Immunotherapy in human colorectal cancer: Challenges and prospective

Table 1 Gene mutations in human colorectal cancer

Pathways	Cell cycle	WNT	MAPK	TGF	P53	PI3K-Akt	Apoptosis
Genes	MLH1[71]	APC[71]	KRAS[72]	SMAD4[73]	P53[74]	PTEN[75]	DCC[76]
	MSH2[71]	CTNNB1[77]	PLA2G2A[78]			NRAS[79]	BAX[80]
	MSH6[81]	MCC[82]	PTPN12[83]			PIK3CA[84]
	RAD54B[85]	AXIN2[86]				FGFR3[87]
	CCND1[88]	ARID1A				AKT1[89]
	BUB1B[90]	SOX9
	AURKA[91]
	EP300[92]

MLH1: MutL homolog 1; MSH2: MutS homolog 2; MSH6: MutS homolog 6; RAD54B: RAD54 homolog B (S. Cerevisiae); CCND1: Cyclin D1; BUB1B: BUB1 mitotic checkpoint serine/threonine kinase B; AURKA: Aurora kinase A; EP300: E1A binding protein P300; PC: Adenomatous polyposis coli; CTNNB1: Catenin (cadherin-associated protein), Beta 1, 88 kDa; MCC: Mutated in colorectal cancers; AXIN2: Axin 2; ARID1A: AT rich interactive domain 1A (SWI-Like); SOX9: SRY (sex determining region Y)-Box 9; KRAS: Kirsten rat sarcoma viral oncogene homolog; PLA2G2A: Phospholipase A2, group IIA (platelets, synovial fluid); PTPN12: Protein tyrosine phosphatase, non-receptor type 12; SMAD4: SMAD family member 4; P53: Tumor protein P53; PTEN: Phosphatase and tensin homolog; NRAS: Neuroblastoma RAS viral (V-Ras) oncogene homolog; PIK3CA: Phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha; FGFR3: Fibroblast growth factor receptor 3; AKT1: V-Akt murine thymoma viral oncogene homolog 1; DCC: DCC netrin 1 receptor; BAX: BCL2-associated X protein.

Table 2 Completed clinical trials of immunotherapy in human colorectal cancer

Ref.	Clinical phase	No. patients	Clinical setting	Immunotherapy	Comments
Morse et al[93]	II	74	Liver or lung metastases from CRC removed by surgery	PANVAC-V + PANVAC-F + DC/PANVAC-V + PANVAC-F + GM-CSF	Good safety record
Vermorken et al[44]	II and III	254	Colon cancer	Active specific immunotherapy (ASI) with an autologous tumor cell- bacillus Calmette-Guérin (BCG) vaccine with surgical resection/resection alone	ASI gave significant clinical benefit in surgically resected patients in stage II colon cancer
	Dukes' stage B2-C3	80	Colon or rectal cancer	ASI with an autologous tumor cell-BCG vaccine	ASI may be beneficial to patients with colon cancer
Hanna et al[94]	Stage II and Stage III		Colon cancer	ASI consisting of autologous tumor cells mixed with BCG (OncoVAX™)	Increase 5-yr survival rate and 5-yr disease-free survival rate, reduce recurrence rate
Marshall et al[95]	Stage IV		Colon cancer	ALVAC-CEA	Safe and can elicit CEA-specific CTL responses
Harris et al[96]	Stage II and stage III	412	Colon cancer	Adjuvant active specific immunotherapy with an autologous tumor cell-BCG vaccine	More beneficial than resection alone

Table 3 Ongoing immunotherapy clinical trials in human colorectal cancer

Type	Cancer	Phase	Name	Identifier	Start time
Monoclonal antibodies	Untreated metastatic colorectal cancer	II	RO5520985 (a bispecific anti-ANG-2/anti-VEGF-A	NCT02141295	5/15/2014
	Colorectal cancer	I/II	IMMU-132 (an Ab-drug conjugate targeting Τrop-2)	NCT01631552	6/26/2012
	Metastatic colorectal cancer	I/II	IMMU-130 (an Ab-drug conjugate targeting CEACAM5)	NCT01605318	5/22/2012
	Metastatic colorectal carcinoma	I	MGD007 (a dual-affinity re-targeting DART protein designed to target the glycoprotein A33)	NCT02248805	9/18/2014
	Metastatic colorectal cancer	I	OMP-131R10 (an anti-RSPO3 Ab)	NCT02482441	6/19/2015
Immune checkpoint inhibitors	MSI positive/negative colorectal cancer	II	MK-3475 (an Ab that blocks negative signals on T cells)	NCT01876511	6/10/2013
	MSI positive colorectal cancer	I	Ipilimumab	NCT02060188	12/18/2013
	MSI negative colorectal cancer	II	Nivolumab	NCT02060188	12/18/2013
	Colorectal cancer	I	MED14736	NCT01975831	10/29/2013
	Colon cancer	I/II	Anti-CD27 (Varlilumab) and Nivolumab	NCT02335918	12/18/2014
Cancer vaccines	Metastatic colorectal cancer	II	DC vaccine	NCT02615574	11/24/2015
	Colorectal cancer	I	AVX701 (targets CEA)	NCT01890213	6/26/2013
	Metastatic colorectal carcinoma	I	SGI-110 in combination with an allogeneic colon cancer cell vaccine (GVAX) and cyclophosphamide (CY)	NCT01966289	10/10/2013
	Colorectal cancer	I	HER-2 vaccine	NCT01376505	6/9/2011
Adoptive cell therapy	Metastatic colorectal cancer	II	TIL (tumor-infiltrating lymphocytes)	NCT01174121	7/31/2010
	Colorectal cancer	I/II	Anti-MAGE-A3-DP4 TCR	NCT02111850	4/9/2014
	Colorectal carcinoma	I/II	CAR T cells	NCT02617134	11/26/2015
	Colorectal cancer	I	NK cells + CliniMACs CD3 and CD56 systems	NCT00720785	7/22/2008
Oncolytic virus therapies	KRAS mutant metastatic Colorectal cancer	I	REOLYSIN in combination with FOLFIRI and Bevacizumab	NCT01274624	1/7/2011
Adjuvant immunotherapies	Recurrent colorectal cancer	I/II	Chemokine modulatory regimen	NCT01545141	2/29/2012
Cytokines	Colorectal carcinoma	I	AM0010 (a recombinant human IL-10)	NCT02009449	12/2/2013
	Colorectal carcinoma	I	Rh IL-15	NCT01572493	4/5/2012