Survivin is overexpressed by 70–80% of pancreatic cancers, and is associated with resistance to chemotherapy and a poor prognosis. Gemcitabine has been a standard treatment for patients with advanced pancreatic cancer for a decade. Recent reports have demonstrated that gemcitabine treatment attenuates the tumor-suppressive environment by eliminating CD11b+/Gr-1+ myeloid-derived suppressor cells (MDSCs). We hypothesize that a cancer vaccine targeting survivin can achieve enhanced efficacy when combined with gemcitabine. In this study, we tested this hypothesis using modified vaccinia Ankara (MVA) expressing full-length murine survivin. The poorly immunogenic mouse pancreas adenocarcinoma cell line, Pan02, which expresses murine survivin and is syngeneic to C57BL/6, was used for this study. Immunization with MVA-survivin resulted in a modest therapeutic antitumor effect on established Pan02 tumors. When administered with gemcitabine, MVA-survivin immunization resulted in significant tumor regression and prolonged survival. The enhanced vaccine efficacy was associated with decreased CD11b+/Gr-1+ MDSCs. To analyze the survivin-specific immune response to MVA-survivin immunization, we utilized a peptide library of 15mers with 11 residues overlapping from full-length murine survivin. Splenocytes from mice immunized with MVA-survivin produced intracellular γ-interferon in response to in vitro stimulation with the overlapping peptide library. Increased survivin-specific CD8+ T cells that specifically recognized the Pan02 tumor line were seen in mice treated with MVA-survivin and gemcitabine. These data suggest that vaccination with MVA-survivin in combination with gemcitabine represents an attractive strategy to overcome tumor-induced peripheral immune tolerance, and this effect has potential for clinical benefit in pancreatic cancer.
Summary
The p53 gene product is overexpressed in ~50% of cancers, making it an ideal target for cancer immunotherapy. We previously demonstrated that a modified vaccinia Ankara (MVA) vaccine expressing human p53 (MVA-p53) was moderately active when given as a homologous prime/boost in a human p53 knock in (Hupki) mouse model. We needed to improve upon the inefficient homologous boosting approach, because development of neutralizing immunity to the vaccine viral vector backbone suppresses its immunogenicity. To enhance specificity, we examined the combination of two different vaccine vectors provided in sequence as a heterologous prime/boost. Hupki mice were evaluated as a human p53 tolerant model to explore the capacity of heterologous p53 immunization to reject human p53-expressing tumors. We employed attenuated recombinant Listeria monocytogenes expressing human p53 (LmddA-LLO-p53) in addition to MVA-p53. Heterologous p53 immunization resulted in a significant increase in p53-specific CD8+ and CD4+ T cells compared to homologous single vector p53 immunization. Heterologous p53 immunization induced protection against tumor growth but had only a modest effect on established tumors. To enhance the immune response we utilized synthetic double-strand RNA (polyI:C) and unmethylated CpG-containing oligodeoxynucleotide (CpG-ODN) to activate the innate immune system via Toll-like receptors (TLRs). Treatment of established tumor-bearing Hupki mice with poly(I:C) and CpG-ODN in combination with heterologous p53 immunization resulted in enhanced tumor rejection relative to treatment with either agent alone. These results suggest that heterologous prime/boost immunization and TLR stimulation increases the efficacy of a cancer vaccine, targeting a tolerized tumor antigen.
The p53 gene product is an attractive target for tumor immunotherapy. The present study aims to understand the potential of MVAp53 vaccine to induce expansion of p53 specific cytotoxic T lymphocyte ex vivo in cancer patients. The result indicated that 14 of 23 cancer patients demonstrated p53 specific IFN-γ production, degranulation, cell proliferation, and lysis of p53 over-expressed human tumor cell lines. These experiments show that MVAp53 stimulation has the potential to induce the expansion of p53 specific cytotoxic T lymphocyte from the memory T cell repertoire. The data suggests that MVAp53 vaccine is an ideal candidate for cancer immunotherapy.
The dramatic changes in the magnetic field at the dipolarization front (DF) provide a suitable environment for electron acceleration, which usually can cause the flux enhancement of energetic electrons behind the front. However, it is unknown whether energetic electrons observed at the DF are energized locally, and which mechanism accelerates the electrons at the DF is unclear. Our study performs a direct quantitative analysis to reveal the acceleration process of energetic electrons at the DF using the high-time-resolution data from NASA's Magnetospheric Multiscale mission. The fluxes of energetic electrons at 90° are enhanced at the front. Under adiabatic conditions, our quantitative analysis indicates that these electrons at the front could be locally accelerated to over 100 keV by betatron acceleration. Eventually, the electron temperature anisotropy formed via the betatron mechanism could provide the free energy to excite whistler waves at the DF. Our quantitative study provides, for the first time, strong direct evidence for the local electron acceleration at the DF.
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