with CD19-targeting CAR-T cells approved for treating B cell acute lymphoblastic leukemia and large diffuse B cell lymphoma in 2017 and a BCMA-targeting CAR-T cell therapy approved in 2021 for the treatment of multiple myeloma [7]. The current CAR-T cell therapies are autologous and, while landmark achievements for cell therapy, limited in their accessibility. T cell extraction, genetic manipulation, expansion, and reinfusion for each Cells 2021, 10, 3497. https://doi.org/10.3390/cells10123497 https://www.mdpi.com/journal/cells