New Avenues for Neurofibromatosis Therapy
Abstract
Neurofibromatosis (NF) is a disease that has several manifestations, some fairly innocuous and others severe. NF, which affects about one in every 3,000 people, is a genetic disease caused by a single mutation in the neurofibromin gene. Loss of neurofibromin results in uncontrolled activation of a well-known oncogene (cancer-promoting gene), which in turn results in an overgrowth of nervous tissue. Patients show symptoms that range from learning disabilities to attention deficit to social and behavioral problems. These individuals are also likely to develop small, diffuse, usually benign tumors, most often on the skin, eyes, and nervous system or in bone tissue. About 20% of those who have type 1 NF (NF-1) develop malignant tumors, specifically, malignant peripheral nerve sheath tumors (MPNSTs). These tumors are often associated with weakening of the immune system, which strips the body of its natural defenses against malignancy. Our proposal seeks to establish a new therapeutic approach for MPNSTs from NF-1 patients. This approach harnesses the principles of immunotherapy, whereby the patient’s own immune system is turned against the tumor. We have developed a powerful synthetic biology platform (STRICT, for Synthetic Tumor Recruited Immuno-Cellular Therapy) that incorporates (1) particular genetic elements, called promoters, that function differently in tumor cells and in healthy cells and (2) immune-stimulatory molecules. We anticipate that STRICT will essentially set the malignant NF-1 cells on a path of self-destruction. We propose, first, to identify those promoters that are specifically active in a malignant human NF-1 tumor cell line by screening our substantial promoter libraries. Second, once these promoters have been identified, we propose to incorporate them into engineered genetic circuits. These circuits, when delivered to cells in culture or to an animal model of NF-1, will be activated only in the MPNST cells; that is, they will have targeted specificity for the diseased cells. Once activated, the circuits will do two things: (1) they will express a particular class of proteins, called T-cell engagers, that appear on the surface of the cell carrying the circuit, sending a signal to cells of the immune system to come and kill that cell; and (2) additionally, the circuits will express and secrete particular proteins (called cytokines and chemokines) that boost the immune response so that the immune cells are more highly responsive to the disease and more likely to seek out and kill tumor cells. Third, we will test the ability of these circuits to cure the malignant symptoms of the disease in a mouse model of NF-1. Since we have already established the effectiveness of STRICT against ovarian cancer, both in culture and in an animal model, we hypothesize here that STRICT will be effective in eliciting a strong immune response that eliminates MPNST cells but does not harm healthy cells, thereby providing the basis for a future therapeutic for NF-1.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910555
Entities
People
- Timothy K. Lu
Organizations
- Massachusetts Institute of Technology
- United States Army