Current and emerging therapeutic approaches for colorectal cancer: A comprehensive review

Table 2 Immunotherapeutic agents and vaccines against colorectal cancer

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.