Tuning MSCs to Antitumor Property for Ovarian Cancer Therapy
Abstract
Ovarian cancer is a life-threatening tumor in women as diagnosis often occurs at a late stage. In recent years, a new therapy type, named immunotherapy, has been broadly investigated for ovarian cancer in hopes of improving the survival rate and reduce tumor recurrence beyond that achieved with standard surgery and chemotherapy treatment. The immune system in our body is capable of eradicating cancer in the same way that it is able to combat infectious diseases. There is a clear logic to developing immunotherapy that harnesses the power of the body’s immune system to destroy ovarian cancer cells. However, an ovarian tumor often develops ways to evade and neutralize these immune attacks, thus resulting in cancer progression. It is widely recognized that development of cancer immunotherapies favors combination strategies for both eliminating immune suppression and enhancing the antitumor activity of immune effector cells. Mesenchymal stem/stromal cells (MSCs) are cells that can mature into a variety of cell types. They play important roles in regenerative medicine and immune modulation. MSCs have been approved in the treatment of graft-versus-host disease in humans. MSCs have also been studied for cancer therapy as they are readily available, exhibit affinity for solid tumors, are not attacked by the immune system, and can be reliably grown in culture. In the context of ovarian cancer, MSCs have been deployed as gene-engineered delivery vehicles, where they are modified to express tumor-targeting factors and exert a tumor-killing function. However, gene engineering has always come with safety concerns. Unmodified MSCs are seldom used to treat ovarian cancer since several studies have suggested that MSCs might improve tumor growth. Nevertheless, more and more studies have confirmed the immunomodulatory and inflammatory modulation of these cells, and the role of MSCs in cancer therapy remains controversial because the subtypes of MSCs and their functional properties have not been fully defined. Successful engraftment of MSCs is a challenge for all types of free cell delivery to achieve lasting therapeutic efficacy. Biomaterials are useful tools to enhance cell engraftment. Biomaterials are also used to augment effectiveness of vaccine and immunotherapies. A great number of hydrogels or scaffolds were applied for tumor therapy in many aspects such as vaccine preparation, cell delivery, and drug-controlled release. We have previously demonstrated that gelatin microcryogels (GMs) provide 3D environment to protect MSCs from the sheer stress in the injection process, improve cell engraftment, and enhance antitumor efficacy of MSCs. Our preliminary study indicates a special subtype of MSCs within the heterogenous population that can orchestrate the immune system and act as antitumor agents. In this proposal, we will test a novel approach for treatment of ovarian cancer in a mouse model that contains antitumor MSCs delivered by injectable, biodegradable, biocompatible, non-antigenic GMs. The relevance of this work to the clinical setting is maximized by the fact that both active elements of this therapy can be accessed and approved for use in humans with cancer. We expect that this study could be finished in two years and, if this study is successful, MSCs could be pushed to clinical study in a fresh cancer-targeting angle. This might be beneficial to treatment of not only ovarian cancer but also certain other types of cancers. We expect to see improved effects of the GM-MSC construct resulting in a full recovery of effective immune responses against tumors and possible eradication of ovarian cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810585
Entities
People
- Huabiao Chen
Organizations
- Massachusetts General Hospital
- United States Army