Table 1.
Myeloid and NK target therapies tested in clinical studies.
| Target | Mechanism of Action | Modality | Drugs/Company | Dose regimen | Current clinical status | Combinations | Indications | Clinical trial number |
|---|---|---|---|---|---|---|---|---|
| CCR2 | CCR2 is expressed by monocytes and macrophages and interacts with CCL2 to mediate chemotaxis of monocytes and TAMs, promoting tumor progression | Small molecule | PF-04136309 (Pfizer) | Continuous | Discontinued post-phase 1b/2 | Folfirinox | Pancreatic ductal adenocarcinoma | NCT01413022 |
| Nab-paclitaxel | NCT02732938 | |||||||
| CSF1R | CSF1 receptor (CSF1R)-mediated signaling is crucial for the differentiation, recruitment, and survival of the mononuclear phagocyte system and macrophages | Small molecule | Pexidartinib (Turalio) (PLX7486), Daiichi Sankyo | Continuous | Phase 2/approved | Monotherapy | Tenosynovial giant cell tumor | NCT01804530 |
| Small molecule | JNJ-40346527 (J&J) | 21-day cycle or PO BID for 4–5 weeks | Discontinued after phase 1b/2 | Monotherapy | Relapsed or refractory Hodgkin lymphoma | NCT01572519 | ||
| Relapsed or refractory AML | NCT03557970 | |||||||
| Surgery | Advanced Prostate Cancer | NCT03177460 | ||||||
| Small molecule | ARRY-382 (Array/Pfizer) | 21-day treatment cycles | Phase1b | Keytruda (anti–PD-1 antibody) | Relapsed or refractory Hodgkin lymphoma, AML | NCT02880371 | ||
| NCT01316822 | ||||||||
| Small molecule | BLZ945 (Novartis) | Phase I (ongoing) | PDR001 (anti–PD-1) | Advanced solid tumors | NCT02829723, NCT02404441 | |||
| Antibody | RG7155/emactuzumab (Roche) | IV Q3W | Phase 2 | Atezolizumab (anti–PD-L1 mAb) | Advanced solid tumors | NCT02323191 | ||
| Selicrelumab (anti-CD40) | NCT02760797 | |||||||
| Paclitaxel and bevacizumab | Platinum-resistant ovarian cancer | NCT02923739 | ||||||
| Antibody | AMG 820-mAb (Amgen) | IV weekly | Phase 1/2 | Pembrolizumab (anti–PD-1 mAb) | Advanced solid tumors |
NCT02713529, NCT01444404 |
||
| Antibody (human mAb) | LY3022855 (Lilly) | IV Q4W | Phase 1 | Durvalumab (anti–PD-L1 mAb) or tremelimumab (anti–CTLA-4 mAb) | Advanced solid tumors | NCT02718911 | ||
| GVAX | ||||||||
| Pancreatic cancer | NCT03153410 | |||||||
| CXCR2/IL8 axis | CXCR2 plays a critical role in the regulation of neutrophil homeostasis and recruitment to the tumor | Small molecule | AZD5069 (AstraZeneca) | Continuous + PD-L1 | Phase1/2 | Durvalumab (anti–PD-L1 mAb) | Head & neck/pancreatic cancer | NCT02499328, NCT02583477 |
| Enzalutamide | mCRPC | NCT03177187 | ||||||
| Antibody | HuMax-IL8/BMS-986253 (BMS) | IV Q2W | Phase1/2 | Nivolumab + degarelix | Hormone-sensitive prostate cancer | NCT03689699 | ||
| Nivolumab | ||||||||
| HCC | NCT04050462 | |||||||
| metastatic or unresectable solid tumors | NCT03400332 | |||||||
| NSCLC/HCC | NCT04123379 | |||||||
| Small molecule | Navarixin/MK-7123 (Merck) | IV infusion on day 1 of each 3-week cycle | Phase 2 | Pembrolizumab | Advanced/metastatic solid tumors | NCT03473925 | ||
| Small molecule | SX-682 (Syntrix Pharmaceuticals) | SX-682 monotherapy for 21 days, then 90 days with pembro | Phase 1 | Pembrolizumab | Metastatic melanoma | NCT03161431 | ||
| Reparixin (IL-8) (Dompe) | Phase 2; discontinued | Paclitaxel | HER2– breast cancer | NCT02001974 | ||||
| NCT02370238 | ||||||||
| Small molecule | NCT01861054 | |||||||
| PI3Kγ | PI3Kγ signaling promotes macrophage pro-inflammatory profile and anti-tumor activity | Small molecule | Eganelisib (IPI-549) | Continuous | Phase 2 | Nivolumab | Advanced urothelial carcinoma | NCT03980041 UC |
| Tecentriq and abraxane (TNBC)/bevacizumab (RCC) | TNBC and RCC | NCT03961698 RCC | ||||||
| AB928 (A2ARi)/pegylated liposomal doxorubicin (PLD)/nanoparticle albumin-bound paclitaxel (NP) | TNBC and ovarian cancer | |||||||
| NCT03719326 TNBC/OV | ||||||||
| NCT03719326 TNBC/GC | ||||||||
| CCL2 | CCL2 chemokine interacts with CCR2 in monocytes and macrophages, impairing migration | Antibody (human mAb) | Carlumab (CNTO888) | IV Q2W | Phase 2 | Monotherapy | MCRP | NCT00992186 |
| Chemotherapy (SoC) | advanced solid tumors | NCT01204996 | ||||||
| CD47/CD47-SIRPα | Promotes the adaptive immune response and enhances the phagocytosis of tumor cells by macrophages | Antibody (hu mAb) | Magrolimab (Hu5F9-G4)/Gilead Sciences | IV every 3 cycles | Phase 3 | Azacitidine | MDS | |
| AML | NCT03248479 | |||||||
| DLBCL | ||||||||
| FL | ||||||||
| Antibody (hu mAb) | CC-90002/Celgene | IV infusion on a 28-day cycle | Phase 2 | Rituximab | Advanced solid and hematologic cancers | DOI: 10.1056/NEJMoa1807315 | ||
| NCT02367196 | ||||||||
| NK2GA | NKG2A/CD94 are inhibitory receptors expressed on T and NK cells. Inhibition of interaction with HLA-E relieves inhibitory signals and leads to cell activation and cytotoxicity | Antibody (hu mAb) | Monalizumab | IV | Phase 1/2 Phase 3 | Durvalumab (MEDI4736) | advanced solid tumors | NCT02671435 |
| Ibrutinib | Relapsed, refractory or previously untreated CLL | |||||||
| Durvalumab | Advanced NSCLC (resistance CPI) | NCT02557516 | ||||||
| Durvalumab | NSCLC | NCT03833440 | ||||||
| Durvalumab | Resectable NSCLC | NCT03822351 | ||||||
| Cetuximab | Metastatic HNSCC | NCT03794544 | ||||||
| NCT02643550 | ||||||||
| Cetuximab | Recurrent or metastatic HNSCC | NCT04590963 | ||||||
| CD30xCD16a | AFM13 is a bispecific, tetravalent chimeric antibody designed for the treatment of CD30-expressing malignancies. AFM13 recruits NK and macrophage cells via binding to CD16A as immune effector cells. https://dx.doi.org/10.1182%2Fblood-2014-12-614636 | Affimed | AFM13 | Weekly IV | Phase 2 | Pembrolizumab | Relapsed or refractory classical Hodgkin lymphoma | NCT02665650 |
| Weekly IV | Phase 1/2 approved (orphan drug designation) | Peripheral T-cell lymphoma | NCT04101331 | |||||
| EGFRxCD16A | AFM24 NK-cell–engaging bispecific antibodies to target EGFR-expressing tumor cells irrespective of their mutational status. | Bispecific engager | Affimed (AFM24) | Weekly IV | Phase 1 | Advanced solid cancers | NCT04259450 | |
| BCMAxCD16a | Bispecific antibody (IgG-scFv) targeting B-cell maturation antigen and CD16a (FcγRIIIA) being developed for treatment of multiple myeloma | Bispecific engager | Roche (RO7297089) | Weekly IV | Phase 1 | Multiple myeloma | NCT04434469 | |
| HER2 x NKG2D x CD16A | HER2 trispecific NK cell engager; binds to HER2 on tumor cells and simultaneously binds to NK cells | Trispecific engager | Dragonfly Therapeutics (DF1001) | Phase 1/2 | Pembrolizumab | Advanced solid tumors | NCT04143711 | |
| KIR2DL-1, -2, -3 | Inhibits major inhibitory receptors on NK cells | Humanized mAb | Innate Pharma/BMS (IPH2102/BMS-986015/lirilumab) | 4 cycles Q4W IV | Phase 1/2 | Ipilimumab or nivolumab | Advanced solid tumors | NCT01750580 NCT01714739 |
| CD16/IL-15/CD33 | Trispecific scFv recombinant fusion protein conjugate composed of heavy and light chains of anti-CD16 and anti-CD33 antibodies and human IL-15 | Trispecific engager | GT Biopharma (GTB-3550) | 3x weekly IV | Phase 1/2 | High-risk heme malignancies | NCT03214666 |
AML, acute myeloid leukemia; BID, twice daily; CLL, chronic lymphocytic leukemia; CPI, checkpoint inhibitor; EGFR, epithelial growth factor receptor; HCC, hepatocellular carcinoma; HNSCC, head and neck squamous cell carcinoma; IV, intravenous; mAb, monoclonal antibody; m-CRPC, metastatic castration-resistant prostate cancer; MDS, myelodysplastic syndrome; NP, nonpegylated; NSCLC, non–small-cell lung carcinoma; PLD, pegylated liposomal doxorubicin; PO, orally; PTCL, peripheral T-cell lymphoma; Q2W, Q3W, Q4W, every 2, 3, 4 weeks; RCC, renal cell carcinoma; scFv, single-chain variable fragment; SoC, standard of care; TNBC, triple-negative breast cancer.