Immunotherapy for colorectal cancer

The incidence of colorectal cancer(CRC)is on the rise,and the prognosis for patients with recurrent or metastatic disease is extremely poor.Although chemotherapy and radiation therapy can improve survival rates,it is imperative to integrate alternative strategies such as immunotherapy to improve outcomes for patients with advanced CRC.In this review,we will discuss the effect of immunotherapy for inducing cytotoxic T lymphocytes and the major immunotherapeutic approaches for CRC that are currently in clinical trials,including peptide vaccines,dendritic cell-based cancer vaccines,whole tumor cell vaccines,viral vector-based cancer vaccines,adoptive cell transfer therapy,antibody-based cancer immunotherapy,and cytokine therapy.The possibility of combination therapies will also be discussed along with the challenges presented by tumor escape mechanisms.

Advances in inducing adaptive immunity using cell-based cancer vaccines: clinical applications in pancreatic cancer

The incidence of pancreatic ductal adenocarcinoma(PDA) is on the rise, and the prognosis is extremely poor because PDA is highly aggressive and notoriously difficult to treat. Although gemcitabine- or 5-fluorouracil-based chemotherapy is typically offered as a standard of care, most patients do not survive longer than 1 year. Therefore, the development of alternative therapeutic approaches for patients with PDA is imperative. As PDA cells express numerous tumor-associated antigens that are suitable vaccine targets, one promising treatment approach is cancer vaccines. During the last few decades, cell-based cancer vaccines have offered encouraging results in preclinical studies. Cell-based cancer vaccines are mainly generated by presenting whole tumor cells or dendritic cells to cells of the immune system. In particular, several clinical trials have explored cell-based cancer vaccines as a promising therapeutic approach for patients with PDA. Moreover, chemotherapy and cancer vaccines can synergize to result in increased efficacies in patients with PDA. In this review, we will discuss both the effect of cell-based cancer vaccines and advances in terms of future strategies of cancer vaccines for the treatment of PDA patients.

Dendritic cell-based cancer immunotherapy for colorectal cancer

Colorectal cancer(CRC) is one of the most common cancers and a leading cause of cancer-related mortality worldwide. Although systemic therapy is the standard care for patients with recurrent or metastatic CRC, the prognosis is extremely poor. The optimal sequence of therapy remains unknown. Therefore, alternative strategies, such as immunotherapy, are needed for patients with advanced CRC. This review summarizes evidence from dendritic cell-based cancer immunotherapy strategies that are currently in clinical trials. In addition, we discuss the possibility of antitumor immune responses through immunoinhibitory PD-1/PD-L1 pathway blockade in CRC patients.

Production of corticotropin-releasing factor and urocortin from human monocyte-derived dendritic cells is stimulated by commensal bacteria in intestine

AIM:To examine whether commensal bacteria are a contributing cause of stress-related mucosal inflammation.METHODS:Human peripheral blood monocyte-deriveddendritic cells(MoDCs)were stimulated by commensal bacterial strains,including Escherichia coli,Clostridium clostridioforme,Bacteroides vulgatus(B.vulgatus),Fusobacterium varium(F.varium),and Lactobacillus delbrueckii subsp.bulgaricus.After incubation,corticotropin-releasing factor(CRF)and urocortin 1(UCN1)mRNA in the cells was examined by real-time reverse transcription polymerase chain reaction.Supernatants from the cells were tested for CRF and UCN1 using an enzyme-linked immunosorbent assay.RESULTS:Both CRF and UCN1 were significantly augmented by B.vulgatus and F.varium at both the mRNA and protein levels.In particular,B.vulgatus stimulated human MoDCs,resulting in extremely high levels of CRF and UCN1.CONCLUSION:Stimulation of MoDCs by B.vulgatus and F.varium may be associated with CRF/UCN1-related intestinal disorders,such as irritable bowel syndrome and inflammatory bowel disease.

Dendritic cell-based vaccine for pancreatic cancer in Japan

"Vaccell" is a dendritic cell(DC)-based cancer vaccine which has been established in Japan. The DCs play central roles in deciding the direction of host immune reactions as well as antigen presentation. We have demonstrated that DCs treated with a streptococcal immune adjuvant OK-432, produce interleukin-12, induce Th1-dominant state, and elicit anti-tumor effects, more powerful than those treated with the known DCmaturating factors. We therefore decided to mature DCs by the OK-432 for making an effective DC vaccine, Vaccell. The 255 patients with inoperable pancreatic cancer who received standard chemotherapy combined with DC vaccines, were analyzed retrospectively. Survival time of the patients with positive delayed type hypersensitivity(DTH) skin reaction was significantly prolonged as compared with that of the patients with negative DTH. The findings strongly suggest that there may be "Responders" for the DC vaccine in advanced pancreatic cancer patients. We next conducted a smallscale prospective clinical study. In this trial, we pulsed HLA class Ⅱ-restricted WT1 peptide(WT1-Ⅱ) in addition to HLA class Ⅰ-restricted peptide(WT1-Ⅰ) into the DCs. Survival of the patients received WT1-Ⅰ and-Ⅱ pulsed DC vaccine was significantly extended as compared to that of the patients received DCs pulsed with WT1-Ⅰ or WT1-Ⅱ alone. Furthermore, WT1-specific DTH positive patients showed significantly improved the overall survival as well as progressionfree survival as compared to the DTH negative patients. The activation of antigen-specific immune responses by DC vaccine in combination with standard chemotherapy may be associated with a good clinical outcome in advanced pancreatic cancer. We are now planning a pivotal study of the Vaccell in appropriate protocols in Japan.

Prognostic significance of plasma interleukin-6/-8 in pancreatic cancer patients receiving chemoimmunotherapy

AIM: To investigate the association of plasma levels of interleukin(IL)-6 and-8 with Wilms' tumor 1(WT1)-specific immune responses and clinical outcomes in patients with pancreatic ductal adenocarcinoma(PDA) treated with dendritic cells(DCs) pulsed with three types of major histocompatibility complex classⅠand Ⅱ-restricted WT1 peptides combined with chemotherapy.METHODS: During the entire treatment period, plasma levels of IL-6 and-8 were analyzed by ELISA. The induction of WT1-specific immune responses was assessed using the WT1 peptide-specific delayed-type hypersensitivity(DTH) test.RESULTS: Three of 7 patients displayed strong WT1-DTH reactions throughout long-term vaccination with significantly decreased levels of IL-6/-8 after vaccinations compared with the levels prior to treatment. Moreover, overall survival(OS) was significantly longer in PDA patients with low plasma IL-6 levels(< 2 pg/m L) after 5 vaccinations than in patients with high plasma IL-6 levels(≥ 2 pg/m L)(P = 0.025). After disease progression, WT1-DTH reactions decreased severely and were ultimately negative at the terminal stage of cancer. The decreased levels of IL-6/-8 observed throughout long-term vaccination were associated with WT1-specific DTH reactions and long-term OS.CONCLUSION: Prolonged low levels of plasma IL-6/-8 in PDA patients may be a prognostic marker for the clinical outcomes of chemoimmunotherapy.