Monter Cancer Center: Div. Northwell Health System, USA
In order to achieve effective control ofadvanced colorectal cancer having failed standard therapeutic approaches, we are employing specific monoclonal antibodies that were developed in our facility to target oncofetal proteins expressed in this tumor system. Phase II FDA trialshave been completed in this group of patients with evidence of positive therapeutic responses.
Pooled allogeneic tumor membrane protein was utilized to identify those immunogens found in colon cancer specimens with the goal of eventually employing them as therapeutic vaccines. Three oncofetal proteins that characterize colorectal Ca were identified. These proteins were evaluated for structure and the role they played in the developing malignancy. It was noted thatthey were always present in the tumor but at sub threshold levels necessary for activating the host immune system. In addition they were found to be absent in essentially all normal colon specimens examined.
Because of the sub threshold levels at which the single or combination of oncofetal proteins were expressed in the malignant state an ineffective immune response that is normally present with bacteria and viruses, is unable to prevent tumor growth and subsequent progression of disease. In order to obtain the needed host immune recognition of lesions such as metastatic colorectal cancer we have found that by pooling these oncofetaltumor membrane proteins, that the proper threshold level of antigen needed toact as an effective immunogen (vaccine), can be achieved. This level has been determined to be approximately 500 ugm. of antigen delivered intradermally in 3 divided monthly doses along with an effective adjuvant. In examining levels of antigen expressed in an entire tumor specimen used in our preparations it was rare to find levels above 10-25 ugm. This explains why once malignant transformation occurs, it continues unabetted since immune suppression is not initiated by the host immune system. Among those treated using pooled antigen as a vaccine, it was found that the high rate of clinical cures seen, was not achieved by the increased number of cytotoxic T cells, but rather by the expression of high levels of an IgG1 targeting the tumor immunogen with subsequent tumor destruction via ADCC (antibody dependent cell cytotoxicity).
At the 2015 ASCO GI Symposium in San Francisco, CA, results of the Phase 1 study of Neo-102 in chemotherapy refractory metastatic colorectal cancer patients revealed a Maximal Tolerated Dose of 3.0 mg/kg IV every 2 weeks. The overall survival observed in this demonstrated 10.4 months comparing favorably to the historical control for a similar population of patients with advanced colorectal Ca (5 months). This has led to a larger Phase 2 multi-center colorectal cancer study using Ensituximab(Neo-102) in the same patient population where results are being confirmed. Because tumors do shed an inhibitory molecule into the serum blocking many of the anti-tumor effects of IgG1 in its ADCC response, new trials are being designed to initiate the study somewhat earlier and with low dose chemo being added to minimize inhibitory antigen. This will follow with the eventual addition of IL-which does enhance NK cell activity.
Biography:
Dr. Myron Arlen, M.D. is a Principal Founder of Neogenix Oncology Inc. in 2003 and has been its Director of Medical Affairs since March 2010. Dr. Arlen has substantial executive experience in the biotechnology industry. Dr. Arlen served as the Chief Executive Officer of Neogenix Oncology Inc. from 2003 to March 2010. Dr. Arlen served as Chairman of Neogenix Oncology Inc. and served as its Director from 2003 to January 2012. Dr. Arlen was trained as a cancer surgeon at Memorial Sloan-Kettering where he remained on staff for 20 years involved in the surgery of advanced cancer problems and the immunotherapeutic approaches to managing the patients. Dr. Arlen established the Surgical Oncology Division at North Shore University Hospital, and formed a practice group (North Shore Surgical Oncology Associates). He has written two major textbooks and published over 80 journal articles related to cancer treatment. In the 1990ʼs, Dr. Arlen helped to found another biotechnology company, International Bio-Immune Systems, Inc. of which he was part of management until 2003
Biological Mimetics, Inc, USA
Over the last 250 years, the use of vaccines, a mainstay of preventative medicine and public health has proven to be one of the most successful and cost-effective medical interventions ever discovered. Despite these great advances to human and animal health of the past 5 decades; the basic immunologic principals and technology does not for the most part work against the many remaining pathogens of humans and animals. This is mainly due to a combination pf evolved host evading strategies of the pathogens and yet unappreciated aleatory characteristics inherent within the vertebrate immune system. These combined make them inherently more resistant due to strain-restricted immunity/antigenic variation/poor memory/disease-enhancement/incomplete immunity and/or shortened forms of immunity all are a major gap in our understanding of the complex evasion mechanisms evolved by the pathogens. “Deceptive Imprinting” is at the heart of a new understanding of how the host may respond to mutable pathogens to create a molecular diversion (decoy) at the level of both the innate and acquired immune host defense systems much like how metallic chaff would confuse a radar system trying to locate a missile or plane. On an immunologic level immunodominance, repertoire sculpting and antigenic variation are coupled such that host immune responses are directed to more strain-restricted and less or non-protective B and T cell immune responses. To circumvent this host evading mechanism we have developed a first generation technology called Immune Refocusing that has been designed specifically to reorder the non-protective immunodominance by identifying/mapping the decoy epitopes and molecularly removing or attenuating it thus redirecting the host immune system to the more protective regions of the microbe.
This lecture will bring together new paradigm shifting first principals of Deceptive Imprinting, immunology, new insight from querying pathogen genomes through “Pressure Point” Technology and application of the technology of Immune Refocusing. These paradigm shifting scientific insights have opened up fresh new approaches to technical advancement and the development of new antigens that can be used for vaccines and deriving new monoclonal antibodies toward inducing improved and broader protective immunity.
Biography:
Dr. Nara currently is the Chief Executive Officer, President, Chairman & co-founder of Biological Mimetics, Inc. and holds the Endowed Eugene Lloyd Entrepreneurial Chair and Professor in Vaccinology, founding Center Director for the Center for Advanced Host Defense, Immunobiotics, and Translational Comparative Medicine in the Department of Biomedical Sciences, in the College of Veterinary Medicine at Iowa State University, is an adjunct professor of Microbiology/Immunology, Carver College of Medicine, University of Iowa. Dr. Nara holds a M.Sc. in Immuno-pharmacology, a combined Doctor of Veterinary Medicine and Ph.D. (retro-virology/oncogenesis) from The Ohio State University, 4 year combined residency in Comparative Pathology and NIH senior post-doctoral Fellowship at both the Armed Forces Institute of Pathology and the NIH respectively. He has received numerous awards and recognition and in 2011 was elected as a Fellow of the American Association for the Advancement of Science (AAAS) for his work related to Deceptive Imprinting and Immune Refocusing Technology.
University of Central Florida, Burnett School of Biomedical Sciences, USA
Type 2 immune stimuli are unique. Unlike Th1 or Th17 stimuli which rely heavily on pattern recognition, type 2 agonists share very little in common with each other. Despite this, diverse type 2 stimuli are able to promote very similar downstream adaptive immune responses. This knowledge has, in turn, led to the development of therapeutic approaches which, for the most part, target the symptoms but do not modify the course of type 2 inflammatory diseases. This then raises the questions, “What do we currently understand about the rules governing type 2 immune initiation?” and “Are we currently using the right tools to enable us to come to a unified view of how our innate immune system recognizes and responds to type 2 agonists?”
This presentation will give an overview on what is currently known about innate immune recognition of type 2 stimuli, the approaches that can be used to develop a type 2 innate immune signature, and the potential therapeutic applications of such a strategy.
Biography:
Dr. Justine Tigno-Aranjuez received her B.S. in Molecular Biology and Biotechnology from the University of the Philippines. She received her PhD. in Pathology from Case Western Reserve University studying the role of adjuvants in shaping T cell responses. She continued at Case Western as a Postdoctoral Fellow and Instructor doing research on the posttranslational control of signaling mediated through the bacterial peptidoglycan sensor NOD2. She is currently an Assistant Professor at the University of Central Florida and continues to study innate immune signaling pathways in inflammatory diseases.
She has published in journals such as Genes & Development, Molecular and Cellular Biology, Cell Reports, The Journal of Immunology, and the Journal of Biological Chemistry. While at Case Western University, she also filed 2 patents in which she was 50% co-inventor. She has been the recipient of an American Cancer Society Postdoctoral Fellowship, an NIDDK NRSA F32 award, and is currently NHLBI K99/R00 recipient.
Institute of Human Virology-School of Medicine, University of Maryland
When referring to a virus strain we are describing the most abundant variant from a closely-related virus swarm containing individual particles with broadly-distributed mutations. A viral isolate containing many variants, called quasi-species, could act as a unit of selection through a continuous dynamic process of genetic variation, competition, and selection. However, it is important to emphasize that the whole “virus swarm” contributes to the characteristics of the virus strain and will be the target of selection instead of individual variants. For example, some variants carrying lethal mutations not only compete with the fittest replicating unit but also cooperate with other mutants complementing each other, thus assuring the survival of the units containing “lethal mutations”. Several studies describe the effect of the mutant spectra in the virus population phenotype making it more virulent or more attenuated according to the predominant quasi-species. For example, defective interfering particles could play a role in attenuating the virulence of a viral swarm by interfering with virus replication. In the case of live vaccines, the final goal is to select one population with attenuated phenotype (low pathogenicity) and high genomic stability (increased fidelity of replication). Ensuring that the viral population, contained in the preparation, does not have the capacity to adapt to new conditions in the host due to low quasi-species diversity but replicating enough to induce protection.
Thus, changes in virus diversity, can affect virus fitness and viral tropism and produce a spectrum of unexpected outcomes after vaccination depending on particular conditions of the virus-host interaction.
With the new sequencing tools, it is easy to characterize viral populations, in this case in vaccine preparation, which allows controlling the proportion of each viral-quasispecies.
This talk will be focused on the use of the study of viral populations for vaccine characterization using as a model a Lassa vaccine candidate.
Biography:
Juan Carlos Zapata research interest is in virus-host interactions using animal models, genomic profiling, and basic molecular virology. It is focused not only on host responses but also on changes that occur in the viral population in order to describe virus-host coevolution. During the characterization of the Lassa vaccine candidate ML29, he identified mutations in the arena virus nucleo capsid protein (NP) that are likely to impact viral pathogenesis and the induction of protective immunity. Additionally, he is involved in a new line of work focusing on retroviral latency. Under Dr. F. Romerio leadership he is working in detecting and characterizing viral factors related with HIV latency in the reservoir cells and with Dr. Y. Tagaya he is implanting patient-derived ATL cells into NSG mice to study cancer pathogenesis, treatment options, and vaccine development against HTLV-1.
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