Duke University

  • Project Contact: Michael Dickman
  • Title: Associate Director, Research Administration
  • Email: gcmail@duke.ed

  • Health

  • North Carolina

  • ---

  • School (Public charity)

  • $2,786,082,190 (2015)

  • 30,004

Executive Summary

We have developed a genetically modified polio virus (PVS RIPO) incapable of causing poliomyelitis to be used as oncolytic (cancer killing) immunotherapy applicable to all solid tumors, except Burkitt's Lymphoma. We have treated 41 patients with recurrent glioblastoma multiforme (GBM) brain tumors, one of the deadliest cancers, who were no longer responding to treatment. Median survival time was 15 months compared to 10.6 months in controls. There are 8 durable responses with 2 patients surviving more than 4 years. PVS RIPO exhibits killing in breast, prostate, pancreas, and other type cancers pre clinically. In addition to continuing trials with GBM, we will begin human trials in these treatment resistant cancers in a few years. The FDA granted PVS RIPO Breakthrough Therapy Designation and Orphan Drug Status for fast track approval for GBM. MacArthur funding would take PVS RIPO through to final approval by the FDA for GBM and extend the therapy to other major cancer types.

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The Problem

We are committed to solving the global problem of advanced, treatment resistant cancer. The burden of untreatable cancer in terms of human suffering, strain to health care systems, and economic loss is immense. We started investigations of PVS RIPO with one of the most deadly and treatment resistant cancers, recurrent GBM, for which there is no effective therapy. PRTBTC has worked with enough patients, using NIH and foundation grants, and philanthropy approaching $50 million to near completion of a 41 patient Phase I clinical trial with PVS RIPO. We lack funding to advance to Phase II trials and then to a multi institutional registration trial. After obtaining at least 30% to 50% long term survivors, and cures for GBM, we will extend PVS RIPO immunotherapy to most solid tumors, beginning with prostate, breast, and pancreatic cancer. PVS RIPO is the only cancer targeting virus capable of infecting/killing virtually any type of solid tumor (due to universal expression of the polio virus receptor in such tumors). Our Breakthrough Therapy Designation in recurrent GBM, a cancer for which immunotherapy is notoriously ineffective, suggests there are no limits to PVS RIPO therapy in any solid cancer. We believe combination therapy of chemotherapy and checkpoint inhibitors with PVS RIPO will increase the response to more than 50% of treated cancers of all types.

Proposed Solution

We have developed a novel immunotherapy approach for virtually all advanced therapy resistant cancers. We use a safe, genetically modified polio virus (PVS RIPO) to harness the cell killing and immune system boosting properties of poliovirus. After injection into a tumor, PVS RIPO kills tumor cells within reach, converts cold tumors into inflamed ones, and initiates a potent immune response. We have an FDA Investigational New Drug Permit and have treated 41 recurrent GBM patients with eight significant responses; the longest survivors living more than 4 years. The median survival of PVS RIPO treated recurrent GBM patients is 15 months, compared to 10.6 months in eligibility matched historical controls. Our solution is a staggered series of clinical trials to apply our cancer treatment to a broad range of cancers. The initial beneficiaries will be brain tumor patients; in the long term, our strategy will benefit patients with solid cancer types who have been unsuccessfully treated with other measures. The benefits will be durable, meaningful cancer control, prolonged life and/or cure. The benefits to humanity from our initiative will be enduring and may exceed what is currently deemed possible. PVS RIPO exerts a novel barrage of pro inflammatory and immunogenic events that produce immunotherapy responses that are not achieved with other proposed cancer targeting virus or immunotherapies. The polio virus has co evolved with Homo sapiens for millennia and therefore the human immune system is shaped to respond forcefully to polio type viruses.

Evidence of Effectiveness

Our proposed solution has been under formal evaluation by the FDA since 2005, including pre clinical regulatory assessment of our therapeutic agent, regulatory monitoring of manufacture and related safety and toxicology tests, and constant monitoring of our clinical trials. In May 2016, the FDA granted Breakthrough Therapy Designation for PVS RIPO against recurrent GBM. This is a very significant distinction, in particular for a strategy developed entirely within an academic institution by our team without involvement of major pharmacology enterprises. Breakthrough Status indicates that the FDA's opinion is that the promise for PVS RIPO in the therapy of brain tumors exceeds the potential benefits of currently available therapy. Separately, beginning in 1996, the pre clinical development of our strategy has been documented in numerous peer reviewed publications. Thus, the empirical foundations for all mechanistic aspects of our proposed solution have been scrutinized by the scientific community from the genesis of the original concept published in 2000 through its implementation into clinical practice culminating in Breakthrough Therapy Designation in 2016. In addition to reports of basic scientific investigations of the mechanisms of PVS RIPO immunotherapy, we have published many peer reviewed, comprehensive reviews on this topic. Our strategy has undergone thorough scrutiny by teams of investigative journalists culminating in two separate airings on CBS 60 Minutes in March 2015, and in May 2016.

Previous Performance

Success in cancer clinical trials is very low. This is why venture capital and the pharmaceutical industry are reluctant to invest and is a major reason we are reaching out to the MacArthur Foundation for support. The program would enable our thorough, conservative approach to cancer immunotherapy with polio virus, which has produced unprecedented results in one of the most difficult cancers to treat. The alternative, an accelerated venture or pharmaceutical investor driven process, is prone to failure or it will only reach easier to treat cancers that respond to already approved immunotherapies. Our Team is uniquely positioned to succeed where other organizations have failed. PRTBTC has been an international leader in neuro oncology and immunotherapy of brain tumors since the 1960s. We have the patient volume (more than 800 new malignant brain tumor patients annually) and a decades long history of successfully executing clinical trials that have led to FDA approval of standard of care agents such as Temozolomide and Bevacizumab. We are a National Cancer Institute Specialized Program of Research Excellence (SPORE) in Brain Cancer site and the early PVS RIPO trials were performed in the SPORE. We hold a National Cancer Institute Clinical Program Project grant, under which additional PVS RIPO GBM trials will be performed. We are international leaders in developing the technology of . We have an investigational pharmacy, embedded statisticians, an experienced regulatory staff, and excellent FDA relationships. We have collaborators at Duke University that can carry out clinical trials in other solid tumor types, such as breast, prostate, pancreas.

The Team

Team Purpose

There are 30,000 new cases of GBM annually in the U.S. and the European Union. Standard of care consisting of surgery, radiation, and chemotherapy in newly diagnosed GBM patients gives a median survival of 15 months; virtually all patients with GBM recur and die because of ineffective treatments. Brain cancer is the leading cause of cancer deaths in children. Cancer is one of the leading causes of death worldwide. The National Cancer Institute reports 14 million new cases and 8.2 million cancer deaths in 2012 (latest available). Our purpose at the Preston Robert Tisch Brain Tumor Center (PRTBTC) is to develop better treatment methods for malignant brain tumors in adults and children. Cure of malignant brain tumors and most types of other cancers is our ultimate goal. We have developed platform treatment technologies of PVS RIPO anti cancer immunotherapy plus chemotherapy and checkpoint inhibitors for GBM and all other major cancer types.

Team Structure

In addition to the leadership team and program membership described (attachment), we have two external groups that advise the team about the activities of the PRTBTC. The first is our External Advisory Board. These scientists are selected from academia and industry and possess broad experience and international recognition in their disciplines. We convene this group on an annual basis and present findings relevant to our grants. For example, projects supported by both of our NIH funded infrastructure grants are reviewed, which include clinical trials. Moreover, consultation is sought about most of our other important grant activities. In addition to our Scientific Advisors, our Brain Tumor Program Board of Advisors, a patient advocate group, has been in place for more than 20 years. They are patients or patient families that have been affected by brain tumors, or in some cases, by other cancers. We convene this Board twice a year with a day long presentation of current research activities. Each spring, a 5k walk and run follows and our patients and patient families compete with one another to raise money for unrestricted, philanthropic support of our work. For the last several years, the group has raised approximately $2 million with this event.