2014 Early Career Investigator Grant Recipient — Matthias Stephan, MD, PhD
Ovarian cancer is often diagnosed after tumor cells have already spread (metastasized) from the ovary, so it is difficult to remove them entirely using surgery and chemotherapy. Fortunately, there are cells naturally occurring in our immune system that have the ability to selectively destroy ovarian tumors without damaging healthy tissue, but they require stimulation to do so. For example, vaccines can train the immune system to fight ovarian cancer, and some of these are currently in clinical trials. However, vaccine therapies typically fail to expand anti-tumor immune cells enough to control metastatic diseases. They can also require months to mount an immune response, by which time the disease may become lethal.
We propose to create an injectable reagent that can quickly reprogram the patient’s immune cells (particularly T lymphocytes) to recognize and destroy ovarian tumors. Specifically, we hypothesize that T cells circulating in the blood can be genetically reconfigured by targeted, gene-bearing nanoparticles to express receptors that bind specifically to ovarian tumor proteins, which will enable them to bring about rapid and vigorous tumor rejection. Our preliminary experiments have already shown that a new type of nanoparticle we developed can efficiently transfer ovarian tumor-reactive receptor genes into T cells grown in the laboratory. We must now demonstrate that nanoparticle-mediated gene transfer can occur in circulating T cells. Our long-term goal is to integrate this approach into the standard-of-care for treatment of ovarian cancer.
The results of this project could substantially modify the way ovarian cancer patients are treated: a) Off-the-shelf nanoparticles that rapidly program existing T lymphocytes to recognize ovarian tumors could enable clinicians to treat diagnosed ovarian cancer patients immediately, before progression of the disease becomes irreversible. b) In contrast to standard chemoradiation therapies, nanoparticle-mediated targeting can direct T cells to selectively destroy only ovarian cancer cells, without damaging healthy tissue or producing toxic side effects. c) Just in the United States, more than 22,000 new ovarian cancer patients are diagnosed each year, so it is important that the DNA nanocarriers we are developing are amenable to fabrication on a large scale, and in a stable form. This means any ovarian cancer patient could be treated with T cell immunotherapy in an outpatient setting, and at reduced costs.
Dr. Stephan joined the Clinical Research Division at Fred Hutchinson Cancer Research Center (FHCRC) as Assistant Member in 2012 to establish a research program that will steer the implementation of next-generation ovarian cancer therapies derived from smart biomaterials and nanotechnology. During his postdoctoral training at the Massachusetts Institute of Technology, Dr. Stephan specialized in synthesizing and applying synthetic material to manipulate immune cells (Nat. Med. 2010 Sep). Coupled with his PhD training in tumor immunology at Cornell University (Nat. Med. 2007 Dec), this experience places Dr. Stephan in an excellent position to develop novel bioengineering approaches for safe and effective ovarian cancer therapy. In recognition of the success he has already achieved, which has been highlighted in a number of reviews, Dr. Stephan was recognized with the “Future Leader in Translational Medicine Award” by the American Academy for Cancer Research, and the Ruth L. Kirschstein National Research Service Award from the National Institutes of Health.
Dr. Stephan’s Liz Tilberis Early Career Award is aimed at creating a new nanoparticle-based reagent that can quickly reprogram a patient’s own white blood cells (specifically T-cells) to recognize and destroy ovarian tumor cells. Dr. Stephan’s vision is that genetic engineering of T cells, which researchers currently perform in the laboratory, could one day be accomplished directly in ovarian cancer patients. Instead of drawing blood, isolating T cells, genetically modifying them to target the ovarian tumor, growing billions of copies, and then infusing them into the patient, injected nanoparticles could quickly attain the same result in the patient’s body. The gene therapy developed by Dr. Stephan and his team would allow doctors to immediately treat diagnosed ovarian cancer patients with an ‘off-the shelf’ reagent that can reprogram their immune system to selectively destroy cancer cells, without damaging healthy tissue. Thus, his research may provide the basis for prompt and effective treatment of ovarian cancer.