Immunotherapy with NK cells: recent developments in gene modification open up new avenues

Abstract

Chimeric antigen receptor (CAR)-T cell therapies have achieved remarkable success. However, application-related toxicities, such as cytokine release syndrome or neurotoxicity, moved natural killer (NK) cells into focus as novel players in immunotherapy. CAR-NK cells provide an advantageous dual killingcapacity by CAR-dependent and-independent mechanisms and induce few side effects. While the majority of trials still use CART cells, CAR-NK cell trials are on the rise with 19 ongoing studies worldwide. This review illuminates the current state of research and clinical application of CAR-NK cells, as well as future developmental potential.

Current status and perspective of CAR-T and CAR-NK cell therapy trials in Germany

“…Prior to infusion of the CAR-modified immune cells, lymphodepletion is performed in most therapeutic settings to allow efficient cell engraftment [10]. It is important to mention that, CAR-NK cells offer the potential to be an "off-the-shelf" product, but also allogeneic CAR-T cell therapies are currently under development [11][12][13][14].…”

Arming Immune Cells for Battle: A Brief Journey through the Advancements of T and NK Cell Immunotherapy

“…As a part of the innate immune system, NK cells represent a first line defense equipped with a broad repertoire of activating and inhibiting receptors, that allow target-specific recognition and controlled cytotoxic activity without prior stimulation [ 3 , 8 ]. In contrast to T cells, NK cells are able to rely on a highly effective mechanism called “missing self-recognition”.…”

“…The CD56 bright CD16 dim subpopulation and their immune modulatory activity are functionally distinguishable from the CD56 dim CD16 bright population, which represents the NK cell subset with direct cytotoxic capacity [ 26 , 27 ]. Expression of CD16 provides NK cells the ability to synergize with the adaptive immune system by killing antibody-coated (opsonized) target cells through the antibody-dependent cell cytotoxicity (ADCC) pathway, which is not available to T cells [ 8 , 22 , 24 , 28 ].…”

“…Despite the demonstration of NK cell persistence and proliferation, only moderate clinical responses have been achieved. Further clinical trials have evaluated different NK cell sources as well as different ex vivo expansion and activation protocols [ 8 , 126 , 127 ]. In 2016, Yang et al published the results of a first clinical trial in which allogeneic NK cells from unrelated donors were transferred without prior immune suppression for treatment of malignant lymphomas and solid tumors (NCT01212341) [ 128 , 129 ].…”

“…In the context of cell therapeutic approaches using primary NK cells, currently more than 30 active clinical trials are listed on clinicaltrials.gov for adoptive/allogeneic NK cell therapy as reported earlier [ 8 ]. Although these studies mainly cover participants suffering from various types of cancers, two studies for the treatment of COVID-19 patients are enlisted as well (NCT04344548 and NCT04365101).…”