Neurofibromatosis type 1 (NF1) is the most common genetic disease causing nervous system tumors. The defining tumors of NF1 arise in the peripheral nervous system (PNS) and include discrete and plexiform neurofibromas. Neurofibromas can and do occur virtually everywhere on the body, with new and multiple tumors developing throughout life. While benign and slow growing, neurofibromas may be debilitating and disfiguring. Moreover, plexiform neurofibromas can progress to malignant peripheral nerve sheath tumors (MPNST) in about 9% of patients, and represent the most frequent cause of death in NF1 patients. These NF1 tumors have an abnormally large number of blood vessels. There are no curative treatments for neurofibromas or MPNSTs. The standard treatment is surgery, but clearly there are limitations to the number and times tumors can be removed and the risks of nerve and muscle damage.
We have developed a novel therapeutic strategy that uses oncolytic viruses to kill tumor cells, sparing normal cells. The virus we use is herpes simplex virus (HSV). The basis for this strategy is that the virus will grow in the tumor cells, making new virus that will spread throughout the tumor and kill it. To make HSV suitable for therapy, it is genetically altered so it cannot cause disease or spread in normal tissue. By removing genes from the virus, we make space to insert therapeutic genes. The goal of this application is to test oncolytic (tumor-killing) HSV in NF1 tumor models in order to obtain the data needed to perform a clinical trial. We have experience using this strategy in another nervous system tumor. We developed an oncolytic HSV, G207, that has been tested in patients with malignant glioma, a lethal brain tumor. In a phase 1 clinical trial, it did not cause any serious adverse effects. The oncolytic HSV vector we will use here, G47delta, is derived from G207 and has improved antitumor activity but similar safety as thus far tested.
Because NF1 tumors are so vascular, we have inserted genes that have anti-angiogenic activity (inhibit the growth of new blood vessels), as well as other antitumor activities, into G47delta in order to enhance its efficacy. These genes encode either: (1) a dominant-negative fibroblast growth factor receptor (dnFGFR), a major tumor signaling pathway; (2) platelet factor 4 (PF4), a chemokine with immune activities; and (3) interleukin 12 (IL-12), one of the most powerful antitumor cytokines. We hypothesize that the combination of oncolytic HSV tumor cell killing and the expression of these transgenes in the tumor environment will provide a powerful and clinically translatable novel therapy for NF1 tumors. We have constructed G47delta vectors expressing dnFGFR, PF4, and IL-12 and already have NF1 tumor models in place. These vectors will be tested in a number of NF1 tumor models: human NF1-deficient neurofibroma and MPNST cell lines implanted into immune-deficient mice and mouse MPNST cell lines implanted into immune-competent mice. Tumors growing in the subcutaneous space, to model subcutaneous neurofibromas, and in the sciatic nerve, to model internal tumors, will be injected with the oncolytic viruses or treated by systemic intravenous delivery. The goal of these studies is to identify the best vector for initial clinical translation, making it sure it is both safe and effective.
As most successful tumor treatments involve multiple forms of therapy, we will also examine whether this strategy, using oncolytic HSV vectors, can be combined with novel drug therapeutics. We will test approved tyrosine kinase inhibitors, Gleevec and Sutent, which can target both NF1 tumors and their blood vessels. By bringing to bear this array of agents able to destroy the diverse cells in NF1 tumors, we will improve the likelihood of a positive clinical outcome for patients.
This application involves a strong multi-disciplinary, multi-institutional consortium in a focused strategy to enable the move of the transgene-expressing oncolytic HSV vectors from the laboratory into the clinic for an effective treatment of NF1 tumors. Our team of investigators is a highly experienced group of NF specialists with complementary expertise, both in clinical medicine and in the basic sciences who have a long history of collaboration. Dr. Rabkin, Massachusetts General Hospital (MGH), is a leader in the development of oncolytic HSV vectors and their translation to the clinic. Dr. Kurtz, Robert Koch Institute, is an expert in NF tumor models and angiogenesis. Dr. Martuza, MGH, is a neurosurgical leader in NF treatment, founder of the oncolytic virus field and of the NF clinic at MGH. Dr. Mautner, University of Hamburg, is a NF1 clinical expert, developer of NF tumor cell lines, and founder of the Hamburg NF Clinic. Dr. Stemmer-Rachamimov, MGH, is a neuropathologist with expertise in NF. Critical to the successful translation is the continuous involvement of NF clinical investigators to keep the preclinical studies focused on the ultimate goal of treating patients. We are confident that by completion of this grant, we will be in a position to begin treating patients with one or more of these vectors.