While immunotherapy has revolutionized the treatment of many types of advanced cancer, most patients still do not derive benefit. The currently available immune checkpoint inhibitors target the adaptive immune system, generating a T-cell antitumor response. However, an antitumor immune response depends on a complex interplay of both innate and adaptive immune cells. The innate immune system is a promising new target, and innate immune checkpoint inhibitors can disrupt inhibitory interactions (“don't eat me” signals) between tumor and both phagocytes and natural killer cells. The checkpoint inhibitor may also provide a stimulatory interaction (“eat me” signal), or this can be achieved through use of combination therapy. This generates antitumor effector functions including phagocytosis, natural cytotoxicity, antibody-dependent effects, and synergistic activation of the adaptive immune system via antigen presentation. This is a rapidly expanding area of drug development, either alone or in combination (with anticancer antibodies or adaptive immune checkpoint inhibitors). Here, we comprehensively review the mechanism of action and up-to-date solid tumor clinical trial data of the drugs targeting phagocytosis checkpoints (SIRPα/CD47, LILRB1/MHC-I, and LILRB2/MHC-I) and natural killer–cell checkpoints (TIGIT/CD112 + CD155, PVRIG/CD112, KIRs/MHC-I, and NKG2A-CD94/HLA-E). Innate immune checkpoint inhibitors could once again revolutionize immune-based cancer therapies.

Immune function is governed in part by a complex array of stimulatory and inhibitory cell–surface interactions. A coordinated cancer immunity cascade must occur for immune-based therapies to be effective, including expression/release of cancer antigens, antigen presentation, immune cell activation, immune cell transport and infiltration into tumor, and cancer cell killing by both adaptive and innate mechanisms through interaction of stimulatory and inhibitory processes (1). Inhibitory immune checkpoints exist to maintain physiologic immune responses, that is, to induce tolerance (Fig. 1). Immune checkpoint inhibitors have been successful in the treatment of many solid tumors, but the majority of advanced solid tumors do not respond and resistance usually emerges (2, 3). The currently available immune checkpoint inhibitors target CTL antigen-4 (CTLA-4), programmed death-1 (PD-1), and its ligand (PD-L1), all attempting to bolster T-cell activation.

Figure 1.

Innate immune cell–surface regulatory interactions and therapeutic targets. Innate immune cell antitumor function is regulated in part by stimulatory (“eat me”) and inhibitory (“don't eat me”) cell–surface interactions with the cancer cell, generally involving a receptor on the immune cell and antigen on the cancer cell. Inhibitory interactions (“checkpoints”) exist to maintain physiologic immune responses, that is, to induce tolerance. Normal human cells generally avoid immune destruction by expressing more inhibitory than stimulatory antigens. Cancer cells, likewise, can evade the innate immune system by expressing inhibitory antigens and lacking stimulatory antigens (left). Cancer cells may also express stimulatory antigens, activating innate immune cells and resulting in phagocytosis (phagocytes) or natural cytotoxicity (NK cells). Conceptually, there are four scenarios under which the balance of stimulatory and inhibitory signaling favors innate immune cell antitumor effects. First, the cancer cell lacks inhibitory antigens and stimulatory signals are present; radiation/chemotherapy may increase cancer cell expression of stimulatory antigens (right, #1). Second, an innate immune checkpoint inhibitor can block the inhibitory checkpoint while a stimulatory signal is present (right, #2). Third, a combination therapy approach can block the inhibitory checkpoint (with an innate immune checkpoint inhibitor lacking an active Fc region) while a second drug (anticancer antibody) can provide the stimulatory signal upon interacting with innate immune cell Fc receptors (right, #3). Finally, an innate immune checkpoint inhibitor containing an active Fc region can both block the inhibitory checkpoint and provide the stimulatory signal upon interacting with an innate immune cell Fc receptor (right, #4). This final strategy is often limited by hematologic toxicity. Created with BioRender.com.

Figure 1.

Innate immune cell–surface regulatory interactions and therapeutic targets. Innate immune cell antitumor function is regulated in part by stimulatory (“eat me”) and inhibitory (“don't eat me”) cell–surface interactions with the cancer cell, generally involving a receptor on the immune cell and antigen on the cancer cell. Inhibitory interactions (“checkpoints”) exist to maintain physiologic immune responses, that is, to induce tolerance. Normal human cells generally avoid immune destruction by expressing more inhibitory than stimulatory antigens. Cancer cells, likewise, can evade the innate immune system by expressing inhibitory antigens and lacking stimulatory antigens (left). Cancer cells may also express stimulatory antigens, activating innate immune cells and resulting in phagocytosis (phagocytes) or natural cytotoxicity (NK cells). Conceptually, there are four scenarios under which the balance of stimulatory and inhibitory signaling favors innate immune cell antitumor effects. First, the cancer cell lacks inhibitory antigens and stimulatory signals are present; radiation/chemotherapy may increase cancer cell expression of stimulatory antigens (right, #1). Second, an innate immune checkpoint inhibitor can block the inhibitory checkpoint while a stimulatory signal is present (right, #2). Third, a combination therapy approach can block the inhibitory checkpoint (with an innate immune checkpoint inhibitor lacking an active Fc region) while a second drug (anticancer antibody) can provide the stimulatory signal upon interacting with innate immune cell Fc receptors (right, #3). Finally, an innate immune checkpoint inhibitor containing an active Fc region can both block the inhibitory checkpoint and provide the stimulatory signal upon interacting with an innate immune cell Fc receptor (right, #4). This final strategy is often limited by hematologic toxicity. Created with BioRender.com.

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There are many mechanisms of resistance to immunotherapy, including loss of tumor antigen expression, increased expression of tumor inhibitory checkpoint ligands (such as PD-L1) which bind cognate ligands on immune cells, and recruitment of suppressive cell populations by tumor-produced immunosuppressive factors (2, 4, 5). Indeed, infiltration of both innate and adaptive immune cells into tumor has been shown to correlate with improved outcomes in many cancer types (6–9.) Novel treatments targeting the innate immune system are promising candidates in medical oncology.

Innate immune cells are derived from both myeloid and lymphoid lineages. Myeloid cells include monocytes, macrophages, dendritic cells (DC), polymorphonuclear cells, and mast cells. Natural killer (NK) cells are innate lymphoid cells. Innate immune cells activate the adaptive immune system via antigen presentation and execute primary effector functions, such as phagocytosis, natural cytotoxicity, and antibody-dependent cellular cytotoxicity and phagocytosis (ADCC and ADCP, respectively) upon activation of their Fc receptors for antibody (10). In fact, the innate immune system is required to generate antigen-specific T-cell activity (11). Innate immune checkpoint inhibitors, with or without adaptive immune checkpoint inhibitors, may overcome resistance to currently approved immune checkpoint drugs.

Innate immune cell function is regulated by a balance of stimulatory and inhibitory cell–surface interactions (Fig. 1). Blocking inhibitory checkpoints (“don't eat me” signals) between tumor and innate immune cells is a novel therapeutic target. The checkpoint inhibitor may also provide a stimulatory interaction (“eat me” signal), or this can be achieved through use of combination therapy. When the balance of stimulatory and inhibitory interactions favors activation of innate immune cells, the result is phagocytosis or natural cytotoxicity of cancer cells. Here, we will review basic science of the checkpoints and the mechanism of action, safety, and efficacy data of all innate immune checkpoint inhibitors currently being studied in solid tumor clinical trials.

All clinical data from solid tumor clinical trials on the innate immune checkpoint inhibitors are included. Studies were identified by searching for the checkpoints and drugs using the PubMed database, ClinicalTrials.gov, and abstracts from the following annual meetings: American Association of Cancer Research, American Society of Clinical Oncology, European Society for Medical Oncology, and the Society for Immunotherapy of Cancer. Objective response rate (ORR) is defined as partial response (PR) or complete response (CR), as assessed in the clinical trial. Disease control rate (DCR) is defined as stable disease (SD), PR, or CR, as assessed in the clinical trial. Table 1 provides a summary of the available solid tumor clinical safety and efficacy data of the innate immune checkpoint inhibitors. Tables 2 and 3 list the active clinical trials on ClinicalTrials.gov.

Table 1.

Results of solid tumor clinical trials of phagocytosis and NK-cell checkpoint inhibitors.

NCTIn combination withPhaseCancer typeORRDCRmPFS (months)Primary toxicitya
SIRPα/CD47 
ALX148 (ALX Oncology, anti-CD47 fusion (CD47 binding domain of SIRPα to inactive human Ig Fc) 
03013218 (22) Alone, pembrolizumab, trastuzumab, or rituximab Solid and NHL 0% (alone) 16% (alone) NR Fatigue, headache, thrombocytopenia 
03013218 (23) Pembrolizumab, trastuzumab Solid 4% (NSCLC) 39% (NSCLC) NR Fatigue, AST elevation, anemia 
    18% (HNSCC) 41% (HNSCC)   
    19% (gastric) 48% (gastric cancer)   
03013218 (24) Pembrolizumab, trastuzumab, or chemo HNSCC and gastric 50% (ICI-naïve HNSCC) NR 4.6 (ICI-naïve HNSCC) Fatigue, AST increase, thrombocytopenia 
    0% (prior ICI HNSCC)  2 (prior ICI HNSCC)  
    20% (gastric cancer)  2.2 (gastric cancer)  
IBI188 (Innovent Biologics, anti-CD47 humanized IgG4 mAb) 
03763149 (33) Alone Solid and lymphoma NR NR NR Nausea, back pain, fatigue 
Lemzoparlimab (TJC4, TJ011133) (AbbVie and I-Mab Biopharma, anti-CD47 fully human IgG4 mAb) 
03934814 (32) Alone Solid NR NR NR Anemia, fatigue, infusion reaction 
Magrolimab (Hu5F9-G4, ONO-7913) (Gilead, anti-CD47 humanized IgG4 mAb) 
02216409 (20) Alone Solid and heme NR NR NR Anemia, fatigue, headaches 
03558139 (25) Avelumab Solid 0% 56% NR Headache, fatigue, infusion reaction, anemia 
02953782 (26) Cetuximab I/II Solid and CRC 7% (KRAS WT CRC) NR (KRAS WT CRC) 3.6 (KRAS WT CRC) Acneiform rash, dry skin, fatigue 
    0% (KRAS MT CRC) 45% (KRAS MT CRC) 1.9 (KRAS MT CRC)  
SRF231 (Surface Oncology, anti-CD47 fully human IgG4 mAb) 
03512340 (30) Alone Solid and heme 0% NR NR Fatigue, headache, pyrexia 
LILRB2/MHC-I 
Etigilimab (OMP-313M32) (Mereo BioPharma, anti-TIGIT IgG1 humanized mAb) 
03119428 (58) Alone or nivolumab Solid 0% 22% NR Rash, fatigue, nausea 
MK-4830 (Merck and Agenus, anti-LILRB2 fully human IgG4 mAb) 
03564691 (38) Alone or pembrolizumab Solid 13% NR NR None reported 
Tiragolumab (MTIG7192A, RG6058) (Genentech, anti-TIGIT humanized IgG1/kappa mAb) 
02794571 (52) Alone or with atezolizumab Solid 0% (alone) 17% (alone) NR Fatigue, anemia 
    6% (w/atezo) NR (w/atezo)   
02794571 (52) Atezolizumab NSCLC (PD-L1+ and ICI-naïve) 50% 79% NR Fatigue, anemia 
03563716 (54) Atezolizumab II NSCLCb 37% NR 5.6 Rash, infusion reactions 
Vibostolimab (MK-7684) (Merck, anti-TIGIT humanized antibody) 
02964013 (55) Alone or pembrolizumab Solid 3% (alone) 35% (alone) NR Fatigue, pruritus, anemia 
    19% (w/pembro) 47% (w/pembro)   
02964013 (56, 57) Alone or pembrolizumab NSCLC 7% (alone) NR 9 (alone) Pruritus, fatigue, rash 
    5% (w/pembro)  13 (w/pembro)  
    29% (ICI-naïve)    
PVRIG/CD112 
COM701 (Compugen, anti-PVRIG humanized IgG4 mAb) 
03667716 (62–64) Alone or nivolumab Solid NR 57% NR Fatigue, nausea, anemia 
KIRs/MHC-I 
Lirilumab (IPH2102, BMS-986015) (Innate Pharma and Bristol-Myers-Squibb, anti-KIR2D fully human IgG4 mAb) 
01750580 (70, 71) Nivolumab or ipilimumab Solid 24% 52% NR Fatigue, pruritus, infusion reaction 
2009–011526–33c; (69) Alone Solid and heme 0% 59% 6.6 (AML) Asthenia, pruritus, fatigue 
      19.6 (CLL)  
      5.3 (ovarian)  
NKG2A-CD94/HLA-E 
Monalizumab (IPH2201) (Innate Pharma and AstraZeneca, humanized anti-NKG2A-CD94 IgG4 mAb) 
02671435 (75) Durvalumab Solid and CRC 8% 38% NR Diarrhea 
02671435 (76, 77) Durvalumab, FOLFOX, and (bevacizumab or cetuximab) I/II CRC 41% (bevacizumab) 88% NR Fatigue, nausea, peripheral neuropathy 
    55% (cetuximab)    
03088059 (78) Alone II HNSCC 0% 22% 1.72 None reported 
02643550 (79–82) Cetuximab I/II HNSCC 20% NR 4.5 Fatigue, pyrexia, headache 
02459301 (83) Alone Gynecologic 0% 41% (dose esc) NR Headache, fatigue, vomiting 
     18% (dose exp)   
NCTIn combination withPhaseCancer typeORRDCRmPFS (months)Primary toxicitya
SIRPα/CD47 
ALX148 (ALX Oncology, anti-CD47 fusion (CD47 binding domain of SIRPα to inactive human Ig Fc) 
03013218 (22) Alone, pembrolizumab, trastuzumab, or rituximab Solid and NHL 0% (alone) 16% (alone) NR Fatigue, headache, thrombocytopenia 
03013218 (23) Pembrolizumab, trastuzumab Solid 4% (NSCLC) 39% (NSCLC) NR Fatigue, AST elevation, anemia 
    18% (HNSCC) 41% (HNSCC)   
    19% (gastric) 48% (gastric cancer)   
03013218 (24) Pembrolizumab, trastuzumab, or chemo HNSCC and gastric 50% (ICI-naïve HNSCC) NR 4.6 (ICI-naïve HNSCC) Fatigue, AST increase, thrombocytopenia 
    0% (prior ICI HNSCC)  2 (prior ICI HNSCC)  
    20% (gastric cancer)  2.2 (gastric cancer)  
IBI188 (Innovent Biologics, anti-CD47 humanized IgG4 mAb) 
03763149 (33) Alone Solid and lymphoma NR NR NR Nausea, back pain, fatigue 
Lemzoparlimab (TJC4, TJ011133) (AbbVie and I-Mab Biopharma, anti-CD47 fully human IgG4 mAb) 
03934814 (32) Alone Solid NR NR NR Anemia, fatigue, infusion reaction 
Magrolimab (Hu5F9-G4, ONO-7913) (Gilead, anti-CD47 humanized IgG4 mAb) 
02216409 (20) Alone Solid and heme NR NR NR Anemia, fatigue, headaches 
03558139 (25) Avelumab Solid 0% 56% NR Headache, fatigue, infusion reaction, anemia 
02953782 (26) Cetuximab I/II Solid and CRC 7% (KRAS WT CRC) NR (KRAS WT CRC) 3.6 (KRAS WT CRC) Acneiform rash, dry skin, fatigue 
    0% (KRAS MT CRC) 45% (KRAS MT CRC) 1.9 (KRAS MT CRC)  
SRF231 (Surface Oncology, anti-CD47 fully human IgG4 mAb) 
03512340 (30) Alone Solid and heme 0% NR NR Fatigue, headache, pyrexia 
LILRB2/MHC-I 
Etigilimab (OMP-313M32) (Mereo BioPharma, anti-TIGIT IgG1 humanized mAb) 
03119428 (58) Alone or nivolumab Solid 0% 22% NR Rash, fatigue, nausea 
MK-4830 (Merck and Agenus, anti-LILRB2 fully human IgG4 mAb) 
03564691 (38) Alone or pembrolizumab Solid 13% NR NR None reported 
Tiragolumab (MTIG7192A, RG6058) (Genentech, anti-TIGIT humanized IgG1/kappa mAb) 
02794571 (52) Alone or with atezolizumab Solid 0% (alone) 17% (alone) NR Fatigue, anemia 
    6% (w/atezo) NR (w/atezo)   
02794571 (52) Atezolizumab NSCLC (PD-L1+ and ICI-naïve) 50% 79% NR Fatigue, anemia 
03563716 (54) Atezolizumab II NSCLCb 37% NR 5.6 Rash, infusion reactions 
Vibostolimab (MK-7684) (Merck, anti-TIGIT humanized antibody) 
02964013 (55) Alone or pembrolizumab Solid 3% (alone) 35% (alone) NR Fatigue, pruritus, anemia 
    19% (w/pembro) 47% (w/pembro)   
02964013 (56, 57) Alone or pembrolizumab NSCLC 7% (alone) NR 9 (alone) Pruritus, fatigue, rash 
    5% (w/pembro)  13 (w/pembro)  
    29% (ICI-naïve)    
PVRIG/CD112 
COM701 (Compugen, anti-PVRIG humanized IgG4 mAb) 
03667716 (62–64) Alone or nivolumab Solid NR 57% NR Fatigue, nausea, anemia 
KIRs/MHC-I 
Lirilumab (IPH2102, BMS-986015) (Innate Pharma and Bristol-Myers-Squibb, anti-KIR2D fully human IgG4 mAb) 
01750580 (70, 71) Nivolumab or ipilimumab Solid 24% 52% NR Fatigue, pruritus, infusion reaction 
2009–011526–33c; (69) Alone Solid and heme 0% 59% 6.6 (AML) Asthenia, pruritus, fatigue 
      19.6 (CLL)  
      5.3 (ovarian)  
NKG2A-CD94/HLA-E 
Monalizumab (IPH2201) (Innate Pharma and AstraZeneca, humanized anti-NKG2A-CD94 IgG4 mAb) 
02671435 (75) Durvalumab Solid and CRC 8% 38% NR Diarrhea 
02671435 (76, 77) Durvalumab, FOLFOX, and (bevacizumab or cetuximab) I/II CRC 41% (bevacizumab) 88% NR Fatigue, nausea, peripheral neuropathy 
    55% (cetuximab)    
03088059 (78) Alone II HNSCC 0% 22% 1.72 None reported 
02643550 (79–82) Cetuximab I/II HNSCC 20% NR 4.5 Fatigue, pyrexia, headache 
02459301 (83) Alone Gynecologic 0% 41% (dose esc) NR Headache, fatigue, vomiting 
     18% (dose exp)   

Abbreviations: AML, acute myeloid leukemia; atezo, atezolizumab; chemo, chemotherapy; CLL, chronic lymphocytic leukemia; CRC, colorectal cancer; DCR, disease control rate; esc, escalation; exp, expansion; heme, hematologic; HNSCC, head/neck squamous cell carcinoma; ICI, anti-PD-(L)1 immune checkpoint inhibitor; mAb, monoclonal antibody; mPFS, median progression-free survival; MT, mutated; NCT, ClinicalTrials.gov identifier; NHL, non-Hodgkin lymphoma; NR, not reported; NSCLC, non-small cell lung cancer; ORR, objective response rate; pembro, pembrolizumab; PFS, progression-free survival; WT, wild-type.

aMost common any-grade treatment-related adverse events.

bChemotherapy-naïve, PD-L1+, EGFR and ALK wild-type.

cEudraCT (European Union Drug Regulating Authorities Clinical Trials Database) identifier.

Table 2.

Clinical trials of phagocytosis checkpoint inhibitors registered on ClinicalTrials.gov.

NCTStatusPhaseCancer typeIn combination withEnrollmenta
SIRPα/CD47 
ALX148 (ALX Oncology, anti-CD47 fusion (CD47 binding domain of SIRPα to inactive human Ig Fc) 
03013218 Recruiting Solid cancers and NHL Pembrolizumab, chemo, or anticancer antibodies 184 
04417517 Recruiting I/II High risk MDS Azacitadine 63 
AO-176 (Arch Oncology, anti-CD47 humanized IgG2 mAb) 
03834948 Recruiting I/II Solid cancers Alone or paclitaxel 132 
04445701 Recruiting I/II Multiple myeloma Alone, dexamethasone or bortezomib 102 
BI 765063 (OSE-172) (OSE Immunotherapeutics and Boehringer Ingelheim, anti-SIRPα humanized IgG4 mAb) 
03990233 Recruiting Solid cancers Alone or BI-754091 116 
CC-90002 (Celgene, anti-CD47 humanized IgG4 mAb) 
02367196 Not yet open Hematologic neoplasms Alone or rituximab 60 
02641002 Terminated AML, MDS Alone 28 
CC-95251 (Celgene, anti-SIRPα humanized mAb) 
03783403 Recruiting Hematologic and solid cancers Monotherapy, rituximab, or cetuximab 230 
DSP107 (Kahr Medical, SIRPα and 4-1BB ligand bi-functional fusion protein) 
04440735 Recruiting Solid cancers Alone or atezolizumab 100 
FSI-189 (Gilead, anti-SIRPα antibody) 
04502706 Not yet open NHL Alone or rituximab 63 
HX009 (Waterstone Pharmaceuticals, anti-PD-1 and -CD47 bispecific antibody fusion protein) 
04097769 Recruiting Solid cancers Monotherapy 37 
IBI322 (Innovent Biologics, recombinant anti-CD47/PD-L1 bispecific antibody) 
04338659 Not yet open Solid cancers Alone 45 
04328831 Recruiting Solid cancers Alone 218 
IBI188 (Innovent Biologics, anti-CD47 humanized IgG4 mAb) 
04511975 Recruiting MDS Azacitadine 32 
04485052 Not yet open AML Azacitadine 126 
04485065 Not yet open MDS Azacitadine 12 
03763149 Not yet open Hematologic and solid cancers Alone 42 
03717103 Recruiting Hematologic and solid cancers Alone or rituximab 92 
IMC-002 (ImmuneOncia Therapeutics, anti-CD47 fully human IgG4 mAb) 
04306224 Recruiting Solid cancers and lymphoma Alone 24 
Lemzoparlimab (TJC4, TJ011133) (AbbVie and I-Mab Biopharma, anti-CD47 fully human IgG4 mAb) 
04202003 Recruiting I/II AML and MDS Alone 42 
03934814 Recruiting Solid cancers and lymphoma Alone, pembrolizumab, or rituximab 88 
Magrolimab (Hu5F9-G4, ONO-7913) (Gilead, anti-CD47 humanized IgG4 mAb) 
02216409 Completed Solid cancers Alone 88 
03558139 Not yet open Solid cancers Avelumab 32 
03248479 Recruiting AML, MDS Alone or azacitadine 257 
03922477 Recruiting AML Atezolizumab 21 
02678338 Completed AML, MDS Alone 20 
03527147 Recruiting NHL Acalabrutinib and Rituximab 88 
04403308 Recruiting Solid cancers Alone 12 
02953509 Recruiting I/II NHL Rituximab 422 
04435691 Recruiting I/II AML Azacitadine or venetoclax 38 
04541017 Not yet open I/II Mycosis fungoides, Sezary syndrome Mogamulizumab 100 
02953782 Completed I/II Solid cancers Cetuximab 78 
03869190 Recruiting I/II Urothelial cancer Atezolizumab 385 
04313881 Recruiting III MDS Azacitadine 180 
SHR-1603 (Jiangsu HengRui Medicine, anti-CD47 humanized IgG4 mAb) 
03722186 Not yet open Hematologic and solid cancers Alone 128 
04282070 Recruiting Nasopharyngeal cancer Alone 40 
03710265 Recruiting Solid cancers Alone 112 
SL-172154 (Shattuck Labs, bifunctional fusion protein SIRPα-Fc-CD40 L against CD47 and CD40) 
04406623 Recruiting Ovarian cancer Alone 40 
04502888 Not yet open SCC of the head/neck or skin Alone (intratumoral) 18 
SRF231 (Surface Oncology, anti-CD47 fully human IgG4 mAb) 
03512340 Completed Hematologic and solid cancers Alone 148 
TG-1801 (TG Therapeutics and Novimmune, anti-CD47/CD19 bispecific antibody) 
03804996 Recruiting B-cell lymphoma Alone or ublituximab 16 
TTI-621 [Trillium Therapeutics, anti-CD47 recombinant fusion (CD47 binding domain of human SIRPα fused human IgG1 Fc)] 
02890368 Terminated Solid tumors, mycosis fungoidesb Alone, anti-PD-(L)1, PEG-IFN-α2a, T-Vec, or RT 56 
02663518 Recruiting Hematologic and solid cancers Alone, rituximab, or nivolumab 260 
TTI-622 [Trillium Therapeutics, anti-CD47 recombinant fusion (CD47 binding domain of human SIRPα fused human IgG1 Fc)] 
03530683 Recruiting Lymphoma or multiple myeloma Alone, rituximab, anti-PD-1, or PI 156 
ZL-1201 (Zai Lab, anti-CD47 humanized IgG4 mAb) 
04257617 Recruiting Hematologic and solid cancers Alone 65 
LILRB2/MHC-I 
MK-4830 (Merck and Agenus, anti-LILRB2 fully human IgG4 mAb) 
03564691 Recruiting Solid tumors Alone, pembrolizumab, chemo, or lenvatinib 290 
NCTStatusPhaseCancer typeIn combination withEnrollmenta
SIRPα/CD47 
ALX148 (ALX Oncology, anti-CD47 fusion (CD47 binding domain of SIRPα to inactive human Ig Fc) 
03013218 Recruiting Solid cancers and NHL Pembrolizumab, chemo, or anticancer antibodies 184 
04417517 Recruiting I/II High risk MDS Azacitadine 63 
AO-176 (Arch Oncology, anti-CD47 humanized IgG2 mAb) 
03834948 Recruiting I/II Solid cancers Alone or paclitaxel 132 
04445701 Recruiting I/II Multiple myeloma Alone, dexamethasone or bortezomib 102 
BI 765063 (OSE-172) (OSE Immunotherapeutics and Boehringer Ingelheim, anti-SIRPα humanized IgG4 mAb) 
03990233 Recruiting Solid cancers Alone or BI-754091 116 
CC-90002 (Celgene, anti-CD47 humanized IgG4 mAb) 
02367196 Not yet open Hematologic neoplasms Alone or rituximab 60 
02641002 Terminated AML, MDS Alone 28 
CC-95251 (Celgene, anti-SIRPα humanized mAb) 
03783403 Recruiting Hematologic and solid cancers Monotherapy, rituximab, or cetuximab 230 
DSP107 (Kahr Medical, SIRPα and 4-1BB ligand bi-functional fusion protein) 
04440735 Recruiting Solid cancers Alone or atezolizumab 100 
FSI-189 (Gilead, anti-SIRPα antibody) 
04502706 Not yet open NHL Alone or rituximab 63 
HX009 (Waterstone Pharmaceuticals, anti-PD-1 and -CD47 bispecific antibody fusion protein) 
04097769 Recruiting Solid cancers Monotherapy 37 
IBI322 (Innovent Biologics, recombinant anti-CD47/PD-L1 bispecific antibody) 
04338659 Not yet open Solid cancers Alone 45 
04328831 Recruiting Solid cancers Alone 218 
IBI188 (Innovent Biologics, anti-CD47 humanized IgG4 mAb) 
04511975 Recruiting MDS Azacitadine 32 
04485052 Not yet open AML Azacitadine 126 
04485065 Not yet open MDS Azacitadine 12 
03763149 Not yet open Hematologic and solid cancers Alone 42 
03717103 Recruiting Hematologic and solid cancers Alone or rituximab 92 
IMC-002 (ImmuneOncia Therapeutics, anti-CD47 fully human IgG4 mAb) 
04306224 Recruiting Solid cancers and lymphoma Alone 24 
Lemzoparlimab (TJC4, TJ011133) (AbbVie and I-Mab Biopharma, anti-CD47 fully human IgG4 mAb) 
04202003 Recruiting I/II AML and MDS Alone 42 
03934814 Recruiting Solid cancers and lymphoma Alone, pembrolizumab, or rituximab 88 
Magrolimab (Hu5F9-G4, ONO-7913) (Gilead, anti-CD47 humanized IgG4 mAb) 
02216409 Completed Solid cancers Alone 88 
03558139 Not yet open Solid cancers Avelumab 32 
03248479 Recruiting AML, MDS Alone or azacitadine 257 
03922477 Recruiting AML Atezolizumab 21 
02678338 Completed AML, MDS Alone 20 
03527147 Recruiting NHL Acalabrutinib and Rituximab 88 
04403308 Recruiting Solid cancers Alone 12 
02953509 Recruiting I/II NHL Rituximab 422 
04435691 Recruiting I/II AML Azacitadine or venetoclax 38 
04541017 Not yet open I/II Mycosis fungoides, Sezary syndrome Mogamulizumab 100 
02953782 Completed I/II Solid cancers Cetuximab 78 
03869190 Recruiting I/II Urothelial cancer Atezolizumab 385 
04313881 Recruiting III MDS Azacitadine 180 
SHR-1603 (Jiangsu HengRui Medicine, anti-CD47 humanized IgG4 mAb) 
03722186 Not yet open Hematologic and solid cancers Alone 128 
04282070 Recruiting Nasopharyngeal cancer Alone 40 
03710265 Recruiting Solid cancers Alone 112 
SL-172154 (Shattuck Labs, bifunctional fusion protein SIRPα-Fc-CD40 L against CD47 and CD40) 
04406623 Recruiting Ovarian cancer Alone 40 
04502888 Not yet open SCC of the head/neck or skin Alone (intratumoral) 18 
SRF231 (Surface Oncology, anti-CD47 fully human IgG4 mAb) 
03512340 Completed Hematologic and solid cancers Alone 148 
TG-1801 (TG Therapeutics and Novimmune, anti-CD47/CD19 bispecific antibody) 
03804996 Recruiting B-cell lymphoma Alone or ublituximab 16 
TTI-621 [Trillium Therapeutics, anti-CD47 recombinant fusion (CD47 binding domain of human SIRPα fused human IgG1 Fc)] 
02890368 Terminated Solid tumors, mycosis fungoidesb Alone, anti-PD-(L)1, PEG-IFN-α2a, T-Vec, or RT 56 
02663518 Recruiting Hematologic and solid cancers Alone, rituximab, or nivolumab 260 
TTI-622 [Trillium Therapeutics, anti-CD47 recombinant fusion (CD47 binding domain of human SIRPα fused human IgG1 Fc)] 
03530683 Recruiting Lymphoma or multiple myeloma Alone, rituximab, anti-PD-1, or PI 156 
ZL-1201 (Zai Lab, anti-CD47 humanized IgG4 mAb) 
04257617 Recruiting Hematologic and solid cancers Alone 65 
LILRB2/MHC-I 
MK-4830 (Merck and Agenus, anti-LILRB2 fully human IgG4 mAb) 
03564691 Recruiting Solid tumors Alone, pembrolizumab, chemo, or lenvatinib 290 

Abbreviations: AML, acute myeloid leukemia; chemo, chemotherapy; mAb, monoclonal antibody; MDS, myelodysplastic syndrome; NCT, ClinicalTrials.gov identifier; NHL, non-Hodgkin lymphoma; PI, proteasome inhibitor; RT, radiation therapy; SCC, squamous cell carcinoma.

aProjected or actual.

bPercutaneously accessible solid tumors or mycosis fungoides for intratumoral injection.

Table 3.

Clinical trials of NK-cell checkpoint inhibitors registered on ClinicalTrials.gov.

NCTStatusPhaseCancer typeIn combination withEnrollmenta
TIGIT/CD112 + CD155 
AB154 (Arcus Biosciences, anti-TIGIT human IgG1 mAb) 
03628677 Recruiting Solid cancers Alone or zimberelimab 66 
04262856 Recruiting II Lung Cancer Zimberelimab or AB928 150 
ASP8374 (PTZ-201) (Astellas, anti-TIGIT fully human IgG4 mAb) 
03945253 Completed Solid cancers Alone 
03260322 Not yet open Solid cancers Alone or pembrolizumab 300 
BGB-A1217 (BeiGene, anti-TIGIT humanized IgG1-variant mAb) 
04047862 Recruiting Solid cancers Tislelizumab 39 
BMS-986207 (Bristol Meyers Squibb, anti-TIGIT human IgG1 mAb with null Fcγ receptor) 
04570839 Recruiting I/II Solid cancers COM701 and nivolumab 100 
02913313 Not yet open I/II Solid cancers Alone or nivolumab 170 
04150965 Recruiting I/II Multiple myeloma Alone or pomalidomide and dexamethasone 104 
Etigilimab (OMP-313M32) (Mereo BioPharma, anti-TIGIT IgG1 humanized mAb) 
03119428 Terminated Solid cancers Alone or nivolumab 33 
SGN-TGT (SEA-TGT) (Seattle Genetics, anti-TIGIT human mAb) 
04254107 Recruiting Hematologic and solid cancers Monotherapy or pembrolizumab 111 
Tiragolumab (MTIG7192A, RG6058) (Genentech, anti-TIGIT humanized IgG1/kappa mAb) 
04584112 Recruiting Triple-negative breast cancer Atezolizumab or chemo 60 
04045028 Recruiting Multiple myeloma, NHL Alone, daratumumab, or rituximab 52 
02794571 Recruiting Solid cancers Alone, atezolizumab, or chemo 400 
04524871 Recruiting I/II HCC Atezolizumab and bevacizumab 100 
03281369 Recruiting I/II Gastric or esophageal cancer Atezolizumab or chemo 410 
03869190 Recruiting I/II Urothelial cancer Atezolizumab 385 
03193190 Recruiting I/II Pancreatic cancer Atezolizumab or chemo 260 
04300647 Recruiting II Cervical cancer Atezolizumab 160 
04543617 Recruiting III Esophageal SCC Atezolizumab 750 
04540211 Recruiting III Esophageal SCC Atezolizumab or chemo 450 
03563716 Not yet open III NSCLC Atezolizumab 135 
04294810 Recruiting III NSCLC Atezolizumab 500 
04513925 Recruiting III NSCLC Atezolizumab 800 
04256421 Recruiting III NSCLC Atezolizumab or chemo 400 
Vibostolimab (MK-7684) (Merck, anti-TIGIT humanized antibody) 
02964013 Recruiting Solid cancers Alone, pembrolizumab, or chemo 432 
04305054 Recruiting I/II Melanoma Pembrolizumab 135 
04305041 Recruiting I/II Melanoma Pembrolizumab and MK-1308 200 
04303169 Recruiting I/II Melanoma Pembrolizumab 65 
04165070 Recruiting II Non–small cell lung cancer Pembrolizumab or chemo 90 
PVRIG/CD112 
COM701 (Compugen, anti-PVRIG humanized IgG4 mAb) 
03667716 Recruiting Solid cancers Alone or nivolumab 140 
04570839 Recruiting I/II Solid cancers BMS-986207 and nivolumab 100 
IPH2101 (1–7F9) (Innate Pharma and Bristol-Myers-Squibb, anti-KIR2D fully human IgG4 mAb) 
01217203 Completed Multiple myeloma Lenalidomide 15 
01256073 Completed AML Alone 21 
00552396 Completed Multiple myeloma Alone 32 
00999830 Completed II Multiple myeloma Alone 27 
01222286 Completed II Smoldering myeloma Alone 30 
01248455 Terminated II Smoldering myeloma Alone 
Lirilumab (IPH2102, BMS-986015) (Innate Pharma and Bristol-Myers-Squibb, anti-KIR2D fully human IgG4 mAb) 
01750580 Completed Solid cancers Ipilimumab 22 
02252263 Completed Multiple myeloma Elotuzumab 44 
03203876 Not yet open Solid cancers Nivolumab and ipilimumab 21 
03532451 Not yet open Bladder cancer Nivolumab 43 
03347123 Not yet open I/II Hematologic and solid cancers Epacadostat and nivolumab 11 
01714739 Completed I/II Solid cancers Nivolumab and ipilimumab 337 
02813135 Recruiting I/II Solid cancers Nivolumab 397 
01592370 Not yet open I/II Hematologic neoplasms Nivolumab 375 
01687387 Completed II Acute myeloid leukemia Alone 152 
02599649 Terminated II MDS Alone, nivolumab, and/or azacitadine 10 
02399917 Terminated II AML Azacitadine 36 
02481297 Completed II Leukemia Rituximab 
03341936 Recruiting II Head and neck cancer Nivolumab 58 
NKG2A-CD94/HLA-E 
Monalizumab (IPH2201) (Innate Pharma and AstraZeneca, humanized anti-NKG2A-CD94 IgG4 mAb) 
02459301 Completed Gynecologic cancers Alone 59 
02921685 Recruiting Hematologic neoplasms Alone 18 
02671435 Not yet open I/II Colorectal cancer Durvalumab and cetuximab 383 
02643550 Recruiting I/II HNSCC Alone, cetuximab, or anti-PD(L)1 140 
02557516 Terminated I/II Chronic lymphocytic leukemia Alone 22 
02331875 Terminated I/II HNSCC Alone 
03088059 Recruiting II HNSCC Alone, durvalumab 340 
04307329 Not yet open II Breast cancer Trastuzumab 38 
03822351 Not yet open II NSCLC Durvalumab 189 
03794544 Not yet open II NSCLC Durvalumab 80 
03833440 Recruiting II NSCLC Durvalumab 120 
04590963 Recruiting III HNSCC Cetuximab 600 
NCTStatusPhaseCancer typeIn combination withEnrollmenta
TIGIT/CD112 + CD155 
AB154 (Arcus Biosciences, anti-TIGIT human IgG1 mAb) 
03628677 Recruiting Solid cancers Alone or zimberelimab 66 
04262856 Recruiting II Lung Cancer Zimberelimab or AB928 150 
ASP8374 (PTZ-201) (Astellas, anti-TIGIT fully human IgG4 mAb) 
03945253 Completed Solid cancers Alone 
03260322 Not yet open Solid cancers Alone or pembrolizumab 300 
BGB-A1217 (BeiGene, anti-TIGIT humanized IgG1-variant mAb) 
04047862 Recruiting Solid cancers Tislelizumab 39 
BMS-986207 (Bristol Meyers Squibb, anti-TIGIT human IgG1 mAb with null Fcγ receptor) 
04570839 Recruiting I/II Solid cancers COM701 and nivolumab 100 
02913313 Not yet open I/II Solid cancers Alone or nivolumab 170 
04150965 Recruiting I/II Multiple myeloma Alone or pomalidomide and dexamethasone 104 
Etigilimab (OMP-313M32) (Mereo BioPharma, anti-TIGIT IgG1 humanized mAb) 
03119428 Terminated Solid cancers Alone or nivolumab 33 
SGN-TGT (SEA-TGT) (Seattle Genetics, anti-TIGIT human mAb) 
04254107 Recruiting Hematologic and solid cancers Monotherapy or pembrolizumab 111 
Tiragolumab (MTIG7192A, RG6058) (Genentech, anti-TIGIT humanized IgG1/kappa mAb) 
04584112 Recruiting Triple-negative breast cancer Atezolizumab or chemo 60 
04045028 Recruiting Multiple myeloma, NHL Alone, daratumumab, or rituximab 52 
02794571 Recruiting Solid cancers Alone, atezolizumab, or chemo 400 
04524871 Recruiting I/II HCC Atezolizumab and bevacizumab 100 
03281369 Recruiting I/II Gastric or esophageal cancer Atezolizumab or chemo 410 
03869190 Recruiting I/II Urothelial cancer Atezolizumab 385 
03193190 Recruiting I/II Pancreatic cancer Atezolizumab or chemo 260 
04300647 Recruiting II Cervical cancer Atezolizumab 160 
04543617 Recruiting III Esophageal SCC Atezolizumab 750 
04540211 Recruiting III Esophageal SCC Atezolizumab or chemo 450 
03563716 Not yet open III NSCLC Atezolizumab 135 
04294810 Recruiting III NSCLC Atezolizumab 500 
04513925 Recruiting III NSCLC Atezolizumab 800 
04256421 Recruiting III NSCLC Atezolizumab or chemo 400 
Vibostolimab (MK-7684) (Merck, anti-TIGIT humanized antibody) 
02964013 Recruiting Solid cancers Alone, pembrolizumab, or chemo 432 
04305054 Recruiting I/II Melanoma Pembrolizumab 135 
04305041 Recruiting I/II Melanoma Pembrolizumab and MK-1308 200 
04303169 Recruiting I/II Melanoma Pembrolizumab 65 
04165070 Recruiting II Non–small cell lung cancer Pembrolizumab or chemo 90 
PVRIG/CD112 
COM701 (Compugen, anti-PVRIG humanized IgG4 mAb) 
03667716 Recruiting Solid cancers Alone or nivolumab 140 
04570839 Recruiting I/II Solid cancers BMS-986207 and nivolumab 100 
IPH2101 (1–7F9) (Innate Pharma and Bristol-Myers-Squibb, anti-KIR2D fully human IgG4 mAb) 
01217203 Completed Multiple myeloma Lenalidomide 15 
01256073 Completed AML Alone 21 
00552396 Completed Multiple myeloma Alone 32 
00999830 Completed II Multiple myeloma Alone 27 
01222286 Completed II Smoldering myeloma Alone 30 
01248455 Terminated II Smoldering myeloma Alone 
Lirilumab (IPH2102, BMS-986015) (Innate Pharma and Bristol-Myers-Squibb, anti-KIR2D fully human IgG4 mAb) 
01750580 Completed Solid cancers Ipilimumab 22 
02252263 Completed Multiple myeloma Elotuzumab 44 
03203876 Not yet open Solid cancers Nivolumab and ipilimumab 21 
03532451 Not yet open Bladder cancer Nivolumab 43 
03347123 Not yet open I/II Hematologic and solid cancers Epacadostat and nivolumab 11 
01714739 Completed I/II Solid cancers Nivolumab and ipilimumab 337 
02813135 Recruiting I/II Solid cancers Nivolumab 397 
01592370 Not yet open I/II Hematologic neoplasms Nivolumab 375 
01687387 Completed II Acute myeloid leukemia Alone 152 
02599649 Terminated II MDS Alone, nivolumab, and/or azacitadine 10 
02399917 Terminated II AML Azacitadine 36 
02481297 Completed II Leukemia Rituximab 
03341936 Recruiting II Head and neck cancer Nivolumab 58 
NKG2A-CD94/HLA-E 
Monalizumab (IPH2201) (Innate Pharma and AstraZeneca, humanized anti-NKG2A-CD94 IgG4 mAb) 
02459301 Completed Gynecologic cancers Alone 59 
02921685 Recruiting Hematologic neoplasms Alone 18 
02671435 Not yet open I/II Colorectal cancer Durvalumab and cetuximab 383 
02643550 Recruiting I/II HNSCC Alone, cetuximab, or anti-PD(L)1 140 
02557516 Terminated I/II Chronic lymphocytic leukemia Alone 22 
02331875 Terminated I/II HNSCC Alone 
03088059 Recruiting II HNSCC Alone, durvalumab 340 
04307329 Not yet open II Breast cancer Trastuzumab 38 
03822351 Not yet open II NSCLC Durvalumab 189 
03794544 Not yet open II NSCLC Durvalumab 80 
03833440 Recruiting II NSCLC Durvalumab 120 
04590963 Recruiting III HNSCC Cetuximab 600 

Abbreviations: AML, acute myeloid leukemia; chemo, chemotherapy; HCC, hepatocellular carcinoma; HNSCC, head/neck squamous cell carcinoma; mAb, monoclonal antibody; NCT, ClinicalTrials.gov identifier; NHL, non-Hodgkin lymphoma; NSCLC, non-small cell lung cancer; SCC, squamous cell carcinoma.

aProjected or actual.

Phagocytosis checkpoint inhibitors

The phagocytes are macrophages, neutrophils, and DCs. Upon activation, phagocytes engulf target cells. Macrophages and neutrophils then directly destroy the target cell (macrophages by lysosomal proteolysis and neutrophils by oxidative burst; ref. 12). DCs, on the other hand, process antigens and load them onto major histocompatibility complex class I (MHC-I) or II (MHC-II) to present to T cells, thereby activating the adaptive immune system (12). Antigen presentation is required for T-cell antitumor activity (10). The amount of tumoral conventional DCs (a subpopulation of DCs even more specialized in antigen presentation) predicts survival across multiple tumor types and predicts response to anti-PD-L1 therapy (9, 13).

Thus, phagocytosis checkpoint inhibitors directly destroy tumor cells and activate the adaptive immune system (via antigen presentation), providing rationale for use with adaptive immune checkpoint inhibitors [targeting CTLA-4 or PD-(L)1], which strengthen T-cell antitumor effects. In addition, while the PD-1–PD-L1 axis is primarily characterized as a T-cell checkpoint, there is evidence of innate immune regulation. Specifically, blockade of the PD-1–PD-L1 axis in mice lacking a functional immune system, other than intact macrophages, generated antitumor response (14). Similarly, PD-L1 knockout tumor cells significantly increased phagocytosis by macrophages (14).

Phagocytosis of cancer cells is regulated by pro- and anti-phagocytic receptor–ligand interactions (Fig. 1). The primary prophagocytic (“eat me”) signals on cancer cells are calreticulin (interacts with LRP1 on phagocytes), SLAMF7 (interacts with Mac-1 on phagocytes), and tumor antigen bound by antibody (interacts with Fcγ receptor on phagocytes); these antigens are minimally expressed on most normal cells (4, 15). Radiotherapy and chemotherapy may also increase cancer cell expression of prophagocytic signals, synergizing with phagocytosis checkpoint inhibitors (4, 16). The primary inhibitory checkpoints between phagocytes and tumor cells, respectively, are SIRPα/CD47, LILRB1/MHC-I, and LILRB2/MHC-I (Fig. 2). Drugs targeting these checkpoints are typically designed to be given with a prophagocytic signal such as an opsonizing anticancer antibody, radiation, or chemotherapy (Fig. 1).

Figure 2.

Innate immune checkpoints and inhibitors. Tumor cells express ligands (“don't eat me” signals) which interact with phagocyte (A) and NK (B) cell-surface receptors, stimulating signaling pathways which inhibit phagocytosis and natural cytotoxicity, respectively. The phagocytosis checkpoints (A) include (a) SIRPα/CD47, (b) LILRB1/MHC-I, and (c) LILRB2/MHC-I. Drugs are being developed to interrupt these signaling pathways, thereby increasing phagocytosis of tumor cells; drugs with presented/published clinical trial data are shown. (a) The anti-CD47 drugs are ALX148 (engineered fusion protein - two high-affinity CD47 binding domains of SIRPα linked to an inactive Fc), magrolimab (anti-CD47 humanized IgG4 mAb), SRF231 (anti-CD47 fully human IgG4 mAb), lemzoparlimab (anti-CD47 humanized IgG4 mAb), and IBI188 (anti-CD47 humanized IgG4 mAb). No compounds blocking the LILRB1/MHC-I axis have available clinical trial results (b). MK-4830 is an anti-LILRB2 fully human IgG4 mAb (c). The NK checkpoints (B) include (a) TIGIT/CD155 + CD112, (b) PVRIG/CD112, (c) Inhibitory KIRs/MHC-I, and (d) NKG2A-CD94/HLA-E. Drugs are being developed to interrupt these signaling pathways, thereby increasing natural cytotoxicity of tumor cells; drugs with presented/published clinical trial data are shown. Tiragolumab, vibostolimab, and etigilimab are anti-TIGIT humanized IgG1 mAbs (a). COM701 is an anti-PVRIG humanized IgG4 mAb (b). Lirilumab is an anti-KIR2D fully human IgG4 mAb (c). Monalizumab is an anti-NKG2A-CD94 humanized IgG4 mAb (d). Created with BioRender.com. B2MG, beta-2-microglobulin; Fc, immunoglobulin fragment crystallizable region; HLA, human leukocyte antigen; Ig, immunoglobulin; KIR, killer cell immunoglobulin-like receptor; LILRB1, leukocyte immunoglobulin-like receptor B1; LILRB2, leukocyte immunoglobulin-like receptor B2; mAb, monoclonal antibody; MHC, major histocompatibility complex; NKG2A, NK group 2 member A; PVRIG, poliovirus receptor related immunoglobulin domain containing; SIRPα, signal-regulatory protein-α; TIGIT, T-cell immunoglobulin and immunoreceptor tyrosine-based inhibition motifs domain.

Figure 2.

Innate immune checkpoints and inhibitors. Tumor cells express ligands (“don't eat me” signals) which interact with phagocyte (A) and NK (B) cell-surface receptors, stimulating signaling pathways which inhibit phagocytosis and natural cytotoxicity, respectively. The phagocytosis checkpoints (A) include (a) SIRPα/CD47, (b) LILRB1/MHC-I, and (c) LILRB2/MHC-I. Drugs are being developed to interrupt these signaling pathways, thereby increasing phagocytosis of tumor cells; drugs with presented/published clinical trial data are shown. (a) The anti-CD47 drugs are ALX148 (engineered fusion protein - two high-affinity CD47 binding domains of SIRPα linked to an inactive Fc), magrolimab (anti-CD47 humanized IgG4 mAb), SRF231 (anti-CD47 fully human IgG4 mAb), lemzoparlimab (anti-CD47 humanized IgG4 mAb), and IBI188 (anti-CD47 humanized IgG4 mAb). No compounds blocking the LILRB1/MHC-I axis have available clinical trial results (b). MK-4830 is an anti-LILRB2 fully human IgG4 mAb (c). The NK checkpoints (B) include (a) TIGIT/CD155 + CD112, (b) PVRIG/CD112, (c) Inhibitory KIRs/MHC-I, and (d) NKG2A-CD94/HLA-E. Drugs are being developed to interrupt these signaling pathways, thereby increasing natural cytotoxicity of tumor cells; drugs with presented/published clinical trial data are shown. Tiragolumab, vibostolimab, and etigilimab are anti-TIGIT humanized IgG1 mAbs (a). COM701 is an anti-PVRIG humanized IgG4 mAb (b). Lirilumab is an anti-KIR2D fully human IgG4 mAb (c). Monalizumab is an anti-NKG2A-CD94 humanized IgG4 mAb (d). Created with BioRender.com. B2MG, beta-2-microglobulin; Fc, immunoglobulin fragment crystallizable region; HLA, human leukocyte antigen; Ig, immunoglobulin; KIR, killer cell immunoglobulin-like receptor; LILRB1, leukocyte immunoglobulin-like receptor B1; LILRB2, leukocyte immunoglobulin-like receptor B2; mAb, monoclonal antibody; MHC, major histocompatibility complex; NKG2A, NK group 2 member A; PVRIG, poliovirus receptor related immunoglobulin domain containing; SIRPα, signal-regulatory protein-α; TIGIT, T-cell immunoglobulin and immunoreceptor tyrosine-based inhibition motifs domain.

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SIRPα/CD47

Signal-regulatory protein-α (SIRPα) is an inhibitory receptor expressed on myeloid phagocytes. SIRPα contains an extracellular Ig domain for ligand binding and intracellular immunoreceptor tyrosine-based inhibition motifs (ITIM; refs. 4, 10). CD47, the ligand for SIRPα, is widely expressed on cancer cells (17). The SIRPα/CD47 interaction results in phosphorylation of the ITIMs and downstream disruption of the cytoskeleton, resulting in inhibition of phagocytosis (17). Blockade of the SIRPα/CD47 axis increases phagocytosis, resulting in cell death and antigen presentation. Tumor killing can be further stimulated if an active Fc domain is supplied, either on the anti-CD47 agent or on a separate anticancer antibody, both of which generate ADCP or ADCC (10). In addition to directly blocking the SIRPα/CD47 interaction, preclinical work has demonstrated an evolving potential drug target. Glutaminyl-peptide cyclotransferase-like protein (QPCTL) is responsible for the formation of pyroglutamate on CD47 at the SIRPα-binding site. Disruption of QPCTL reduces binding of CD47 to SIRPα, enhancing ADCP and ADCC (15).

While CD47 is widely expressed among normal human cells (including hematopoietic cells), SIRPα/CD47 blockade preferentially results in phagocytosis of tumor, as normal human cells typically lack stimulatory “eat me” signals (4, 15). A notable exception is red blood cells (RBC), which are subject to dose-dependent phagocytosis in the setting of SIRPα/CD47 blockade (18). Strategies to minimize anemia include administering a priming dose of the SIRPα-CD47 blocker (resulting in RBC phagocytosis then reticulocytosis, which express higher levels of CD47 and are thus resistant to phagocytosis) or selecting the Fc domain of the anti-CD47 mAb to minimize interactions with the phagocyte Fcγ receptor (either by using an inactive Fc domain or using an Fc domain of IgG2/4, which more weakly interact with Fcγ receptors than do IgG1/3; refs. 19, 20).

ALX148:

ALX148 (ALX Oncology) is an engineered fusion protein containing two high-affinity CD47-binding domains of SIRPα linked to an inactive Fc region of human Ig (21). ALX148 is being evaluated in combination with anticancer antibodies and/or with anti-PD-1 agents in both solid [with development focused on non–small cell lung cancer (NSCLC), head/neck squamous cell carcinoma (HNSCC), and gastric/gastroesophageal junction carcinoma] and hematologic malignancies. Phase I efficacy data are encouraging, and treatment appears to be tolerable (including minimal hematologic toxicity).

In a phase I study, 25 patients with advanced refractory solid tumors or non-Hodgkin lymphoma were treated with ALX148 alone (NCT03013218; ref. 22). ORR was 0% and DCR was 16%. The most common treatment-related adverse events (TRAE) were headache (16%), fatigue (12%), dizziness (8%), rash (8%), and thrombocytopenia (8%). Grade ≥3 TRAEs were infection, pancreatitis, thrombocytopenia, and neutropenia (1 each).

Seventy-nine patients with advanced refractory solid tumors were treated with ALX148 in combination with pembrolizumab (NSCLC or HNSCC, N = 50) or in combination with trastuzumab (HER2+, primarily gastric/gastroesophageal junction carcinoma, N = 29; NCT03013218; ref. 23). Patients with NSCLC previously received pembrolizumab or had PD-L1 tumor proportion score <50%, patients with HNSCC had progressed on platinum-based therapy, and HER2+ patients had previously received trastuzumab. ORR and DCR, respectively, were 4% and 39% for NSCLC, 18% and 41% for HNSCC, and 19% and 48% for gastric/gastroesophageal junction carcinoma. Treatment was well tolerated. Any grade TRAEs included fatigue (11%), aspartate aminotransferase (AST) increase (9%), alanine aminotransferase (ALT) increase (8%), anemia (8%), and thrombocytopenia (6%).

An overlapping patient cohort was subsequently presented (NCT03013218; ref. 24). Patients included 52 with HNSCC that had progressed on platinum-based therapy (with or without prior anti-PD-1 therapy) and were treated with ALX148 and pembrolizumab, one with previously untreated HNSCC treated with ALX148, pembrolizumab, and platinum doublet, and 30 with HER2+ gastric/gastroesophageal junction cancer that had progressed on platinum doublet with trastuzumab and were treated with ALX148 and trastuzumab with or without ramucirumab/paclitaxel. ORR, median progression-free survival (mPFS, months), and median overall survival (mOS, months) were 40%, 4.6, and not reached in the previously treated anti-PD-1 naïve HNSCC arm treated with ALX148/pembrolizumab; 0%, 2.0, and 7.4 in the anti-PD-1 experienced HNSCC arm treated with ALX148/pembrolizumab; and 20%, 2.2, and 8.1 in the gastric/gastroesophageal junction cancer arm treated with ALX148/trastuzumab. TRAEs in the arms treated with ALX148 and either pembrolizumab or trastuzumab were fatigue (18%), AST increase (11%), thrombocytopenia (10%), ALT increase (9%), anemia (9%), and pruritus (9%).

Magrolimab (Hu5F9-G4, ONO-7913):

Magrolimab (Gilead, recently acquired from Forty Seven) is an anti-CD47 humanized IgG4 mAb (18). It is being evaluated in solid tumors and hematologic malignancies. Anemia is common but can be mitigated by administration of a priming dose of magrolimab with intrapatient dose escalation (20). Thrombocytopenia and leukopenia are usually not severe. There are many ongoing phase I–III trials evaluating magrolimab in both solid and hematologic cancers (Table 2).

In a phase I study, 60 patients with refractory advanced solid tumors (plus 2 patients with diffuse large B-cell lymphoma) were treated with magrolimab (NCT02216409; ref. 20). ORR was 3% (ovarian and fallopian tube carcinoma). The most common hematologic toxicities were anemia (57%, typically with a hemoglobin decrease of 1–2 g/dL after the priming dose with rapid subsequent improvement; 4 patients required transfusions), lymphopenia (18%), and thrombocytopenia (11%). The most common nonhematologic toxicities were fatigue (64%), headache (50%), fever and chills (45% each), and hyperbilirubinemia (34%, usually transient unconjugated hyperbilirubinemia associated with anemia during the priming period). Thus, efficacy of magrolimab monotherapy appears to be limited.

In a subsequent phase Ib study, 34 patients with refractory solid tumors (primarily ovarian cancer) were treated with magrolimab and avelumab (NCT03558139; ref. 25). Among the 18 response-evaluable patients with ovarian cancer, ORR was 0% and DCR was 56%. TRAEs were similar.

Magrolimab was evaluated with cetuximab in patients with solid tumors (phase Ib, N = 32) and previously treated colorectal cancer (phase II, N = 46; NCT02953782; ref. 26). The most common any-grade TRAEs were aceniform rash (36%), dry skin (33%), fatigue (32%), infusion reaction (31%), headache (30%), diarrhea (23%), nausea (23%), chills (23%), and anemia (22%); 4% of patients discontinued treatment due to an AE. Among KRAS wild-type colorectal cancer (N = 30), ORR was 7% (all cetuximab-experienced), mPFS was 3.6 months, and mOS was 10.1 months. Among KRAS-mutant colorectal cancer (N = 40), ORR was 0%, DCR was 45%, mPFS was 1.9 months, and mOS was 10.4 months. Tumor biopsies showed increases in tumor-infiltrating macrophages.

SRF231:

SRF231 (Surface Oncology) is an anti-CD47 fully human IgG4 mAb (27–29). In preclinical models, SRF231 binds to RBC CD47 but does not cause RBC phagocytosis (27). It is being developed in both solid and hematologic malignancies. Among 37 response-evaluable patients with advanced refractory solid (N = 45) and hematologic malignancies (N = 1) treated with SRF231, ORR was 0% with SD reported (phase I, NCT03512340; ref. 30). The most common TRAEs were fatigue (43%), headache (35%), and fever (30%).

Lemzoparlimab (TJC4, TJ011133):

Lemzoparlimab (AbbVie and I-Mab Biopharma) is an anti-CD47 fully human IgG4 mAb with a novel conformational epitope, resulting in minimal binding to human RBCs and platelets in preclinical models (31). It is being evaluated in both and solid tumors. A phase I trial of lemzoparlimab in patients with solid tumors and lymphoma is ongoing (NCT03934814). Thus far, 20 patients with advanced refractory solid tumors were treated with lemzoparlimab in dose escalation (part 1; ref. 32). The most common any grade TRAEs were anemia (30%, primarily transiently during cycle 1 with average reduction in hemoglobin 1.5 g/dL), fatigue (25%), infusion reaction (20%), and diarrhea (15%); no grade ≥3 TRAEs were reported. Part 2 is planned, which will evaluate lemzoparlimab with pembrolizumab or rituximab.

IBI188:

IBI188 (Innovent Biologics) is an anti-CD47 humanized IgG4 mAb that is being evaluated in both solid and hematologic malignancies (10). Among 20 patients with refractory/advanced solid tumors or lymphoma treated with IBI188, the most common any-grade TRAEs were nausea (35%), back pain (35%), fatigue (30%), vomiting (20%), elevated bilirubin (20%), and anemia (15%). Grade ≥3 TRAEs were elevated bilirubin, thrombocytopenia, and anemia (5% each; NCT03763149; ref. 33).

LILRB1/MHC-I

Leukocyte Ig-like receptor B1 (LILRB1) is expressed on both innate (monocytes, macrophages, eosinophils, basophils, DCs, and certain NK cells) and adaptive (certain T and B cells) immune cells (4). MHC-I, expressed on nucleated cells (including cancer cells), is a heterodimer composed of a heavy α-chain and a β2-microglobulin chain (4, 34). Antigen-bound MHC-I on cancer cells is recognized by cytotoxic T cells, and engagement of MHC-I by the T-cell receptor and CD8 results in cytotoxicity (4, 34). However, expression of MHC-I on cancer cells has been correlated with resistance to phagocytosis, likely due to an inhibitory interaction between LILRB1 on phagocytes and the β2-microglobulin subunit of MHC-I on cancer cells (4, 35). While cytotoxic T-cell antitumor activity is dependent upon intact interaction with MHC-I, specifically blocking the LILRB1/β2-microglobulin axis is a possible innate immune drug target. There are currently no active clinical trials targeting this checkpoint, which may be explained by (i) the relatively recent discovery that the LILRB1/MHC-I interaction correlates with resistance to phagocytosis in cancer cells (in 2018; ref. 4) and (ii) drugs cannot interfere with the MHC-I/T-cell receptor interaction).

LILRB2/MHC-I

LILRB2 is also expressed on both innate (monocytes, macrophages, basophils, and DCs) and adaptive (CD4+ T cells) immune cells and interacts with MHC-I on nucleated cells (unknown specific ligand; ref. 4). LILRB2 is also referred to as ILT4, LIR2, monocyte/macrophage Ig-like receptor 10, MIR-10, and CD85d. It has been shown preclinically that LILRB2 antagonism promotes macrophage maturation and activation (36).

MK-4830:

MK-4830 (Merck and Agenus) is an anti-LILRB2 fully human IgG4 mAb (37). In a phase I study, 84 patients with advanced refractory solid tumors were treated with MK-4830 alone (N = 50) or in combination with pembrolizumab (N = 34; NCT03564691; ref. 38). Among all patients, ORR was 13%; most (91%) were in the combination group, 45% were anti-PD-1 naïve, and some were durable (>1 year). TRAEs occurred in 52% of patients and most were grade 1–2.

NK-cell checkpoint inhibitors

NK cells contain both stimulatory and inhibitory receptors, serving as possible drug targets (Fig. 2). NK-cell stimulatory receptors include DNAM-1 (also called CD226), NKG2C, NKG2D, and natural cytotoxicity receptors (NKP30, NKP44, and NKP46); these interact with cell-surface and soluble markers of stressed cells, including tumor cells, such as cell-surface NK ligands (10, 39–41). The result is natural cytotoxicity, via secretion of cytokines (IFNγ, TNFα, and GMCSF), and DC recruitment and activation via production of chemoattractants (such as CCL5, CXL1, and CXL2; refs. 10, 39, 40). Thus, NK-cell inhibitory checkpoint inhibitors, like phagocytosis checkpoint inhibitors, strengthen the adaptive immune antitumor response. NK cell–mediated recruitment and activation of DCs has been demonstrated in preclinical melanoma models and may predict response to anti-PD-1 therapy (13, 42).

Healthy cells express low levels of stimulatory ligands and high levels of inhibitory ligands; NK cells identify cancer cells by the opposite pattern; however, cancer cells can evade detection by altering ligand expression (43). Intratumoral NK-cell activity and infiltration has been correlated with improved outcomes in multiple solid tumor types and stages (44–49). The primary inhibitory checkpoints between NK cells and tumor cells, respectively, are TIGIT/CD112 + CD155, PVRIG/CD112, KIRs/MHC-I, and NKG2A-CD94/HLA-E (Fig. 2). NK-cell inhibitory checkpoint inhibitors are frequently being evaluated in combination with anti-PD-(L)1 therapy.

TIGIT/CD112 + CD155

T-cell Ig and ITIM domain (TIGIT) is an ITIM-containing inhibitory receptor expressed on NK cells, and also T-cell subsets (CD4+ T cells, CD8+ T cells, and regulatory T cells; ref. 10). The ligands for TIGIT are CD112 (also called PVRL2 and nectin-2) and CD155 (also called PVR), both of which are expressed on tumor cells (10). TIGIT competes for binding to CD112 and CD155 with DNAM-1, a stimulatory NK-cell receptor (43). In preclinical models, TIGIT blockade has been shown to increase anti-tumor NK-cell activity and CD8+ T-cell cytokine production/cytotoxicity; antitumor T-cell effect was NK-cell dependent (43, 50, 51). Preclinical data suggests synergy between TIGIT blockade and PD-(L)1 blockade, a strategy implemented in clinical trials (43, 50, 52).

Tiragolumab (MTIG7192A, RG6058):

Tiragolumab (Genentech) is an anti-TIGIT humanized IgG1 mAb designed to inhibit the interaction of TIGIT with CD155 (52, 53). In a phase I study, 73 patients with refractory advanced solid tumors were treated with tiragolumab alone (phase Ia, N = 24) or in combination with atezolizumab (phase Ib, N = 49) (NCT02794571; ref. 52). In phase Ia, ORR was 0% and DCR was 17%. In phase Ib, ORR was 6% (N = 3, all with PD-L1+ tumors, 2 with NSCLC and 1 with HNSCC) and DCR was not reported. Given promising efficacy, an expansion cohort was initiated in PD-L1+, checkpoint inhibitor naïve patients. This included 14 patients with NSCLC treated with tiragolumab and atezolizumab, in whom ORR was 50% and DCR was 79%. TRAEs occurred in 67% of patients in phase Ia (most common: fatigue in 38%) and 59% of patients in phase Ib (most common: anemia in 31%). Grade 3–4 TRAEs were uncommon.

In a prospective, randomized, double-blind, placebo-controlled phase II study, 135 patients with chemotherapy-naïve, PD-L1+, EGFR and ALK wild-type, locally advanced/metastatic NSCLC were randomized 1:1 to atezolizumab with or without tiragolumab (CITYSCAPE, NCT03563716; ref. 54). After a median follow-up of 10.9 months, tiragolumab + atezolizumab significantly improved ORR (37% vs. 21%) and median PFS (5.6 vs. 3.9 months). Patients in the tiragolumab arm experienced similar AEs as the placebo arm. TRAEs, grade ≥3 TRAEs, and AEs leading to treatment withdrawal occurred in 81%, 15%, and 8% of patients treated with tiragolumab + atezolizumab and 72%, 19%, and 10% of patients treated with placebo + atezolizumab. Tiragolumab is currently being studied in multiple phase III clinical trials, focused on esophageal squamous cell carcinoma and NSCLC (Table 3).

Vibostolimab (MK-7684):

Vibostolimab (Merck) is an anti-TIGIT IgG1 humanized mAb which is being evaluated in early-phase clinical trials in solid tumors, with a focus on NSCLC (55). In a phase I study, 34 patients with refractory advanced solid tumors were treated with vibostolimab alone and 47 patients in combination with pembrolizumab (NCT02964013; ref. 55). In the monotherapy and combination therapy groups, respectively, ORR was 3% and 19% and DCR was 35% and 47%. AEs occurred in 53% (6% grade ≥3) of patients treated with monotherapy and 65% (12% grade ≥3) of patients treated with combination therapy. The most common AEs were fatigue, pruritus, infusion reaction, anemia, nausea, and rash.

A 120-patient NSCLC dose expansion was initiated (NCT02964013; refs. 56, 57). Patients were treated with either vibostolimab alone or in combination with pembrolizumab and analysis was stratified by prior anti-PD-(L)1 therapy. Thus, the cohorts included anti-PD-(L)1 refractory NSCLC treated with vibostolimab alone (N = 41) or in combination with pembrolizumab (N = 38), and anti-PD-(L)1 naïve refractory NSCLC (N = 41). ORR was 7% in anti-PD-(L)1 refractory NSCLC treated with vibostolimab monotherapy, 5% in anti-PD-(L)1 refractory NSCLC treated with vibostolimab in combination with pembrolizumab, and 29% in anti-PD-(L)1 naïve NSCLC treated with vibostolimab in combination with pembrolizumab (with a trend toward higher ORR among patients with PD-L1 tumor proportion score ≥ 1%). Many responses were durable. Across all patients, TRAEs occurred in approximately 70% of patients and most frequently were pruritus, fatigue, rash, fever, arthralgia, and anorexia. Grade 3–4 TRAEs occurred in approximately 15% of patients and included lipase elevation, hypertension, and pneumonitis (the latter after receiving combination therapy and resulted in death).

Etigilimab (OMP-313M32):

Etigilimab (Mereo BioPharma) is an anti-TIGIT IgG1 humanized mAb (58). Preclinical studies of intratumor immune cells demonstrated increased NK-cell cytotoxicity and T-cell (both CD4+ and CD8+) activation/infiltration (59). However, ORR was 0% and DCR 22% among 18 patients with refractory advanced solid tumors treated with etigilimab in a phase I study reported in 2018 (NCT03119428; ref. 58). This study was terminated August 2020 and no additional clinical trials are currently registered.

PVRIG/CD112

Poliovirus receptor related Ig domain containing (PVRIG, also called CD112 receptor) is an inhibitory receptor expressed on NK cells and CD8+ T cells which recognizes CD112 but not CD155 on tumor cells (41, 51). Like TIGIT, PVRIG also competes with the NK cell–activating receptor DNAM-1 for binding to CD112. In preclinical studies, anti-PVRIG therapy has been shown to increase NK-cell cytotoxicity and CD8+ T-cell cytokine production/cytotoxicity (51, 60).

COM701:

COM701 (Compugen) is an anti-PVRIG humanized IgG4 mAb (61, 62). Twenty-eight patients with advanced refractory solid tumors were treated with COM701 with (N = 16) or without (N = 12) nivolumab in a phase I study (NCT03667716; refs. 62–64). In the entire population DCR was 57%. No patients stopped treatment due to toxicity. The most common treatment-emergent AEs (TEAE) were fatigue (46%), nausea (31%), and anxiety (23%) in patients with COM701 alone; with combination therapy, 88% of TEAEs were grade 1–2 (anemia, edema, rash, and fatigue most commonly).

KIRs/MHC-I

Killer cell Ig-like receptors (KIR) are expressed on most NK cells and a minority of T cells (primarily CD8+ memory T cells) and recognize MHC-I on tumor cells (10, 65). There are numerous individual KIRs, with nomenclature determined by the number of extracellular Ig-like domains (“2D” or “3D” following “KIR”) and the size of the cytoplasmic tail (long/“L” or short/“S”; refs. 65, 66). KIRs can either be activating or inhibitory, and inhibitory KIRs typically have a long cytoplasmic tail. The inhibitor KIRs include KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL4, KIR2DL5, KIR3DL1, KIR3DL2, and KIR3DL3 (11, 39, 65, 66). Individual KIRs bind HLA class I subgroups.

In fact, all NK cells express at least one inhibitory receptor (either a KIR or NKG2A) and normal tissues express low levels of NK cell–activating ligands, allowing for self-tolerance (67). Loss or mutation of tumor MHC-I generates an antitumor NK-cell response by responding to missing self (11, 65). On the contrary, MHC-I molecule upregulation allows cancer cells to evade immune destruction. In 1999, it was shown that KIR-HLA mismatches between donor and recipient during hematopoietic stem cell transplant for acute myeloid leukemia generated a T cell–independent graft-versus-leukemia effect, by preventing the inhibitory interaction between KIRs on donor NK cells and MHC-I on recipient cancer cells (68). Hence, the development of many anti-KIR drugs has focused on hematologic malignancies.

Combination approaches include blocking KIRs (or NKG2A-CD94, see below) with the addition of an anti-PD-(L)1 agent, anti CTLA-4 agent, or anticancer antibody (the latter increasing NK-cell ADCC; ref. 66). Blockade of CTLA-4 or PD-(L)1 can stimulate cytokine secretion from T cells (such as IL2), enhancing NK-cell function. Conversely, blockade of KIRs can stimulate cytokine secretion from NK cells (such as IFNγ), enhancing myeloid and T-cell antitumor function (40).

Lirilumab (IPH2102, BMS-986015, BMS-986015-01):

Lirilumab (Innate Pharma and Bristol-Myers-Squibb), is a fully human IgG4 mAb directed against a common epitope shared by KIR2D (i.e., anti-KIR2DL1–3 effect; ref. 69). This is identical to the structure of IPH2101 (previously developed in malignant hematology) except for one mutation introduced into the constant region of the heavy chain to increase yield and prevent half-antibody formation that can occur with human IgG4 (69). Lirilumab is being evaluated in both solid and hematologic malignancies (leukemia, lymphoma, and multiple myeloma).

In a phase I study, 136 patients with refractory advanced solid tumors were treated with lirilumab in combination with nivolumab (N = 136, NCT01714739) or ipilimumab (N = 22, NCT01750580; refs. 70, 71). TRAEs occurred in approximately 70% of patients in each cohort and most commonly were fatigue, pruritus, infusion reaction, nausea/vomiting, rash, and diarrhea. Grade 3–4 TRAEs occurred in 13% of the nivolumab cohort and 9% of the ipilimumab cohort, including grade 4 thrombocytopenia (N = 1), grade 3 pancreatitis (N = 1), and grade 3 radiation skin injury (N = 1). Overall toxicity in the nivolumab cohort was similar to nivolumab monotherapy, with the exception of manageable infusion reactions. Among 29 response-evaluable patients with platinum-refractory HNSCC, ORR was 24% and DCR was 52%.

A separate phase I trial included patients with both hematologic (N = 22) and solid malignancies (breast N = 6, ovarian N = 7, pancreatic N = 1, and endometrial N = 1) treated with lirilumab (EudraCT 2009-011526-33; ref. 69). Among all patients (including those with hematologic malignancy), any grade TRAEs were primarily mild and occurred in 68% of patients. Most commonly these were pruritus (19%), asthenia (16%), fatigue (14%), infusion reaction (14%), and headache (11%). Grade 3–4 TRAEs occurred in 19% of patients and included elevated lipase, lymphopenia, presyncope, elevated bilirubin, abnormal liver function tests, urticaria, and angioedema. Among only solid tumor patients, ORR was 60% (4 breast cancer, 4 ovarian cancer, and 1 pancreas cancer). mPFS was not reached for breast cancer and 5.3 months for ovarian cancer. Additional phase I–II trials are currently recruiting patients with solid tumors (Table 3).

NKG2A-CD94/HLA-E

NK group 2 member A (NKG2A) and CD94 form a heterodimeric ITIM-containing (on NKG2A) inhibitory receptor, which is expressed on cytotoxic lymphocytes (NK cells and a subset of CD8+ T cells; refs. 10, 72–74). NKG2A is the first inhibitory receptor expressed during NK-cell development (66). After differentiation, NK cells may coexpress NKG2A with KIRs or NKG2A may be lost (66). The NKG2A-CD94 heterodimer recognizes the nonclassical MHC-I HLA-E, which is upregulated on both hematologic and solid tumors (10, 39, 43, 72). In contrast, classical MHC-I molecules are often downregulated on tumor, allowing immune evasion (73). Increased tumor expression of HLA-E has been associated with decreased NK-cell cytotoxicity and worse prognosis in both hematologic and solid cancers (39, 43). Synergistic antitumor effect with PD-(L)1 blockade has been noted in preclinical models, an effect which is dependent on both NK and CD8+ T cells (72).

Monalizumab (IPH2201):

Monalizumab (Innate Pharma and AstraZeneca) is a humanized IgG4 mAb which binds to the NKG2A-CD94 heterodimeric receptor, blocking its interaction with HLA-E and promoting effector NK- and CD8+ T-cell functions (39, 73). In preclinical studies, monalizumab alone promoted NK-cell cytotoxicity, monolizumab with durvalumab promoted NK- and CD8+ T-cell effector functions, and monalizumab with cetuximab enhanced NK cell–mediated ADCC (72, 73). Monalizumab is being evaluated in solid tumors (primarily colorectal cancer, HNSCC, NSCLC, and gynecologic cancer), often in combination with anticancer antibodies and/or anti-PD-(L)1 agents.

Initially, 55 patients with refractory advanced solid tumors [including 40 patients with microsatellite stable (MSS) metastatic colorectal cancer (mCRC) in dose expansion] were treated with monalizumab and durvalumab (NCT02671435; ref. 75). In the colorectal cancer expansion cohort, among 37 response-evaluable patients, ORR was 8% and DCR was 38%. In the entire population, 48% had any grade TRAEs (diarrhea most common) and grade ≥3 TRAEs were rare.

Development in colorectal cancer was continued. In a phase I/II study of treatment-naïve MSS mCRC, 18 patients were treated with monalizumab + durvalumab + FOLFOX + bevacizumab and 17 patients were treated with monalizumab + durvalumab + FOLFOX + cetuximab (RAS/BRAF wild-type and left-sided tumor only; NCT02671435; refs. 76, 77). ORR and DCR, respectively, were 41% and 88% in the bevacizumab cohort and 53% and 88% in the cetuximab cohort. Any TEAE occurred in nearly all patients. In the bevacizumab cohort, the most common TEAEs were fatigue, nausea, and peripheral neuropathy (any TEAE grade ≥3 78%). In the cetuximab cohort, the most common TEAEs were peripheral neuropathy, rash, and dermatitis acneiform (any TEAE grade ≥3 71%).

Monalizumab monotherapy was also evaluated in a phase II trial in refractory advanced HNSCC, where 27 patients [100% prior platinum, 59% prior anti-PD-(L)1 agent] (UPSTREAM, NCT03088059; ref. 78). The site of primary tumor included oral cavity, oropharynx, hypopharynx, and larynx. ORR was 0%, DCR was 22%, median PFS was 7.4 weeks, and median OS was 28 weeks. Grade 3 or higher TEAEs occurred in 59% of patients; however, none were attributed to treatment. Prespecified ORR was not met and the study was closed at interim analysis for futility.

Development in HNSCC was continued, but in combination with cetuximab. In a multicenter phase I/II trial, 40 patients with recurrent or metastatic HNSCC [100% prior platinum, 45% prior anti-PD-(L)1 agent, 13% prior cetuximab, and no more than two prior lines of therapy for advanced disease] were treated with monalizumab and cetuximab (NCT02643550; refs. 79–81). ORR was 28% [36% in anti-PD-(L)1-naïve patients and 17% in anti-PD-(L)1-experienced patients]. Among all patients, median duration of response was 5.6 months, median PFS was 4.5 months, and median OS was 8.3 months. Treatment was well tolerated. The most common monalizumab-related AEs were fatigue (17%), pyrexia (13%), and headache (10%). Six percent of TRAEs were grade 3–4. In a separate expansion cohort, 40 patients with recurrent or metastatic HNSCC previously treated with both platinum and an anti-PD-(L)1 agent were treated with monalizumab and cetuximab, and early results show ORR 20% (all PR) (82). A randomized phase III trial of monalizumab and cetuximab is recruiting in this population (Table 3).

In addition, 58 patients with refractory advanced gynecologic malignancies (platinum-sensitive ovarian, platinum-resistant ovarian, squamous cervical, and epithelial endometrial carcinoma) were treated with monalizumab monotherapy (NCT02459301; ref. 83). Antitumor efficacy was poor. ORR and DCR, respectively, in the dose-ranging cohort were 0% and 41% and in the dose-expansion cohort were 0% and 18%. Overall treatment was well tolerated and none of the AEs were felt to be immune mediated. The most common TRAEs were headache, fatigue, nausea/vomiting, and abdominal pain (>15% each). Grade ≥3 TRAEs included lymphopenia (19%), anemia (16%), vomiting (5%), fatigue (3%), and neutropenia (2%).

While immune checkpoint inhibitors targeting the PD-(L)1 and CTLA-4 axes have revolutionized cancer treatment, novel immune-based therapies are desperately needed. Innate immune checkpoint inhibitors alone or in combination (with anticancer antibodies or adaptive immune checkpoint inhibitors) are a promising novel anticancer strategy. These drugs can unleash the innate immune system against tumor, generating phagocytosis and natural cytotoxicity (both of which can be enhanced with the addition of an anticancer antibody), and synergistically activate the adaptive immune system via antigen presentation (often combining well with adaptive immune checkpoint inhibitors).

As repeatedly noted, there is considerable overlap in checkpoint expression and effects of checkpoint modulation between the innate and adaptive immune systems. TIM-3 and LAG-3 are inhibitory receptors expressed on both innate and adaptive immune cells (10, 11, 84, 85). While they serve primary as adaptive immune checkpoints (with blockade resulting in T-cell stimulation), there is evidence of innate immune effects (86–89). There are many areas of ongoing and future research, and studies may elucidate a larger role of these checkpoints in antitumor efficacy.

Phagocytosis and NK-cell checkpoint inhibitors are currently being evaluated in clinical trials with solid tumor safety and efficacy data summarized here. In specific solid tumor types, several agents have demonstrated promising early efficacy signals (ALX148 in HNSCC and gastric cancer, tiragolumab and vibostolimab in NSCLC, and monalizumab in colorectal cancer and HNSCC). Currently, phase III trials are underway for tiragolumab (esophageal SCC and NSCLC) and monalizumab (HNSCC). While clinical development is still early and ongoing monitoring is needed, innate immune checkpoint inhibitors (as monotherapy) do not appear to frequently cause immune-related AEs, as inhibitors of PD-(L)1 and CTLA-4 do, likely due to low expression of prophagocytic signals on normal tissues (90, 91). In addition, strategies have been developed to mitigate on-target toxicities, such as cytopenias seen with anti-CD47 agents.

The development of innate immune checkpoint inhibitors continues at a rapid pace. Tables 2 and 3 list the active clinical trials on ClinicalTrials.gov and there are many additional compounds in preclinical development. The use of novel genetic screening techniques may identify additional cell-surface regulators of innate immune cell function, serving as new therapeutic targets (92). Innate immune checkpoint inhibitors are an exciting new therapeutic class in both solid and hematologic malignancies that have the potential to expand the use of immunotherapy in many cancer types, significantly improving patient outcomes.

R.W. Lentz reports grants from NIH during the research and preparation of the manuscript. S.S. Mitra reports nonfinancial support from 47Inc during the research and preparation of the manuscript; in addition, S.S. Mitra has a patent for Treatment of Pediatric Brain Tumors with Targeting of CD47 Pathway pending to Siddhartha Mitra. W.A. Messersmith reports other from ALX Therapeutics during the research and preparation of the manuscript. No disclosures were reported by the other authors.

This work was supported by NIH NRSA T32CA236734 (to R.W. Lentz).

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