Adoptive natural killer cell therapy: a human pluripotent stem cell perspective

Highlights

• hPSCs are achievable to produce universal off-the-shelf NK cells.

• Fully defined protocols have been developed for NK cell induction.

• CARs have been designed and employed in NK cells.

• More stringent safety control over CAR-NK cells is needed.

In this review, we will discuss the current developments in the field of stem cell immuoengineering, with a focus on the studies of natural killer (NK) cells over the past 5 years. The key advances in stem cell immunoengineering include the generation of human NK cells from human pluripotent stem cells (hPSCs), the genetic modification of hPSCs and hPSC-derived NK cells for improved cellular function, as well as the applications of cell culture platforms for stem cell manufacturing. We will also review the application of available genome editing tools to design and engineer hPSCs as universal donor cells to produce off-the-shelf NK cells applicable to any patient. Current challenges impeding the translation of NK cells and future directions to understand and address these challenges will also be discussed.

Introduction

Cancer is a major cause of death in US, with about 1.8 million new patients diagnosed and over 0.6 million cancer-related deaths in 2019. While treatments like chemotherapy, radiation and surgery are available to remove the cancer, the cure rates are unsatisfactory, particularly for refractory cancers, requiring new therapeutic approaches. Adoptive cellular immunotherapies with T and natural killer (NK) cells have provided new alternatives to fight cancer. NK cells are attractive because of their unique innate ability to kill tumor cells without prior sensitization or antigen presentation. Unlike T cells, allogeneic NK cell transplantation does not cause graft-versus-host disease (GVHD), rendering it as a promising universal approach for treating cancer. Despite their significant potential, NK cell-based therapies suffer from several major drawbacks: lack of in vivo persistence, challenge in obtaining sufficient healthy NK cells, resistance to genome editing, and suboptimal cytotoxicity against solid tumor. Thus, the ability to easily generate large numbers of universally histocompatible NK cells and ease of genome editing enable the continuously renewing human pluripotent stem cells (hPSCs) as a promising source to develop a truely off-the-shelf cellular immunotherapy. In this review, we compare enabling technologies for massive production and genome editing of NK cells, with a focus on recent advances in hPSC-derived NK cell immunotherapy. We highlight the genetic engineering approaches for improved immunotherapy and discuss remaining challenges for optimal NK cell production.