Dendritic cell-based vaccination combined with gemcitabine increases survival in a murine pancreatic carcinoma model

Abstract

Background: Tumour-specific cytotoxic T lymphocytes (CTLs) can be activated in vivo by vaccination with dendritic cells (DCs). However, clinical responses to DC-based vaccination have only been observed in a minority of patients with solid cancer. Combination with other treatment modalities such as chemotherapy may overcome immunoresistance of cancer cells. It has been shown previously that gemcitabine sensitises human pancreatic carcinoma cells against CTL-mediated lysis. Here, a murine pancreatic carcinoma model was used to investigate whether combination with gemcitabine increases therapeutic efficacy of DC-based vaccination. Methods: Bone marrow-derived DCs from C57BL/6 mice were loaded with UV-irradiated, syngeneic Panc02 carcinoma cells and were administered subcutaneously. For prophylactic vaccination, mice were vaccinated three times at weekly intervals prior to tumour challenge with Panc02 cells. Therapeutic vaccination was started when tumours formed a palpable nodule. Gemcitabine was administered intraperitoneally twice weekly. Results: Prophylactic DC-based vaccination completely prevented subcutaneous and orthotopic tumour development and induced immunological memory as well as tumour antigen-specific CTLs. In the subcutaneous tumour model, therapeutic DC-based vaccination was equally effective as gemcitabine (14% vs 17% survival at day 58 after tumour challenge; controls, 0%). Combination of the two strategies significantly increased survival of tumour-bearing mice (50% at day 58 after tumour challenge). DC-based vaccination also prevented death from pulmonary metastatisation after intravenous injection of Panc02 cells. Conclusion: DC-based immunotherapy may not only be successfully combined with gemcitabine for the treatment of advanced pancreatic carcinoma, but may also be effective in preventing local recurrence or metastatisation in tumour-free patients.

Establishment of an orthotopic pancreatic cancer mouse model: Cells suspended and injected in Matrigel

“…The Pan02 cell lines were established by Corbett et al [22] via injection of 3-methyl-cholanthrene into the pancreas of female C57BL/6 mice. It has been widely used for immunological studies of pancreatic cancer [23][24][25] . The direct injection method, which involves injection of pancreatic cancer cells directly into the mouse pancreas using surgical exposure and ultrasound guidance, is most commonly applied to establish orthotopic xenograft pancreatic carcinoma.…”

The importance of correctly timing cancer immunotherapy

“…Similarly, metronomic administration of a high dose cocktail of chemotherapeutic agents (including cyclophosphamide, paclitaxel and docetaxel) during vaccination with a multi-peptide cocktail of peptides (comprising hepatitis C virus-derived antigens and tumor-associated antigens) resulted in an enhanced specific T-cell response and a reduced Treg frequency in hepatocellular carcinoma (HCC) patients [79]. Coadministration of gemcitabine with DC-based vaccines in a pancreatic carcinoma model showed a synergistic antitumor effect [116]. Treatment of patients with ovarian cancer with a p53 SLP vaccine in combination with pegintron (pegylated IFNα) 7 days before the first cycle of gemcitabine and repeated at day 22, during gemcitabine treatment, resulted in a strong p53-specific T-cell response.…”

An ISCOM vaccine combined with a TLR9 agonist breaks immune evasion mediated by regulatory T cells in an orthotopic model of pancreatic carcinoma

“…The proportion of target to control population was determined and percentage of killing was calculated as described. 13 …”

“…29 Indeed, in mice that had rejected the tumor we detected a high frequency of CTL against p15E, an Ag expressed by wild-type Panc02 cells. 13 Thus, ISCOM vaccines are capable of inducing epitope spreading, thereby diversifying antitumor CTL responses.…”

“…11,12 In another study, we demonstrated that a DC vaccine combined with gemcitabine-based chemotherapy can achieve prolonged survival in an orthotopic model of pancreatic carcinoma. 13 Other groups have shown that intratumoral immunization with DC pulsed with tumor RNA or alpha-galactosylceramide can induce antitumor immunity in murine models of pancreatic cancer. 14,15 However, the production of DC vaccines is a time consuming and expensive process.…”