THE STORY BEHIND IMMUNOVATIVE THERAPIES
Dr. Michael Har-Noy (formerly Michael Gruenberg), is the founder of Immunovative Therapies Ltd and the inventor of the Mirror EffectTM technology. He has overcome many hardships and worked for many years in both academic and corporate settings applying his medical, immunology and bioengineering expertise to try to harness the power of the immune system to treat cancer and HIV. Immunotherapy however has had a long history of disappointing results in the clinic. In the early 2000’s, when most of the biotechnology field, both academic and corporate, became very pessimistic about the prospects of incorporating immunotherapy as a modality for the treatment of cancer, Dr. Har-Noy persisted in his belief that immunotherapy could find a place in clinical treatment. One evening while analysing all the prior failed immunological data with his beloved dogs on his lap, Dr. Har-Noy had a “eureka moment”.
Overcoming difficult hurdles
Therapeutic cancer vaccines designed to stimulate an immune response against cancer had disappointing results in the clinic. This was thought to be due to the ability of tumors to both suppress a potentially effective immune response and to divert an effective response into an ineffective response. These properties of cancer were frustrating immunologists and some even declared that it might not be possible to overcome these hurdles.
‘The holy grail’ of transplant research: Separating the GVT effect from GVHD
Dr. Har-Noy was studying an effective immune response that could cure patients of chemotherapy-resistant metastatic tumors. This is the immune response that occurs when you transplant a healthy immune system from a tissue matched donor (usually a sibling) into a cancer patient. After transplant, the donor immune cells (graft) mediate a powerful anti-tumor mechanism called graft vs tumor (GVT) effect that was curative for many types of cancer. The GVT effect has been described as the most powerful anti-tumor mechanism ever discovered because it can kill chemotherapy-resistant metastatic cancer. Unfortunately, the GVT effect was intimately related to a devastating, often lethal, side effect where the graft cells also killed normal host tissues. This side effect is called graft vs host disease (GVHD). The toxicity and intimate relationship of GVHD with GVT limited the clinical application of stem cell transplantation. This lead many to investigate ways to separate the beneficial GVT effect from the detrimental GVHD side effect, Those in the transplant field state that the separation of the GVT effect from GVHD is the “holy grail of transplant research”
Despite considered efforts and resources being dedicated to try to separate GVT from GVHD, the effects could not be reliably separated. While the field was working on ways to separate the GVT effect from the GVHD effect, Dr. Har-Noy realized the effects needed to remain intact and related in order to mediate the road map of immune-mediated tumor killing.
Reversing the direction of the immunological flow
Dr Har-Noy’s innovation was to imagine that the effects could remain intimately related, but the direction of the immunological flow reversed. Dr. Har-Noy proposed that the immunological flow could be initiated from the host instead of the graft, whereby the infusion of graft cells would be rejected by the host (host vs graft or HVG). In order to assure the proper signals were released upon HVG rejection, Dr Har-Noy bioengineered a graft with the properties he believed would support HVT effects. This bioengineered graft is known as “AlloStim®”, is now the lead product candidate of Immunovative®. The concept and technology for reversing the flow of the immunological events of transplant from combined GVT/GVHD to HVG/HVT was called the “Mirror EffectTM”.
Developing the Mirror Effect Technology
Dr. Har-Noy founded Immunovative Therapies to develop products based on the Mirror EffectTM technology. The Company has recruited a team of professionals in manufacturing, immunological monitoring, clinical trials and business to create a company with the technology, expertise and business expertise backed by a family of experienced financial entrepreneurs and investors to become a leader in the biopharmaceutical field.
AlloStim® has successfully completed pre-clinical development, manufacturing scale-up and was cleared as an Investigational New Drug (IND) by the USA FDA in 2009. AlloStim® has now advanced to the Phase II/III clinical development stage. This is the last clinical stage before applying for permission to market from the FDA.
Successful development of Mirror Effect products could have a dramatic impact on patients suffering from cancer and incurable infectious diseases, and could radically change clinical practice.
Harnessing the power of the immune system to treat cancer and HIV
Dr. Michael Har-Noy, the founder of Immunovative Therapies, Ltd has extensive experience in medicine, immunology and bioengineering with special expertise in cellular therapies and large-scale production of living mammalian cells. His inventions include: hollow-fiber bioreactor technology used world-wide for the large-scale production of cell-derived biological products and technology for the large-scale expansion of immune cells without the need for toxic cytokines. Dr. Har-Noy has worked for many years in both academic and corporate settings, applying his medical, immunology and bioengineering expertise to harness the power of the immune system to treat cancer and HIV.
Concept 1: Infusing expanded immune cells to patients
His first attempts to harness the immune system power to treat disease were based upon the hypothesis that patients with cancer and HIV had weakened immune systems. Therefore, Dr. Har-Noy applied his immunology and bioengineering expertise in an effort to isolate and then expand immune cells to enormous numbers outside the body using specialized, custom bioreactors. The concept was to strengthen weakened immune systems by removing immune cells that were in short supply, growing them to large numbers in a bioreactor and then infusing the expanded immune cells back to patients. Despite being successful in expanding as few as 1 million immune cells to over 100 billion in bioreactors, he was never able to achieve dramatic anti-tumor immune responses in patients using this advanced technology.
Concept 2: Adding vaccine methods to immune cell expansion technology
Dr. Har-Noy then hypothesized that perhaps quantity was not enough and that quality of the immune cells might be the solution for boosting immune responses to cancer. Based on this concept, he started to experiment with adding vaccine methods to his immune cell expansion technology. Vaccine technology, he reasoned, could first educate immune cells against tumors. Then these ‘educated’ immune cells could be isolated and expanded as therapy. Again these attempts were a great technological success, but still did elicit results in the clinic that generated great excitement.
By the early 2000’s, many cancer vaccines failed in late stage clinical trials. Cell therapy methods remained only a laboratory boutique therapy, without much commercial promise. In addition, many failed attempts to develop vaccines against HIV were being reported. This added to previous failures to develop vaccines against hepatitis C. The culmination of negative news in the immunotherapy field resulted in leading oncologists and venture capital groups believing that immunotherapy was not going to work. Funding for immunotherapy became very difficult and many immunotherapy companies went out of business during this period.
Sustaining belief in immunotherapy
Dr. Har-Noy persisted in his belief that immunotherapy could find a place in clinical treatment. He was able to raise funds from private investors and physicians to keep his research active. Some insights into the reasons for the observed lack of efficacy of cancer vaccine treatment approaches were revealed. Numerous reports were published describing how tumor cells were able to evade immune attack and actively suppress the immune system. These immune avoidance mechanisms and immune suppressive mechanisms were powerful, complicated and redundant, which only served to solidify belief that a vaccine to treat existing cancer and HIV could never be achieved.
Witnessing an interesting phenomenon
In the background of the negative wave pouring over immunotherapy research, Dr. Har-Noy joined the bone marrow transplant department at Hadassah Medical Center in Jerusalem in 2003. While at Hadassah, Dr. Har-Noy witnessed an interesting phenomenon that was first reported by the National Cancer Institute in 1996. When patients with cancer received a transplant of immune cells from a normal donor (usually a sibling), these cells were able to kill metastatic tumors that were resistant to chemotherapy. This proved to him that it was possible for the immune system to overcome the obstacles preventing the effectiveness of immunotherapy. It was also reported that a patient with HIV that received a transplant to treat his leukemia was subsequently put into long-term remission for his HIV disease. However, most of the patients whose tumors disappeared after transplant also suffered from a side effect where the same immune cells that killed the tumor also killed normal cells. This horrible side effect of transplant is called GVHD. GVHD is a devastating and often lethal side effect of transplant procedures.
Discovering anti-tumor phenomena is not a simple recognition of foreign cells
While much of the transplant field was trying unsuccessfully to separate the beneficial anti-tumor effects of the transplant procedure from the devastating side effects, Dr. Har-Noy found it interesting that transplant procedures led to an immune-mediated ‘sterilization’ of tumor cells from the body and subsequent development of ‘memory cells’ that could prevent recurrence of tumors. While most researchers at the time believed the anti-tumor effects of the transplant procedures were due primarily to the recognition of the donor immune system of the tumor cells in the patient as foreign, Dr. Har-Noy and others found that transplant patients developed immunity to the tumors within their own immune cells. This suggested that the anti-tumor phenomena were not a simple recognition of foreign cells, as anti-tumor effects could be elicited in the host immune system against host tumors. Dr. Har-Noy was also intrigued to understand how the donated immune cells could kill the host tumors and overcome the tumor immunosuppressive and immunoavoidance mechanisms that were preventing development of effective vaccines.
Building a road map of the anti-tumor effect
Dr. Har-Noy conducted immunological tests on both bone marrow transplant patients and mice. This provided immunological data describing how transplanted immune cells could eliminate tumors and overcome the tumor’s ability to evade immune attack. It was noted by Dr. Har-Noy and others in the field, that the best responders to transplant suffered from the worst GVHD side-effects and often died of the side-effect even though their tumors were eliminated. By analyzing the immunological data comparing responders to non-responders to transplant procedures as well as non-responders to a variety of cancer vaccines, Dr. Har-Noy was able to isolate, by a process of elimination, certain immune events that correlated with anti-tumor elimination after transplant. Analysis of this data provided a ‘road map’ of an immunological cascade of events that occurred in the responding bone marrow transplant patients, but not in the others. Dr. Har-Noy realized that this road map defined the mechanism that a successful vaccine needed to elicit in order to kill tumors and disable their ability to avoid immune attack.
Having a road map of this proven anti-tumor effect that resulted in curative responses in many patients, Dr. Har-Noy was able to reverse engineer this effect to design a novel donor cell type. These patent cells are known as AlloStim®. AlloStim® is completely mismatched living immune cells that are bioengineered to elicit the same anti-tumor effects of transplant but without the toxicity of GVHD.
Revolutionising how we treat incurable diseases
This discovery accomplished what the transplant field and vaccine fields have attempted to accomplish for decades. Thus, Dr Har-Noy and Immunovative Therapies are the first and only to separate the powerful GVT effect from GVHD toxicity. It is believed that this discovery has potential to change the manner in which we treat disease and has potential to benefit millions suffering from incurable diseases.