Nanotechnology to Genetically Reprogram Tumor Cells for Treatment of Metastatic Ovarian Cancer
Abstract
Rationale and Objective: Ovarian cancer is the second most common gynecological cancer and has the lowest survival rate, due in part to the fact that patients with ovarian cancer are often diagnosed at late stages, when tumors have metastasized. Tumor-killing T cells can be activated if they receive certain key biological signals that train these immune cells to recognize and destroy ovarian cancer. In this project, synthetic biodegradable nanoparticles will be used to genetically reprogram ovarian cancer cells, causing them to display all of the crucial signals needed to activate T cells. Essentially, the nanoparticles will cause the ovarian cancer cells to “flip” roles: the ovarian cancer cells will stop evading immune cells and instead start training immune cells to recognize and destroy cancer cells in a patient-specific manner. Effectively, the ovarian cancer cells will actively participate in their own destruction, as they will be forced to instruct T cells to target and kill ovarian cancer throughout the body. Critically, the instruction that these engineered cancer cells provide to T cells will drive an immune reaction against other cancer cells, whether locally or at distant metastatic sites. This proposal will evaluate the ability of the particles to reprogram ovarian cancer cells. Success will be validated in mouse models of metastatic ovarian cancer by showing significant improvements to long-term survival, as well as demonstrating that the anti-cancer immune response is widespread through the entire body. Critical Problem: Ovarian cancer is often diagnosed only after the original tumor has spread, making it difficult to treat. Traditional cancer treatments, like many standard chemotherapies, are associated with negative side effects that can affect the whole body, including general immunosuppression. Here, we aim to engineer degradable polymer-based nanoparticles that can be injected locally into a tumor. This local administration prevents wide-spread adverse side effects of the treatment, but, by generating an immune response specific to a patient’s tumor that starts locally and then moves throughout the body, it can lead to safe and specific anti-cancer efficacy including at metastatic sites. New Paradigm and New Technology: For patients with metastatic ovarian cancer, the available treatments consist largely of chemotherapy and radiation, both of which can cause severe adverse side effects that impact those patients’ quality of life. The proposed new technology has the potential to solve these problems through a new paradigm of treatment based on tumor reprogramming. This nanoparticle-based gene therapy is designed to stimulate a strong immune response that is patient specific to a patient’s tumors, without requiring invasive biopsies of tumor profiling. This innovative biotechnology harnesses and unleashes the body’s natural ability to identify, move toward, and kill cancer cells, even at distant metastatic sites. In addition, a major advantage of this innovative system is its simplicity. One of the challenges in targeting tumors is that cancer cells are highly irregular, and it is difficult to predict which proteins they display, as these protein patterns are different from one patient to another. Many efforts to develop tumor immunotherapies require that doctors know ahead of time what the patient’s tumor cells look like in order to train immune cells to recognize them. Our new paradigm of hijacking tumor cells to act as immune activators means that the cancer cells themselves are teaching immune cells what to look for. Thus, doctors can generate a specific anti-cancer response without having to know the molecular details about the cancer cells ahead of time. This saves patients from invasive sampling and broadens accessibility. Further, it provides patients with an even better, more personalized efficacious therapy. The wide applicability of this treatment to different patients makes this tr
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110297
Entities
People
- Jordan J Green
Organizations
- Johns Hopkins University
- United States Army