Topic Highlight
Copyright ©The Author(s) 2016.
World J Gastroenterol. May 7, 2016; 22(17): 4275-4286
Published online May 7, 2016. doi: 10.3748/wjg.v22.i17.4275
Table 1 Clinical trials of dendritic cell-based cancer immunotherapy in patients with colorectal cancer
CEADCs loaded with CEA peptide (HLA-A2 restricted)I21 advanced CEA-expressing malignancies including 11 CRCSkin punch biopsy at DC injection sites demonstrated pleomorphic, perivascular infiltration of cells consistent with a DTH responseMorse et al[46]1999
DCs loaded with CEA mRNAI13 patients with resected hepatic metastases of CRC9 of the 13 CRC patients relapsed at a median of 122 dMorse et al[47]2003
DCs modified with a recombinant fowlpox vector encoding CEA and a triad of costimulatory molecules [rF-CEA(6D)-TRICOM]I14 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 CEAI14 patients (5 CRC, 3 lung cancer, and 1 urachal adenocarcinoma)Of the 9 patients analyzed, all with stable disease (n = 5) displayed increased NK activityOsada 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 peptide10 CRC patientsCRC 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 detectedSakakibara et al[51]2011
DCs loaded with altered CEA peptide (HLA-A2 restricted) with Flt3 ligandI12 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 metastasesFong et al[52]2001
DCs loaded with CEA peptide (HLA-A24 restricted)I10 advanced CEA-expressing malignancies including 7 CRC2 patients (CRC and lung cancer) exhibited positive DTH reactions against CEA and remained stable for 6 and 9 mo, respectivelyItoh et al[53]2002
DCs loaded with CEA peptides (HLA-A2- or HLA-A24-restricted)I10 CRC patients (6 HLA-A24 and 4 HLA-A2) who had failed standard chemotherapyCEA-specific CTLs were detected in 7 patients; 2 patients exhibited stable disease for at least 12 wkLiu et al[54]2004
DCs loading with CEA peptide (HLA-A24 restricted)I8 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 vaccinationMatsuda et al[55]2004
DCs loaded with CEA peptide (HLA-24 restricted)I8 patients with CEA-expressing metastatic gastrointestinal or lung adenocarcinomaLong-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 effectiveUeda et al[56]2004
DCs loaded with CEA peptide (HLA-2 restricted)I10 CRC patients with resection of liver metastasesCEA-specific CTLs were demonstrated in 7 patients; CEA-specific CTLs were detected in a resected lymph node in 1 patientLesterhuis et al[57]2006
DCs loaded with CEA altered peptideI9 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 responsesBabatz et al[58]2006
WT1DCs loaded with WT1 peptide (MHC class I and class II restricted)I3 advanced CRCWT1-specific CTLs were detected and persisted for 2 yr with prolonged disease-free and overall survivalShimodaira et al[8]2015
MAGEDCs loaded with MAGE-3 peptide (HLA-A2 or A24 restricted)I12 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 patientsSadanaga et al[65]2001
DCs loaded with MAGE-3 or MAGE-1 peptides (HLA-A2 0r A24 restricted)I28 patients with advanced gastrointestinal carcinoma, including 7 CRCPeptide-specific CTL responses, tumor marker decreases, and minor tumor regressions were observed in some patients after vaccinationTanaka et al[66]2008
CEA and MUC1DCs modified with CEA/MUC1 (PANVAC)II74 patients, disease free after CRC metastasectomy and perioperative chemotherapyCEA-specific CTLs were detectedMorse et al[67]2013
CEA, MAGE, and HER2DCs loaded with CEA/MAGE/HER2/neu/pan-DR peptides (HLA-A2 restricted) and keyhole limpet hemocyanin (KLH) proteinI13 advanced CRCAll patients exhibited progressive disease. CEA-specific CTLs were detected in 3 of 11 evaluated patients. Multiple TAAs-specific CTLs were inducedKavanagh et al[70]2007
Autologous whole tumor mRNADCs transfected with whole-tumor mRNAI15 advanced CRC received the immunotherapy and KLH intravenously11 of the 13 CRC patients evaluated developed a positive KLH skin test, and 7 CRC patients exhibited CEA-specific responsesRains et al[75]2001
Autologous whole tumor cellsDCs-autologous whole-tumor fusion cells and IL-12I5 gastrointestinal tumors, including CRCAmong 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 detectedHomma et al[78]2005
Allogeneic whole tumor cell lysateDCs loaded with allogeneic tumor cell lysateI6 advanced CRC (HLA-A2)Antitumor immune responses in some patients and transient stabilization or even reduction of CEA levels were detectedTamir et al[82]2007
DCs loaded with allogeneic melanoma cell lysate expressing at least one of six MAGE-A antigensII20 advanced CRC1 patient experienced a partial response, 7 patients achieved stable disease, and 5 patients exhibited prolonged progression-free survivalToh et al[83]2009
Table 2 Clinical trials of immune checkpoint therapy in patients with colorectal cancer
PD-1Pembrolizumab, anti-PD-1 immune checkpoint inhibitorII11 MMR-deficient CRC, 21 MMR-proficient CRC, and 9 MMR-deficient non-CRCThe 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 CRCLe et al[89]2015