Project description:To investigate changes in the tumor microenvironment at a gene expression level induced by TGFb-derived peptide vaccination in a murine model of PDAC (Pan02)
Project description:Investigate changes in the gene expression in the tumor upon vaccination with an Arg2-derived peptide in a murine tumor model (Pan02)
Project description:We report here that a EMMPRINs-specific cancer peptide vaccination, where the peptide was modified and synthesied as a multiple antigenic peptide (MAP), significantly inhibited tumor growth and metastases. Specifically, we describe changes in the gene expression profile as assessed by RNAseq in tumors derived from mice implanted with the colon tumorigenic carcinoma (CT26 cells), and vaccinated with either a control scrambled multiple antigenic peptide (Scr-MAP) or with an epitope-specific EMMPRIN multiple antigenic peptide (designated 161-MAP).
Project description:Human Glioblastoma Multiforme tumors taken before dendritic cell vaccination, the recurrent tumors taken after vaccination and control GBM tumors from non vaccinated patients. Experiment Overall Design: Six Glioblastoma Multiforme patients underwent surgery. Their brain tumors were removed and analyzed via microarray. The lysate from the tumors were cultured with the patients' dendritic cells and the DCs were injected back into the patients. The patients GBMs returned and they underwent surgery a second time and those tumors were also analyzed via microarray. Tumors from the first and second GBM surgeries of 5 patients who did not receive DC vaccines are included as controls.
Project description:Interventions: arm1: The right peptides (up to 4 peptides) for vaccination to individual patients will be selected in consideration of the pre-existing host immunity assessed by the titers of anti-peptide IgG before vaccination, and subcutaneously injected with incomplete Freund’s adjuvant every week (3.0 mg/each peptide; 6 times/cycle). Dai-kenchu-to(5 g/time, 3 times/day) will be orally administered from the date of the first vaccination to the date of the sixth vaccination. If the patients want to continue the vaccination after completion of the first cycle of 6 vaccinations, the peptide vaccination will be allowed to continue (every 2-4 weeks).
arm2: The right peptides (up to 4 peptides) for vaccination to individual patients will be selected in consideration of the pre-existing host immunity assessed by the titers of anti-peptide IgG before vaccination, and subcutaneously injected with incomplete Freund’s adjuvant every week (3.0 mg/each peptide; 6 times/cycle). If the patients want to continue the vaccination after completion of the first cycle of 6 vaccinations, the peptide vaccination will be allowed to continue (every 2-4 weeks).
Primary outcome(s): Comparison of immune-enhancing effects (changes in anti-peptide IgG titers in plasma)between two groups.
Study Design: Parallel Randomized
Project description:To understand why cancer vaccine-induced T cells often fail to eradicate tumors, we studied immune responses in mice vaccinated with gp100 peptide emulsified in incomplete Freund's adjuvant (IFA), commonly used in clinical cancer vaccine trials. After gp100 peptide/IFA vaccination, tumor-specific CD8+ T cells (adoptively transferred from gp100-specific TCR-transgenic pmel-1 mice) accumulated not in tumors but at the persisting, antigen-rich vaccination site. Once there, primed T cells became dysfunctional and underwent antigen-driven, IFN-γ and FasL-mediated apoptosis, resulting in systemic hyporesponsiveness to subsequent vaccination. Provision of anti-CD40 antibody, TLR7 agonist and interleukin-2 (covax) reduced T cell apoptosis but did not prevent vaccination site sequestration. A non-persisting vaccine formulation shifted T cell localization towards tumors, inducing superior anti-tumor activity. Short-lived formulation also reduced systemic T cell dysfunction and promoted memory formation, as shown by gene expression profiling and other measures. Persisting peptide/IFA vaccine depots, currently used to vaccinate cancer patients, can induce specific T cell sequestration at vaccination sites followed by dysfunction and deletion; short-lived depot formulations may overcome these limitations and result in greater therapeutic efficacy of peptide-based cancer vaccines. To study the fate of melanoma-specific CD8+ T cells after peptide vaccination, we tracked T cell receptor-transgenic pmel-1 T cells in mice vaccinated with heteroclitic gp100_25-33 peptide emulsified in IFA. Splenic pmel-1 CD8+ T cells were purified at 6 and 21 days after vaccination with either gp100/IFA/covax or gp100/saline/covax, and then their total RNA was extracted and used for comparison by gene expression profiling.
Project description:To understand why cancer vaccine-induced T cells often fail to eradicate tumors, we studied immune responses in mice vaccinated with gp100 peptide emulsified in incomplete Freund's adjuvant (IFA), commonly used in clinical cancer vaccine trials. After gp100 peptide/IFA vaccination, tumor-specific CD8+ T cells (adoptively transferred from gp100-specific TCR-transgenic pmel-1 mice) accumulated not in tumors but at the persisting, antigen-rich vaccination site. Once there, primed T cells became dysfunctional and underwent antigen-driven, IFN-γ and FasL-mediated apoptosis, resulting in systemic hyporesponsiveness to subsequent vaccination. Provision of anti-CD40 antibody, TLR7 agonist and interleukin-2 (covax) reduced T cell apoptosis but did not prevent vaccination site sequestration. A non-persisting vaccine formulation shifted T cell localization towards tumors, inducing superior anti-tumor activity. Short-lived formulation also reduced systemic T cell dysfunction and promoted memory formation, as shown by gene expression profiling and other measures. Persisting peptide/IFA vaccine depots, currently used to vaccinate cancer patients, can induce specific T cell sequestration at vaccination sites followed by dysfunction and deletion; short-lived depot formulations may overcome these limitations and result in greater therapeutic efficacy of peptide-based cancer vaccines.
Project description:Personalized peptide vaccination (PPV) is one of the attractive immunotherapy with high immune-boosting effects. However, as with most therapeutic agents, PPV does not elicit beneficial immune and/or clinical responses in all of the treated cancer patients. To identify prognostic biomarker for the selection of patients most likely to benefit from PPV, we conducted whole genome gene expression analysis of prevaccination peripheral blood mononuclear cells (PBMCs) of 112 castration-resistant prostate cancer (CRPC) patients.