Institution Short Name: St. Jude Children’s Research Hospital

Many children, who are diagnosed with bone or muscle tumors (sarcomas), which have spread to more than one site in their body, cannot be cured. Thus, there is an urgent need to develop new therapies.  

We propose to develop a therapy, called immunotherapy, which uses the patient’s own immune system to destroy their sarcoma. Immunotherapies comes in many different forms, and this grant is focused on cell therapy, which consists of taking immune cells from patients, genetically engineering them to recognize and kill tumor cells, and then infusing cells back into the patient.  

Cell therapy has already been very effective for certain types of blood cancers. However, the activity of immune cell therapy against sarcoma and other solid tumors has been limited. In this Alliance for Cancer Gene Therapy funded research we will develop a novel approach to attack sarcomas with genetically engineered immune cells, which relies on attacking not only the cancer cell but also the supporting blood vessels, which are critical for tumor growth.  

In addition, we will explore if broadening the attack to target not only one, but two proteins present on sarcomas improves the anti-sarcoma activity of immune cells. State of the art technologies will be used, and we will test the anti-sarcoma activity of our immune cells in models that closely mimic human disease. At the conclusion of the research, we expect to have optimized our immune cell therapy approach for sarcoma and based on our results are planning to develop a clinical study.  

This Alliance for Cancer Gene Therapy Research Fellow is funded in part by Swim Across America and Wendy Walk.

Brain tumors are among the leading causes of cancer-related death in both adults and children, with malignant gliomas being one of the most aggressive and difficult to treat. Clearly, new strategies for treating patients with this disease are desperately needed. Type I interferons (IFN) have potent, pleiotropic anti-tumor activity. Despite exciting pre-clinical results, however, the anti-tumor efficacy of IFN in clinical trials has been limited.  

Important contributing factors have included a very short half-life, making effective dosing problematic, and significant systemic toxicity at therapeutic doses. We hypothesize that an alternative method and schedule of drug administration in which there is continuous, local delivery should avoid the systemic toxicity of IFN while maximizing its potent anti-tumor activities.  

We believe that a gene therapy approach in which adeno-associated virus (AAV) vectors are used to transfer an expression cassette for IFN-B to target cells is the safest and most effective way to establish continuous, local delivery of IFN. Because GBM, unlike most human cancers, is problematic locally, rarely being metastatic, it is a tumor particularly well suited for this approach. The overriding goal is to obtain sufficient preclinical safety and efficacy data to support and initiate a clinical trial of local AAV IFN-B mediated gene transfer for patients with recurrent malignant glioma. 

 The major specific aims are: Aim 1: To complete the demonstration of anti-tumor synergy between AAV-mediated local delivery of IFN-B and adjuvant cytotoxic therapy, in relevant brain tumor models. Aim 2: To assess the safety of AAV-mediated continuous local delivery of IFN-B in the brain using relevant rodent and nonhuman primate models. Aim 3: To perform a Phase I dose-escalating clinical trial of local administration of AAV IFN-B to the resection bed in patients with recurrent glioblastoma multiforme following surgical removal of recurrent disease. 

 We feel that our approach has a high likelihood of resulting in a successful clinical trial for the following reasons: 

 1. Pre-clinical data. We have very encouraging pre-clinical data using a highly relevant orthotopic rat resection model that AAV-IFN-B has significant anti-tumor activity against residual human GBM xenografts.  

2. GMP vector production facility. We have our own GMP facility on campus to make clinical grade AAV vectors. In addition, we have developed a baculovirus-mediated production system that generates AAV at very high titer. 

 3. Toxicity studies. We have access to nonhuman primates on campus to perform relevant, pre-clinical toxicity studies. 

 4. Experience with gene transfer clinical trials. We have just opened a clinical trial of AAV-mediated, liver-targeted gene transfer for hemophilia B.  

5. Access to patients. Through our collaboration with the Neurosurgery Department at the University of Tennessee Health Science Center, Memphis, we have access to a large number of patients.