Glioblastoma (GBM) is a highly malignant brain cancer that cannot be cured with surgery, radiation and chemotherapy. Survival of patients afflicted with this cancer is less than 15 months. Several clinical trials have failed to improve this survival. Even immunotherapy that has seen success for several cancers has not been effective in GBM.

Oncolytic viruses are laboratory engineered versions of viruses designed to specifically attack tumor cells, like GBM. This causes GBM cell death but also sets up a “vaccine-like” response, allowing for the immune system to further attack and hopefully destroy the GBM.

Dr. Chiocca has been involved in clinical trials of oncolytic viruses for GBM and has completed a 51-patient clinical trial in GBM using an oncolytic virus based on herpes simplex virus 1 (HSV). Using experience and knowledge from this trial, he proposes to bring a “next-generation” oncolytic HSV to the clinic. This “next generation” oncolytic virus was designed to increase the ability of the virus to grow in and destroy GBM cells while also remaining safe in normal tissues. To get this new oncolytic virus to the clinic to treat human patients, Dr. Chiocca needs to perform studies requested by the FDA to show that the clinical lots can be grown and have met predefined quality metrics, and that this new oncolytic HSV possesses a safety profile in mice that allows dosing in human patients. These studies, which will be funded through a grant from ACGT, will allow Dr. Chiocca to file an Investigational New Drug application to the FDA that will permit him to start this new clinical trial.

Glioblastoma is the most common and aggressive type of primary brain tumor. Despite therapeutic advances over the past decade, the diagnosis of glioblastoma is associated with a median overall survival time of 8 months and a 5-year survival rate of less than 5%. Even if treatment with the current standard of care for glioma patients, which consists of surgery, temozolomide, and radiotherapy, is initially successful, nearly all malignant gliomas eventually recur. At the moment of recurrence, no treatment successfully cures the disease. 

Naturally occurring or genetically modified viruses that selectively kill cancer cells are called oncolytic viruses. 

In our laboratory, we have developed a platform of oncolytic viruses termed Delta-24. A new generation of this cancer-selective oncolytic adenovirus model, Delta-24-RGD, has arrived in the clinical arena and has been tested in patients with recurrent glioblastoma showing encouraging safety and efficacy results. Thus, 20% of patients treated with Delta-24-RGD as a single treatment survived more than 3 years after a single dose of this biological agent. Unfortunately, rapid clearance of the virus by the immune system prevents a response in a higher percentage of patients. In addition to other pre-clinical and clinical evidence, data from our clinical trial demonstrate that to improve the percentage of patients that respond to the therapy, we need to decrease the immune response against the virus, which in turn will increase the immune response against the tumor. 

Therefore, this proposal aims to improve the response to virotherapy by attenuating the immune response against oncolytic adenovirus, with the goal of boosting the anti-tumor efficacy of this strategy. To this end, we propose two different strategies that can eventually be combined in a clinical trial. The first approach consists of making the virus less detectable by the immune system via substituting the most immunogenic viral protein with another viral protein for which the patients have not developed a pre-existing immune response. This new virus will persist longer in the tumor environment and thus maintain the window of opportunity to develop an anti-tumor immune response for a more prolonged time. 

Our second approach involves the generation of tolerogenicity for the virus. To achieve this objective, we will target dendritic cells, which are in charge of the antigen presentation to the immune effector cells, using nano molecules to deliver viral antigens. 

This strategy will diminish the response of the immune system against viral antigens, allowing the immune defenses to be focused on the tumor. If this highly innovative project is successful, we have the resources and infrastructure already in place to further translate these two strategies, as single approaches or in combination, to treat malignant brain tumors in the clinical scenario. 

Glioblastoma (GBM) is the most common brain cancer and remains largely incurable. The recent identification of chemotherapy and radiotherapy resistant stem cells in GBMs may help explain why conventional therapies are ineffective.  

Immunotherapy may be able to kill GBM stem cells since immune-mediated killing does not rely on the conventional mechanisms of cell killing. HER2 is tumor protein is positive in >80% of GBMs, but not by the normal brain, making it an attractive target for immunotherapy.  

We have shown that HER2-specific T cells from GBM patients kill GBM stem cells and induce remission of GBMs grown in mice. We now wish to evaluate our approach clinically and test if HER2-specific T cells can be safely given to patients with HER2-positive GBMs (Aim 1) and intend to study their will persistence and antitumor activity in the human body (Aim 2).  

While our preclinical studies demonstrated the potent antitumor activity of HER2-specific T cells, tumors recurred in several treated animals. This limitation in T-cell efficacy is most likely due to the inhibitory tumor environment. GBMs (including GBM stem cells) contain high level of the STAT3, a protein which is not only necessary for GBM stem cell survival but also induces the expression of T cell suppressive factors. Thus, Aim 3 will test in preclinical models our hypothesis that combining STAT3 inhibition with HER2-specific T cells will more effectively eradicate GBMs than T cells alone.  

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.