Table 1 Existing immune checkpoint inhibitors and new immune inhibitory molecules
From: Next generation of immune checkpoint inhibitors and beyond
Target | Agent | Mechanism of action | Indications | Advantages | Limitations | |
|---|---|---|---|---|---|---|
FDA-approved immune checkpoint inhibitors | CTLA-4 | Ipilimumab | Inhibits CTLA-4 and allows T cell activation | CRC (in combination with nivolumab), HCC (in combination with nivolumab), melanoma (alone or in combination with nivolumab), mesothelioma (in combination with nivolumab), NSCLC (in combination with nivolumab), RCC (in combination with nivolumab) | Often better tolerated than chemotherapy - Used in a variety of solid and hematologic malignancies - Durable responses Potential for “cure” even in metastatic disease FDA-approved - Biomarkers available to predict response to therapy | Only a small proportion of patients benefit - Limited in cancers with “cold” TMEs - Autoimmune-like toxicities: - Cytopenias - Diarrhea/colitis - Fatigue - Hepatitis - Hypophysitis - Hypothyroidism - Myocarditis - Nephritis - Pneumonitis - Rash/pruritus - Uveitis |
PD-1 | Cemiplimab | Inhibits PD-1 and allows T cell activation | BCC, CSCC, NSCLC | |||
Nivolumab | Inhibits PD-1 and allows T cell activation | CRC (alone or in combination with ipilimumab), esophageal SCC, HCC (alone or in combination with ipilimumab), HL, HNSCC, melanoma (alone or in combination with ipilimumab), mesothelioma (in combination with ipilimumab), NSCLC (alone or in combination with ipilimumab), RCC (alone or in combination with ipilimumab), urothelial carcinoma | ||||
Pembrolizumab | Inhibits PD-1 and allows T cell activation | BC, cervical cancer, CRC, CSCC, endometrial carcinoma, esophageal carcinoma, gastric carcinoma, HCC, HL, HNSCC, melanoma, mesothelioma, MCC, MSI-High/MMR-deficient/TMB-high cancers, NSCLC, large B cell lymphoma, RCC, SCLC, urothelial carcinoma | ||||
PD-L1 | Atezolizumab | Inhibits PD-L1 and allows T cell activation | BC, HCC, melanoma, NSCLC, SCLC, urothelial carcinoma | |||
Avelumab | Inhibits PD-L1 and allows T cell activation | MCC, RCC, urothelial carcinoma | ||||
Durvalumab | Inhibits PD-L1 and allows T cell activation | NSCLC, SCLC, urothelial carcinoma | ||||
New immune checkpoint inhibitors and other inhibitory targets | LAG-3 (CD223) | LAG525 (IMP701), REGN3767 (R3767), BI 754,091, tebotelimab (MGD013), eftilagimod alpha (IMP321), FS118 | Inhibit LAG-3 and allow T cell activation | NA | Often better tolerated than chemotherapy - Can be used to enhance response to other ICIs - Responses seen in therapy refractory disease - Some may work in “cold” TMEs - Novel biomarkers available to further personalize treatment | Clinical outcomes not available for some agents - May not be potent enough to be used as monotherapy - Best combination strategies and indications are unclear - Use with other ICIs may increase toxicities - Toxicities may be similar to those found with the use of existing ICIs: - Cytopenias - Fatigue - Rash/pruritus - Diarrhea/colitis - Hepatitis - Pneumonitis - Unique toxicities and areas of concern: - Antigen sink (CD47) - Increased risk of infections - Hemolytic anemia (CD47) - Infertility (LIF) - Myositis - Neurotoxicity (SEMA4D) - On-target, off-tumor toxicities - Poor wound healing |
TIM-3 | MBG453, Sym023, TSR-022 | Inhibit TIM-3 and allow T cell activation | ||||
B7-H3, B7-H4 | MGC018, FPA150 | Inhibit B7-H3 or B7-H4 and allow T cell activation | ||||
A2aR | EOS100850, AB928 | Inhibits A2aR and allow T cell and APC activation | ||||
CD73 | CPI-006 | Inhibit CD73 and allow T cell and APC activation | ||||
NKG2A | Monalizumab | Inhibits NKG2A and allows T cell activation | ||||
PVRIG/PVRL2 | COM701 | Inhibits PVRIG and allows T cell activation | ||||
CEACAM1 | CM24 | Inhibits CEACAM1 and allows T and NK cells activation | ||||
CEACAM 5/6 | NEO-201 | Inhibits CEACAM5 and 6 which allows T cell activation while interfering with tumor cell growth | ||||
FAK | Defactinib | Inhibits FAK and interferes with tumor growth | ||||
CCL2/CCR2 | PF-04136309 | Inhibits CCR-2 and allows T cell recruitment and activation | ||||
LIF | MSC-1 | Inhibits LIF and allows T cell and APC activation while interfering with cancer growth | ||||
CD47/SIRPα | Hu5F9-G4 (5F9), ALX148, TTI-662, RRx-001 | Inhibits CD47 or SIRPα and allows T cell and APC activation | ||||
CSF-1 (M-CSF)/CSF-1R | Lacnotuzumab (MCS110), LY3022855, SNDX-6352, emactuzumab (RG7155), pexidartinib (PLX3397) | Inhibits CSF-1 and allows APC activation | ||||
IL-1 and IL-1R3 (IL-1RAP) | CAN04, Canakinumab (ACZ885) | Inhibits IL-3 or IL-1RAP and allows T cell and APC activation | ||||
IL-8 | BMS-986253 | Inhibits IL-8 and decreases immunosuppressive TME while interfering with tumor growth | ||||
SEMA4D | Pepinemab (VX15/2503) | Inhibits SEMA4D and decreases immunosuppressive TME while interfering with tumor growth | ||||
Ang-2 | Trebananib | Inhibits Ang-2 and allows APC activation while interfering with cancer growth | ||||
CLEVER-1 | FP-1305 | Inhibits CLEVER-1 and allows APC activation | ||||
Axl | Enapotamab vedotin (EnaV) | Inhibits Axl and allows APC activation while interfering with cancer growth | ||||
Phosphatidylserine | Bavituximab | Inhibits phosphatidylserine and allows T cell and APC activation while interfering with cancer growth |