Table 2.
Antibodies/antigenic composition
|
Origin
|
Target/CRC stage
|
Approval date/trial number/yr
|
Description/interventions
|
Inference
|
Monoclonal antibodies | |||||
Cetuximab | Chimeric | EGFR | February 12, 2004 | Cetuximab alone for mCRC | Adding cetuximab to first-line chemotherapy in patients with WT KRAS mCRC was statistically beneficial for OS and PFS[153] |
July 6, 2012 | For mCRC cetuximab + FOLFIRI | ||||
Panitumumab | Humanized | EGFR | September 27, 2006 | For mCRC panitumumab + FOLFOX for WT KRAS mCRC. For WT RAS mutation mCRC | In WT KRAS mCRC, PFS was improved, objective response was higher, and there was a trend toward improved OS with panitumumab-FOLFOX4[42,43,154] |
May 23, 2014 | |||||
June 29, 2017 | |||||
Nimotuzumab | Humanized | EGFR | NCT05278728. Completed | Phase II study nimotuzumab along with radiotherapy and concurrent capecitabine | No significant outcomes |
NCT05278728. Completed | Phase IIa study of nimotuzumab to treat CRC | Ongoing | |||
Necitumumab | Human | Cetuximab-resistant EGFR | NCT00835185. Completed | Phase II study necitumumab plus modified FOLFOX6 for locally advanced and mCRC | First-line necitumumab + mFOLFOX6 was active with manageable toxicity in locally advanced or mCRC |
Bevacizumab | Humanized | VEGF | February 26, 2004 | For mCRC | The addition of bevacizumab to 5-fluorouracil-based combination significantly increased patient survival[155,156] |
Ramucirumab | Human | VEGFR-2 | April 24, 2015 | Ramucirumab with FOLFIRI as second-line treatment for mCRC | The addition of ramucirumab to FOLFIRI improved patient outcomes in the RAISE trial[157] |
Nivolumab | Human | PD-1 | August 1, 2017 | Nivolumab approved for MSI-H/dMMR mCRC | Nivolumab provided durable responses and disease control in pre-treated patients with dMMR/MSI-H mCRC[51] |
Ipilimumab | Human | CTLA-4 | July 11, 2018 | Nivolumab plus low dose ipilimumab approved for previously treated MSI-H/dMMR mCRC | Clinical effect with nivolumab + low-dose ipilimumab was significant and long-lasting for MSI-H/dMMR mCRC[57] |
Cemiplimab | Human | PD-1 | NCT04157985. Ongoing | Phase III study: evaluating length of treatment with cemiplimab and other inhibitors in solid tumor patients | Ongoing |
Atezolizumab | Humanized | PD-L1 | NCT02788279. Completed | Phase III study: atezolizumab with or without cobimetinib vs regorafenib in previously treated mCRC | Did not meet its primary endpoint of improved OS with atezolizumab plus cobimetinib or atezolizumab vs regorafenib |
NCT05118724. Ongoing | Phase II study: atezolizumab with/without IMM-101 in patients with MSI-H/dMMR stage III CRC ineligible for oxaliplatin | Ongoing | |||
NCT05456165. Ongoing | Phase II study: atzolizumab in combination with neoantigen targeting vaccine | Ongoing | |||
Avelumab | Human | PD-L1 | NCT03854799. Ongoing | Phase II study: avelumab + capecitabine combined with radiation | Ongoing |
NCT03475953. Ongoing | Phase I/II Study: regorafenib plus avelumab in solid tumors | Ongoing | |||
Dostarlimab | Humanized | PD-1 | NCT04165772. Ongoing | PD-1 blockade in dMMR, locally advanced rectal cancer | Ongoing: dMMR, locally advanced rectal cancer was highly sensitive to single-agent PD-1 blockade. Longer follow-up is needed to assess the duration of response |
Pembrolizumab | Humanized | PD-1 | June 29, 2020 | Pembrolizumab for first-Line treatment of patients with unresectable or metastatic MSI-H or dMMR CRC | Approved based on Phase III Keynote-117 Trial in which pembrolizumab significantly reduced the risk of disease progression or death by 40%[158] |
Relatimab | Human | LAG-3 | NCT05328908. Ongoing | Phase III study of nivolumab-relatlimab fixed-dose combination vs regorafenib or TAS-102 in participants with mCRC | Ongoing |
NCT03642067. Ongoing | Study of nivolumab and relatlimab in patients with MSS advanced CRC | Ongoing | |||
Peptide based vaccines[80] | |||||
SART3 | - | Metastatic | 2001 | Used with adjuvant incomplete Freund’s adjuvant | Increased cellular immune responses to both CRC cells and the vaccinated peptide |
Recombinant Ep-CAM (with liposome carrier) | - | I-III | 2001 | Used with adjuvant alum | The overall immune response was safe and effective for patients with CRC and advanced cancer against Ep-CAM |
II-IV | 2004 | Used with adjuvant GM-CSF | |||
Metastatic | 2004 | Used with adjuvant GM-CSF | |||
CTP37-DT | - | III-IV | 2002 | Used with adjuvant Nor-MDP (Muramyl dipeptide) | Longer OS with an excellent safety profile in patients with CRC |
Recombinant CEA expressed in baculovirus system | Expressed in baculovirus-insect cell system | Stage I-III | 2004 | Used with adjuvant alum and GM-CSF | Potent and long lasting antigen specific IgG and T cell response |
Survivin-2B Human | - | Metastatic | 2004 | Used with adjuvant UFT (uracil-tegafur) | Excellent safety profile with potent immune response against HLA-A24-expression in patients with CRC |
G17DT (N-terminus of gastrin 17) | - | Metastatic | 2014 | Used with adjuvant diphtheria toxoid | In combination with irinotecan this vaccine has an acceptable immune response with significantly longer survival |
OCV-C02 | - | Metastatic | 2017 | Two peptide epitopes derived from RNF43 and TOMM34 and used with adjuvant montanide ISA 51 | Safe immune response in recurrent or advanced stage CRC patients resistant to standard chemotherapy |
RNF43 and TOMM34-derived peptides | - | III | 2018 | Used with uracil-tegafur/leucovorin, montanide ISA 51 | Strong immune response with increased OS in patients with stage III CRC |
PolyPEPI1018 | - | Metastatic | 2020 | Used with adjuvant montanide ISA 51 Human | Safe and well-tolerated and induced robust CRC-specific T cell responses, similar to personalized neoantigen vaccines |
mRNA-based vaccines[80] | |||||
NCI 4650 (mRNA 4650) | - | Metastatic | 2019 | - | Partly safe and neoantigen specific CD8 and CD4 T cells responses against CRC neoepitopes |
mRNA 4157 | - | Metastatic | 2019 | In combination with pembrolizumab | Partly safe and strong neoantigen specific T cell responses against CRC neoepitopes |
V 941 (mRNA 5671) | - | Metastatic | 2019, NCT03948763 | In combination with pembrolizumab | KRAS vaccine clinical trial is underway, and the results are eagerly awaited |
RO 7198457 (RG 6180) | - | Metastatic | 2020 | In combination with atezolizumab | Partly safe and strong neoantigen specific immune responses |
Cell based vaccines[80] | |||||
Tumor cell | Tumor cell | II and III | 2000 | In combination with BCG | Less potency with 5-yr OS of 84.6% |
Cancer Vax | Tumor cell | IV | 2001 | In combination with BCG | Significant increase in anti-TA90 IgG and IgM titers, and the OS was 21.9 mo |
HSPPC-gp96 | Tumor cell | IV | 2003 | - | Two-year overall survival and disease-free survival improved |
CEA mRNA | DCs | IV | 2003 | In combination with IL-2 | Well tolerated and safe immunization observed in patients with advanced malignancies |
OPA-DC | DCs | Metastatic | 2011 | CEA peptide-loaded DCs matured with a combination of OK432, prostanoid, and interferon-α | Increased CEA-specific cytotoxic T cell response and NK cell levels in 8 patients with stable disease |
Autologous tumor lysate DC (ADC) | DCs | Metastatic | 2016 | - | Not recommended: the use of ADC alone, in a phase III trial |
Autologous tumor antigens-loaded DC | DCs | Metastatic | 2018 | In combination with 5-fluorouracil | Treatment was safe and had shown particularly prominent IL-12 production for immunization against neoantigens |
Vector based vaccines | |||||
ALVAC-CEA/B7 | Canary pox virus vector | Metastatic | 2008; 2013 | In combination with chemotherapy | Acceptable safety profile and induced CEA-specific T cell responses in patients with mCRC |
AVX701 | Alphavirus vector | III | 2010 | VRP expressing CEA | Well tolerated and elicit robust CEA-specific T cell and antibody responses in patients with CRC |
GI-6207 | Saccharomyces cerevisiae | Metastatic | 2014 | - | Strong antigen-specific CD8+ T cells and CD4+ T responses and extended stable disease |
GI-6301 | Saccharomyces cerevisiae | Metastatic | 2015 | - | Decreased tumor density and serum CEA levels in CRC treated patients |
pLADD | Listeria monocytogenes | Metastatic | 2017, NCT03189030 | Listeria bacterial vector in combination with neoantigens | Induced neoantigen-specific CD8+ T cells and gamma delta T cells |
Cholera | Bacteria | I-IV | 2018 | - | Cholera vaccination largely decreased the mortality rate of CRC |
GI-4000 | Saccharomyces cerevisiae | Metastatic | 2018 | - | Excellent safety profile and favorable immunogenicity in the majority of subjects |
ADXS-NEO | - | Metastatic | 2019 | Bacteria expressing personalized tumor antigens | Increased CD4+/CD8+ T cell-mediated immune response |
ADC: Antibody drug conjugate; BCG: Bacillus Calmette–Guérin; CEA: Carcinoembryonic antigen; CRC: Colorectal cancer; CTLA-4: Cytotoxic T-Lymphocyte-associated antigen-4; DCs: Dendritic cells; dMMR/MSI-H: Microsatellite instability high and deficient mismatch repair; EGFR: Epidermal growth factor receptor; Ep-CAM: Epithelial cell adhesion molecule; FOLFIRI: 5-flurouracil, leucovorin, and irinotecan; FOLFOX4/6: 5-flurouracil, leucovorin, and oxaliplatin; GM-CSF: Granulocyte macrophage colony-stimulating factor; HLA: Human leukocyte antigen; HSPPC-gp96: Heat shock protein peptide glycoprotein Complex-96; Ig: Immunoglobin; IL: Interleukin; LAG-3: Lymphocyte activation gene 3; mCRC: Metastatic colorectal cancer; MSS: Microsatellite stable; NK: Natural killer cell; Nor-MDP: Nor-muramyl dipeptide; OS Overall survival; PFS: Progression-free survival; PD-1: Programmed cell death receptor 1; PD-L1: Programmed cell death ligand 1; RNF43: Ring finger protein 43; SART3: Squamous cell carcinoma antigen identified by T cells 3; TOMM34: Translocase of outer mitochondrial membrane 34; VEGF: Vascular endothelial growth factor; VEGFR: Vascular endothelial growth factor receptor; WT: Wild-type.