Leveraging Natural Killer Cell Innate Immunity against Hematologic Malignancies: From Stem Cell Transplant to Adoptive Transfer and Beyond

Abstract

Numerous recent advancements in T-cell based immunotherapies have revolutionized the treatment of hematologic malignancies. In the race towards the first approved allogeneic cellular therapy product, there is growing interest in utilizing natural killer (NK) cells as a platform for off-the-shelf cellular therapies due to their scalable manufacturing potential, potent anti-tumor efficacy, and superior safety profile. Allogeneic NK cell therapies are now being actively explored in the setting of hematopoietic stem cell transplantation and adoptive transfer. Increasingly sophisticated gene editing techniques have permitted the engineering of chimeric antigen receptors, ectopic cytokine expression, and tumor recognition signals to improve the overall cytotoxicity of NK cell therapies. Furthermore, the enhancement of antibody-dependent cellular cytotoxicity has been achieved through the use of NK cell engagers and combination regimens with monoclonal antibodies that act synergistically with CD16-expressing NK cells. Finally, a greater understanding of NK cell biology and the mechanisms of resistance have allowed the preclinical development of NK checkpoint blockade and methods to modulate the tumor microenvironment, which have been evaluated in early phase trials. This review will discuss the recent clinical advancements in NK cell therapies in hematologic malignancies as well as promising avenues of future research.

Harnessing natural killer cells for refractory/relapsed non-Hodgkin lymphoma: biological roles, clinical trials, and future prospective

“…NK-92 cells exhibit potent cytotoxicity against several cancer cells, a phenomenon primarily ascribed to the overexpression of numerous activating receptors, concurrent downregulation of almost all inhibitory receptors, and heightened expression of perforin and granzyme. Furthermore, NK-92 cells can continuously proliferate with a doubling time of 2–4 days, are easily obtainable, and have a homogeneous phenotype [ 163 , 164 ]. However, due to their cancerous nature, NK-92 cells must be mitotically inactivated prior to infusion into patients to inhibit undesired clonal proliferation, which restricts their persistence and expansion in vivo, and allogeneic administration demands very high doses of NK-92 cells [ 165 ].…”

“…Furthermore, preclinical data indicated that the combination of haNK cells withmAbs, such as daratumumab for multiple myeloma (MM) and rituximab for NHL, may have a synergistic effect. However, further clinical investigation is required to validate these approaches for NHL [ 163 ].…”