Dendritic cell-based cancer immunotherapy for colorectal cancer

Table 1 Clinical trials of dendritic cell-based cancer immunotherapy in patients with colorectal cancer

Targets	Immunotherapy	Phase	Patients	Results	Ref.	Year
CEA	DCs loaded with CEA peptide (HLA-A2 restricted)	I	21 advanced CEA-expressing malignancies including 11 CRC	Skin punch biopsy at DC injection sites demonstrated pleomorphic, perivascular infiltration of cells consistent with a DTH response	Morse et al[46]	1999
	DCs loaded with CEA mRNA	I	13 patients with resected hepatic metastases of CRC	9 of the 13 CRC patients relapsed at a median of 122 d	Morse et al[47]	2003
	DCs modified with a recombinant fowlpox vector encoding CEA and a triad of costimulatory molecules [rF-CEA(6D)-TRICOM]	I	14 patients with HLA-A2 (11 CRC and 3 non-small cell lung cancer)	CEA-specific T cells responses were detected in 10 patients; 5 patients were stable through at least 1 cycle of immunization (3 mo)	Morse et al[48]	2005
	Fowlpox vector encoding CEA	I	14 patients (5 CRC, 3 lung cancer, and 1 urachal adenocarcinoma)	Of the 9 patients analyzed, all with stable disease (n = 5) displayed increased NK activity	Osada et al[49]	2006
	Mature DCs induced by activation with a combination of OK-432, low-dose prostanoid, and IFN-α and loaded with CEA peptide		10 CRC patients	CRC patients with stable disease (n = 8) exhibited increased levels of NK cell frequency and CEA-specific CTL activity with a central memory phenotype. Lack of CTL activity was found in 2 CRC patients with progressive disease, but NK cell proliferation was detected	Sakakibara et al[51]	2011
	DCs loaded with altered CEA peptide (HLA-A2 restricted) with Flt3 ligand	I	12 patients with HLA-A2+ malignancies (10 CRC and 2 non-small cell lung cancer)	CEA-specific CD8+ CTLs were detected in 7 patients; 1 patient with progressive metastatic CRC had a complete resolution of pulmonary metastasis and malignant pleural effusion at 4 mo after vaccination, and 1 patient with CRC developed a mixed response after vaccination, with regression of some but not all liver metastases	Fong et al[52]	2001
	DCs loaded with CEA peptide (HLA-A24 restricted)	I	10 advanced CEA-expressing malignancies including 7 CRC	2 patients (CRC and lung cancer) exhibited positive DTH reactions against CEA and remained stable for 6 and 9 mo, respectively	Itoh et al[53]	2002
	DCs loaded with CEA peptides (HLA-A2- or HLA-A24-restricted)	I	10 CRC patients (6 HLA-A24 and 4 HLA-A2) who had failed standard chemotherapy	CEA-specific CTLs were detected in 7 patients; 2 patients exhibited stable disease for at least 12 wk	Liu et al[54]	2004
	DCs loading with CEA peptide (HLA-A24 restricted)	I	8 patients with advanced CEA-expressing gastrointestinal malignancies (7 CRC and 1 gall bladder cancer)	4 patients developed CEA-specific CTL responses; a DTH reaction was observed in 1 patient, with skin biopsy at the injection site showing lymphocyte infiltration, and 3 patients, including 2 CRC, exhibited stable disease after vaccination	Matsuda et al[55]	2004
	DCs loaded with CEA peptide (HLA-24 restricted)	I	8 patients with CEA-expressing metastatic gastrointestinal or lung adenocarcinoma	Long-term stable disease or marked decreases in the serum CEA level was observed in some patients. CEA-specific immune responses were demonstrated in most of the patients in whom treatment was clinically effective	Ueda et al[56]	2004
	DCs loaded with CEA peptide (HLA-2 restricted)	I	10 CRC patients with resection of liver metastases	CEA-specific CTLs were demonstrated in 7 patients; CEA-specific CTLs were detected in a resected lymph node in 1 patient	Lesterhuis et al[57]	2006
	DCs loaded with CEA altered peptide	I	9 patients with CEA-expressing malignancies (7 CRC and 2 lung cancer)	5 patients exhibited CEA altered peptide-specific CTL responses, and 3 patients exhibited CEA-specific CTL responses	Babatz et al[58]	2006
WT1	DCs loaded with WT1 peptide (MHC class I and class II restricted)	I	3 advanced CRC	WT1-specific CTLs were detected and persisted for 2 yr with prolonged disease-free and overall survival	Shimodaira et al[8]	2015
MAGE	DCs loaded with MAGE-3 peptide (HLA-A2 or A24 restricted)	I	12 patients with advanced gastrointestinal carcinoma (6 stomach, 3 esophagus, and 3 CRC)	MAGE-3-specific CTL responses were observed in 4 patients. Tumor markers were decreased in 7 patients, and evidence of minor tumor regression was detected in 3 patients	Sadanaga et al[65]	2001
	DCs loaded with MAGE-3 or MAGE-1 peptides (HLA-A2 0r A24 restricted)	I	28 patients with advanced gastrointestinal carcinoma, including 7 CRC	Peptide-specific CTL responses, tumor marker decreases, and minor tumor regressions were observed in some patients after vaccination	Tanaka et al[66]	2008
CEA and MUC1	DCs modified with CEA/MUC1 (PANVAC)	II	74 patients, disease free after CRC metastasectomy and perioperative chemotherapy	CEA-specific CTLs were detected	Morse et al[67]	2013
CEA, MAGE, and HER2	DCs loaded with CEA/MAGE/HER2/neu/pan-DR peptides (HLA-A2 restricted) and keyhole limpet hemocyanin (KLH) protein	I	13 advanced CRC	All patients exhibited progressive disease. CEA-specific CTLs were detected in 3 of 11 evaluated patients. Multiple TAAs-specific CTLs were induced	Kavanagh et al[70]	2007
Autologous whole tumor mRNA	DCs transfected with whole-tumor mRNA	I	15 advanced CRC received the immunotherapy and KLH intravenously	11 of the 13 CRC patients evaluated developed a positive KLH skin test, and 7 CRC patients exhibited CEA-specific responses	Rains et al[75]	2001
Autologous whole tumor cells	DCs-autologous whole-tumor fusion cells and IL-12	I	5 gastrointestinal tumors, including CRC	Among the 3 patients evaluated, 1 exhibited stable disease, and 2 exhibited progressive disease. No DTH-positive patients were detected in this trial. Good therapeutic responses in some patients with brain tumors were detected	Homma et al[78]	2005
Allogeneic whole tumor cell lysate	DCs loaded with allogeneic tumor cell lysate	I	6 advanced CRC (HLA-A2)	Antitumor immune responses in some patients and transient stabilization or even reduction of CEA levels were detected	Tamir et al[82]	2007
	DCs loaded with allogeneic melanoma cell lysate expressing at least one of six MAGE-A antigens	II	20 advanced CRC	1 patient experienced a partial response, 7 patients achieved stable disease, and 5 patients exhibited prolonged progression-free survival	Toh et al[83]	2009

DC: Dendritic cell; CRC: Colorectal cancer; DTH: Delayed-type hypersensitivity; CTL: Cytotoxic T lymphocyte.

Table 2 Clinical trials of immune checkpoint therapy in patients with colorectal cancer

Target	Immunotherapy	Phase	Patients	Results	Ref	Year
PD-1	Pembrolizumab, anti-PD-1 immune checkpoint inhibitor	II	11 MMR-deficient CRC, 21 MMR-proficient CRC, and 9 MMR-deficient non-CRC	The immune-related objective response rate and immune-related progression-free survival rate were 40% (4 of 10 patients) and 78% (7 of 9 patients), respectively, for MMR-deficient CRC and 0% (0 of 18 patients) and 11% (2 of 18 patients) for MMR-proficient CRC	Le et al[89]	2015

PD-1: Programmed death 1; CRC: Colorectal cancer; MMR: DNA mismatch repair.