The present study shows that flow diversion surgery for congenital choledochal cysts with PBM significantly reduces the risk of subsequent development of malignancy in the biliary tract, and it is vital to choose the appropriate operative procedure to prevent occurrence of these postoperative complications.
A postoperative dendritic cell vaccine plus activated T-cell transfer would be a feasible and effective treatment for preventing recurrence and achieving long-term survival in ICC patients.
BackgroundThe prognosis of patients with advanced biliary tract cancer (BTC) is extremely poor and only a few standard treatments are available for this condition. We performed a phase I trial to investigate the safety, immune response and anti-tumor effect of vaccination with three peptides derived from cancer-testis antigens.MethodsThis study was conducted as a phase I trial. Nine patients with advanced BTC who had unresectable tumors and were refractory to standard chemotherapy were enrolled. Three HLA-A*2402 restricted epitope peptides-cell division cycle associated 1 (CDCA1), cadherin 3 (CDH3) and kinesin family member 20A (KIF20A)-were administered subcutaneously, and the adverse events and immune response were assessed. The clinical effects observed were the tumor response, progression-free survival (PFS) and overall survival (OS).ResultsThe three-peptide vaccination was well-tolerated up to a dose of 3 mg per peptide (9 mg total). No grade 3 or 4 adverse events were observed after vaccination. Peptide-specific T cell immune responses were observed in all patients and stable disease was observed in 5 of 9 patients. The median PFS and OS were 3.4 and 9.7 months. The Grade 2 injection site reaction and continuous vaccination after PD judgment appeared to be prognostic of OS.ConclusionsMultiple-peptide vaccination was well tolerated and induced peptide-specific T-cell responses.Trial registrationThis study was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR000003229).
Purpose: The prognosis of patients with advanced biliary tract cancer (BTC) is extremely poor and there are only a few standard treatments. We conducted a phase I trial to investigate the safety, immune response, and antitumor effect of vaccination with four peptides derived from cancer-testis antigens, with a focus on their fluctuations during long-term vaccination until the disease had progressed.Experimental Design: Nine patients with advanced BTC who had unresectable tumors and were refractory to standard chemotherapy were enrolled. HLA-A Ã 2402-restricted epitope peptides, lymphocyte antigen 6 complex locus K, TTK protein kinase, insulin-like growth factor-II mRNA-binding protein 3, and DEP domain containing 1 were vaccinated subcutaneously once a week at doses of 0.5, 1, or 2 mg and continued until disease progression. The adverse events were assessed by Common Terminology Criteria for Adverse Events and the immune response was monitored by an enzyme-linked immunospot assay or by flow cytometry. The clinical effects observed were tumor response, progression-free survival (PFS), and overall survival (OS).Results: Four-peptide vaccination was well tolerated. No grade 3 or 4 adverse events were observed. Peptide-specific T-cell immune responses were observed in seven of nine patients and clinical responses were observed in six of nine patients. The median PFS and OS were 156 and 380 days. The injection site reaction and CTL induction seemed to be prognostic factors of both PFS and OS.Conclusions: Four-peptide vaccination was well tolerated and seemed to provide some clinical benefit to some patients. These immunologic and clinical responses were maintained over the long term through continuous vaccinations.
We have generated effector T cells from tumor-draining lymph nodes that are efficacious in adoptive immunotherapy. We now examined the effect of concomitant tumors on the generation of effector T cells. We inoculated MCA 205 in the flanks of normal mice and mice bearing MCA 205 lung metastases. Tumor-draining lymph node cells from these mice were activated and expanded in vitro, and adoptively transferred to mice bearing lung metastases. Effector T cells (TDLN) generated from tumor-draining lymph nodes in mice with only flank tumor mediated potent antitumor activity. However, antitumor efficacy of the effector T cells generated from tumor-draining lymph nodes in mice with pre-existent lung tumor (cTDLN) was reduced. Phenotyping studies showed that dendritic cells in cTDLN expressed higher levels of B7-H1; while cTDLN T cells expressed higher levels of PD-1. The levels of IFNγ were reduced, and the levels of CD4+Foxp3+ regulatory T cells were increased from cTDLN vs. TDLN. The in vitro activation of cTDLN was increased by blocking B7-H1 or TGF-β. Importantly, we found a synergistic upregulation of IFNγ with simultaneous blockade of B7-H1 and TGF-β that was much greater than observed with TDLN. In vitro activation of cTDLN with anti-B7-H1 and anti-TGF-β and in vivo administration of these antibodies after adoptive transfer resulted in the abrogation of the suppression associated with cTDLN. These results demonstrate a major role of the B7-H1/PD-1 axis and TGF-β as synergistic suppressive mechanisms in cTDLN. Our data has clinical relevance in the generation of effector T cells in the tumor-bearing host.
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