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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
  1. BC, Breast cancer; BCC, basal cell carcinoma; CRC, colorectal cancer; CSCC, cutaneous squamous cell carcinoma; CTLA-4, cytotoxic T lymphocyte-associated molecule-4; HCC, hepatocellular carcinoma; HL, Hodgkin lymphoma; HNSCC, Head and neck squamous cell carcinoma; ICI, immune checkpoint inhibitor; MCC, Merkel cell carcinoma; MMR, mismatch repair; MSI, microsatellite instability; NSCLC, non-small cell lung cancer; NK, natural killer; PD-1, programmed cell death receptor-1; PD-L1, programmed cell death receptor-1 ligand; RCC, renal cell carcinoma; SCC, squamous cell carcinoma; SCLC, small cell lung cancer; TMB, tumor mutational burden; TME, tumor microenvironment