Rewiring Suppressive Tumor Microenvironment Signals for Immune Activation Using T Cells Engineered with Synthetic Promoters
Abstract
Our research project will address the topic area of cancer immunotherapy. In the past decade, immunotherapy has revolutionized cancer treatment. While impressive results have been observed in some patients, the majority of patients with solid tumors do not respond to currently available immunotherapies. Past and ongoing research has identified several common mechanisms acting locally at the diseased site, by which tumors impede the anti-cancer function of immune cells. Efforts to counter-act immune suppression and boost anti-tumor responses with stimulatory compounds can improve the response rates, but also frequently increase the severity of side effects, which diminishes the quality of life and limits the maximal tolerable drug dose. In this study, we aim to selectively boost the immune response right at the tumor site to avoid systemic toxicities, thus improving therapeutic effects without eliciting severe adverse outcomes. One promising mode of immunotherapy is to genetically modify immune cells with enhanced anticancer properties in the laboratory, then reinfuse them into patients – a process termed adoptive cell therapy. Unlike molecule-based drugs, such as checkpoint blockade or targeted therapies, cell-based drugs are biologically dynamic and can be genetically programmed to sense-and-respond to specific conditions, thereby achieving precise therapeutic results. Our objective is to develop cell-based drugs consisting of molecular sensors that will specifically detect well-established immune suppressive signals found in many tumors. Once immune cells have been equipped with a sensor; the sensor will inform the infused cells of their proximity to the tumor, and only then activate the production of cancer-fighting compounds. Leveraging the programmability of cells, our proposed technology will allow selective delivery of anti-tumor therapeutics to safely and effectively augment the immune response. Adoptive cell therapy is a rapidly growing field with increasing clinical utility. Our pipeline can be readily integrated with current manufacturing practices for cell-based therapies. Given the therapeutic relevance of the tumor sensor technology, we expect our research products to be ready for clinical testing within 5 years after the completion of the current proposal. Importantly, selectively amplifying immunity in tumors by sensing the local physiological environment will usher in the next generation of effective treatments to minimize toxicity and preserve quality of life. Application of this conceptual advancement is not limited to any one type of cancer, thereby benefitting the general public and military personnel inflicted with a variety of cancers. Successful completion of this project will lead to novel cell-based therapeutic strategies that could translate to improved outcomes for cancer patients faced with intractable diseases.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110626
Entities
People
- Timothy K. Lu
Organizations
- Massachusetts Institute of Technology
- United States Army