Engineering the next generation of CAR-NK immunotherapies

Int J Hematol. 2021 Nov;114(5):554-571. doi: 10.1007/s12185-021-03209-4. Epub 2021 Aug 28.


Over the past few years, cellular immunotherapy has emerged as a novel treatment option for certain forms of hematologic malignancies with multiple CAR-T therapies now routinely administered in the clinic. The limitations of generating an autologous cell product and the challenges of toxicity with CAR-T cells underscore the need to develop novel cell therapy products that are universal, safe, and potent. Natural killer (NK) cells are part of the innate immune system with unique advantages, including the potential for off-the-shelf therapy. A recent first-in-human trial of CD19-CAR-NK infusion in patients with relapsed/refractory lymphoid malignancies proved safe with promising clinical activity. Building on these encouraging clinical responses, research is now actively exploring ways to further enhance CAR-NK cell potency by prolonging in vivo persistence and overcoming mechanisms of functional exhaustion. Besides these strategies to modulate CAR-NK cell intrinsic properties, there are increasing efforts to translate the successes seen in hematologic malignancies to the solid tumor space. This review will provide an overview on current trends and evolving concepts to genetically engineer the next generation of CAR-NK therapies. Emphasis will be placed on innovative multiplexed engineering approaches including CRISPR/Cas9 to overcome CAR-NK functional exhaustion and reprogram immune cell metabolism for enhanced potency.

Keywords: Cellular immunotherapy; Chimeric antigen receptor; Genetic engineering; Metabolic reprogramming; Natural killer cells.

Publication types

  • Review

MeSH terms

  • Animals
  • Clinical Trials as Topic
  • Combined Modality Therapy
  • Disease Management
  • Disease Susceptibility
  • Gene Editing
  • Genetic Engineering* / methods
  • Genetic Therapy
  • Hematologic Neoplasms / diagnosis
  • Hematologic Neoplasms / etiology
  • Hematologic Neoplasms / therapy
  • Humans
  • Immunotherapy, Adoptive / adverse effects
  • Immunotherapy, Adoptive / methods*
  • Immunotherapy, Adoptive / trends*
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism*
  • Receptors, Chimeric Antigen / immunology*
  • Translational Research, Biomedical
  • Treatment Outcome


  • Receptors, Chimeric Antigen