Ovarian cancer using novel nanoparticle formulations

DESCRIPTION provided by applicant Ovarian cancer is the fifth most leading cause of cancer related deaths in women in the US It has been observed that the cancer relapses within relatively short periods of time even after the surgery and chemotherapy Therefore immunotherapeutic strategies may serve as an alternative to control the recurrence or progression of ovarian cancer Oral vaccines are relatively easy to administer However the degradation of the antigenic component of the vaccine in the gastro intestinal tract is a major problem In this research study we will formulate and evaluate the efficacy of oral ovarian cancer nanoparticulate vaccine in mice to prevent retard the ovarian cancer growth The antigenic material for the vaccine will be prepared from ID murine ovarian cancer cells as this cell line correlates well with human ovarian cancer cell lines in terms of various similar markers and provides a unique model to study ovarian cancer progression and pre therapeutic trials in mice with intact immune systems In this proposal ovarian cancer antigens M cell targeting ligands immuno stimulatory cytokines and toll like receptor TLR ligands such as CpG oligonucleotide that can induce T cell responses will be encapsulated into nanoparticles made up of a biodegradable and biocompatible polymer matrix containing a mixture of an enteric polymer to prevent their degradation under acidic conditions in the stomach and also a sustained release polymer enabling the release of the antigen in a controlled manner These vaccine nanoparticles will be administered to female C BL mice with ovarian tumors by the oral route These particles are targeted to M cells present in Peyerandapos s patches in the intestine which take up the encapsulated vaccine to generate immunity by presenting the antigen to dendritic cells and macrophages Serum samples will be obtained to determine the antigen specific IgG levels to assess the systemic immunity We will also carry out mechanistic studies to investigate the role of CD T cells CD T cells NK cells and B cells in anti tumor immunity induced by the oral vaccines We will also evaluate the efficacy of the vaccine microparticles after a including M cell inducing RANKL b Treg depletion studies with low dose of cyclophosphamide or anti CD Ab in order to evaluate immunotolerance in pre existing tumor models and c adoptive transfer of T cells Long term memory responses of the vaccine will also be assessed since this is a necessary component of a successful vaccine Recently major advances have been made in the formulation methodology at the Nanotechnology Laboratory allowing us to produce nanoparticles using the spray drying methodology in a single step process This is a major advantage from the standpoint of advancing the vaccine formulation from bench to clinic as scale up of this process can be achieved with no further modifications PUBLIC HEALTH RELEVANCE Ovarian cancer is the fifth most leading cause of cancer related deaths in women in the US The first line treatment for advanced ovarian cancer involves surgery followed by chemotherapy However the cancer relapses within relatively short periods of time even after the treatment We will investigate if vaccination with nanoparticles containing the ovarian cancer antigens is effective To test this hypothesis animals with tumors will be vaccinated orally to determine the efficacy of the vaccine Our vaccine particle manufacturing process is a simple and inexpensive one step continuous process Data obtained from this research plan will aid to engineer ovarian cancer vaccines