RECENTLY FUNDED CAREER DEVELOPMENT PROJECTS

Targeting ovarian cancer metastases with biomaterial-supported T-cell implants

Matthias Stephan, MD, PhD
Fred Hutchinson Cancer Research Center

Management of metastatic ovarian cancer continues to be a critical clinical problem. At the time of diagnosis, most patients have extensive metastatic disease throughout the abdomen, which often makes it impossible to remove all tumor despite radical surgery and chemotherapy. In theory, cells of our own immune system have the ability to selectively lyse ovarian tumor cells. Based on this premise, transfusions of tumor-reactive lymphocytes, referred to as adoptive cell therapy (ACT), are currently being tested in ovarian cancer patients as one of the most promising treatment options. However, major hurdles remain that seriously limit the use of ACT to treat ovarian cancer patients: a poor survival of infused cells and inefficient cell homing to tumor tissue. To address this challenge we propose a radically different cell delivery strategy in which lymphocytes are seeded onto porous polymer scaffolds along with supporting molecules that help them multiply and activate. Once prepared, scaffolds can be surgically implanted into the peritoneal cavity. Scaffolds act as active depots, dispersing lymphocytes throughout the abdomen to purge ovarian cancer deposits. At the same time, immune stimulants released by the scaffold could render delivered T-cells resistant to tumor-secreted suppressive factors. Our long-term goal is to develop this technology into a clinical device to provide gynecological surgeons with a more effective treatment option for ovarian cancer. Our overall hypothesis is that the ability of tumor-reactive T-cells to eradicate ovarian cancer metastases can be dramatically enhanced by providing a sustained release of appropriately stimulated T-cells from a bioactive material vehicle. Our hypothesis will be evaluated with the following two specific aims: (1) To optimize the composition of polymer scaffolds to expand embedded tumor-reactive T-cells within the device and disperse them into the peritoneal cavity, and (2) To examine the ability of material-controlled T-cell delivery to treat disseminated intraperitoneal ovarian tumor metastases more effectively than conventional T-cell injections. Data generated from these studies will ultimately serve to provide the rationale of utilizing biomaterial as T cell delivery vehicles in future clinical trials of adoptive immunotherapy in patients with ovarian cancer..

Antibody-mediated short interfering RNA Delivery for Ovarian Cancer Therapy

M. Corinna Palanca-Wessels, MD, PhD
Fred Hutchinson Cancer Research Center

Ovarian cancer is the most deadly gynecologic malignancy in the United States principally due to its usual diagnosis at an advanced stage and eventual development of drug resistance. A disheartening 5-year overall survival rate of 30% has remained largely unchanged over the past two decades despite intensive research efforts. RNA interference is a mechanism of gene regulation that can be manipulated through the use of short interfering RNA (siRNA) to specifically suppress genes that contribute to chemotherapy resistance. However, a major hurdle for clinical implementation of siRNA is effective tumor-specific intracellular delivery. This application will optimize a siRNA delivery system consisting of an antibody directed against mesothelin to promote receptor-mediated intracellular siRNA uptake by ovarian cancer cells and a pH-responsive polymer to enhance endosomal escape of siRNA into the cytoplasm. The project aims are to: 1) demonstrate and optimize mesothelin antibody-mediated siRNA delivery in vitro; 2) identify siRNA sequences that potentiate cytotoxicity in ovarian cancer cells in conjunction with platinum and/or taxane drugs in vitro 3) evaluate the efficiency of siRNA-mediated gene suppression using an antibody-targeted siRNA polymer carrier in a mouse ovarian tumor xenograft model. This research builds upon promising work by the applicant and comprises part of a career development plan that will enable her to successfully transition into a fully independent research position. Her long-term goal is to establish a translational research program to test novel therapies that exploit tumor specific antigens and RNA interference for more effective treatment of ovarian cancer.