Table 1.

Selected trials and therapeutic approaches targeting natural killer (NK) cells in cancer and/or HIV1 immunotherapy and associated limitations of such approaches.

Therapeutic approaches	Type	Mode of action	Limitations and challenges	Trial registry identifier(s)*	References
Release of NK suppression	mAbs to NKG2A Monalizumab (previously IPH2201)	Blockade of NKG2A mediated inhibition of NK cells; synergizes with other checkpoint inhibitors or mAbs	Potential autoreactivity and off-target effects; optimal combination therapy	NCT02643550 NCT02921685 NCT02671435 NCT03822351 NCT03833440	Shimasaki et al., 2020
	mAbs to KIRs Lirilumab (IPH2102)	Blockade of inhibitory KIR mediated inhibition of NK cells	Potential autoreactivity and off-target effects; optimal combination therapy	NCT03532451 NCT01714739 NCT01687387 NCT01750580 NCT02252263 NCT02399917 NCT02481297	Ramsuran et al., 2018
Rev-up endogenous NK cell responses	BiKEs and TriKEs	Engage an activating receptor on NK cells (i.e., CD16), bridging it to a target cell; high efficacy; good safety profile	Complexity of design process; CD16 polymorphism; levels of CD16 expression on NK cells and CD16 cleavage	NCT01221571 NCT03192202 NCT03214666	Gleason et al., 2012; Rothe et al., 2015; Apps et al., 2016; Tay et al., 2016; Vallera et al., 2016; Sarhan et al., 2018a
	bNAbs	HIV neutralization; Fc mediated functions and ability to trigger NK cell-mediated ADCC	ADCC capacity of bNAbs; NK cell responsiveness; Fc receptor polymorphisms; possibility of generation of escape mutants	NCT02018510 NCT02825797	Halper-Stromberg and Nussenzweig, 2016; Li et al., 2017; Bar-On et al., 2018; Mendoza et al., 2018
Toll-Like receptor (TLR) agonists	TLR agonists	Enhance activation of components of adaptive and innate immunity, including NK cells	Potential off-target effects and toxicity	NCT02077868 NCT02200081 NCT02668770 NCT02858401 NCT03060447	Lu et al., 2016; Smith et al., 2018
Immunostimulatory cytokines +/- adoptive NK cell therapy	IL-2, IL12, IL-18, IL-15; IL-15 superagonists	Ex vivo cytokine NK cell expansion and activation; In vivo modulation and augmentation of NK cells responses	Systemic toxicity; optimal dosing required for expanded NK cells to prevent exhaustion; development of new compounds with improved pharmacokinetics	NCT01885897 NCT02191098 NCT04290546 NCT02890758 NCT03346499 NCT03899480	Romee et al., 2012; O'Sullivan et al., 2015; Huot et al., 2017
NK cell engineering	CAR-NK cell adoptive therapy; multiple cellular sources	Redirect NK cells against specific antigen to enhance lysis of target cells	Optimized CAR constructs to increase efficacy; remaining challenges to manufacturing and scaling up; potential toxicity	NCT02892695 NCT03056339 NCT03415100 NCT03941457	O'Sullivan et al., 2015; Romee et al., 2016; Oei et al., 2018; Angin et al., 2019

^*Trial Registry Identifier(s) in cancer/or HIV immunotherapy.