The latest addition to this group is lacutamab (IPH4102), a first-in-class anti-KIR3DL2 Ab

The latest addition to this group is lacutamab (IPH4102), a first-in-class anti-KIR3DL2 Ab. CAR-T cell therapies. In this review, we summarize recent advances in NK cell-based cancer immunotherapy with a focus on immune checkpoint receptors, some of which are unique to NK cells and CAR-NK cells. IMMUNE CHECKPOINT RECEPTORS KIR, LIR, and CD94/NKG2A Inhibitory KIRs, 2DL1, 2DL2, 2DL3, 2DL5, 3DL1, 3DL2, Fas C- Terminal Tripeptide and 3DL3, have long cytoplasmic tails comprising two ITIMs (7). Inhibitory KIRs recognize human leukocyte antigen (HLA)-A, B, or C (Fig. 1). The main roles of KIRs in NK cells are described above. They have highly polymorphic immunoglobulin (Ig) domains specific to HLA molecules (8). Multiple myeloma (MM) cells upregulate MHC class I molecules, thus blocking inhibitory KIRs could enhance the antitumor effect Fas C- Terminal Tripeptide of NK cells in MM. Treatment with anti-KIR2D antibody (Ab) (Lirilumab; IPH2102) has been proven safe without mediating toxicity and autoimmunity in patients with MM and acute myeloid leukemia (AML) (9, 10). Anti-KIR Ab treatment enhanced NK cytotoxicity in patients with MM, but the Phase II clinical trial of lirilumab in MM resulted in failure due to lack of efficacy and presumably a loss of KIR2D expression in NK cells (11). Anti-KIR Abs have been tested alone or in combination with other therapeutics, including lenalidomide, anti-CD20 Ab (rituximab), and immune checkpoint blockades in various hematological disorders, including MM, lymphoma, and myelodysplastic syndromes (12-15). The latest addition to this group is lacutamab (IPH4102), a first-in-class anti-KIR3DL2 Ab. It has been demonstrated to be safe, and 36% of patients with relapsed/refractory cutaneous T cell lymphoma responded to it in a Phase I trial (16). Apart from immune checkpoint blockade, pre-treatment with IL-12/15/18 reduces the expression of KIRs in NK cells and enhances NK cytotoxicity against tumor cells (17), suggesting that expanded NK cells could be potent antitumor therapeutics by themselves or as CAR bearers. Clinical trials using immune checkpoint blockade are summarized in Table 1. Open in a separate window Fig. 1 Interactions between immune checkpoint receptors and their cognate ligands. NK cells express multiple immune checkpoint receptors, which can interact with their cognate ligands on tumor cells as well as other immune cells, in particular, dendritic cells and Tregs. The red circles represent immune checkpoint receptors while the blue circles represent the ligands. SIGLEC7 and SIGLEC9 have common ligands that are sialic acids. The pink squares represent the classical ITIM motif and the light blue squares represent the ITSM motif, which have been implicated in mediating inhibitory signals. The light green squares Rabbit polyclonal to HGD represent the ITT-like motif. Cytoplasmic domains of other immune checkpoint receptors contain fewer known motifs (not marked as squares). CD73 is a nucleotidase, which does not have conventional inhibitory signaling domains. The black lines indicate receptor-ligand interactions. Table 1 Current status of clinical trials based on immune checkpoint receptors (23). NKG2A is well known as an HLA-E receptor but has recently been suggested as an HLA-G receptor (24). However, the action mechanisms for the dual blockade may require further Fas C- Terminal Tripeptide investigation. CD94/NKG2A is a heterodimeric inhibitory receptor related to C-type lectins, recognizing another non-classical MHC class I molecule, HLA-E. ITIMs are phosphorylated upon receptor engagement and recruit tyrosine phosphatases SHP-1 and SHP-2 (25, 26). SHP-1 mediates dephosphorylation of Vav1 (27). In addition, Crk phosphorylation contributes to the inhibition of NK cells through NKG2A-HLA-E interaction (28). ITIM-based inhibition appears to be dominant over activation in NK cells against normal cells. Recruitment of SHP-1 by MHC-I-specific ITIM-bearing receptors inhibited signaling at a proximal step, such that most downstream signals were prevented (29). HLA-E is overexpressed in human colorectal cancers with poor prognosis (30). Ovarian and cervical cancer cells express HLA-E.