Immunotherapy: Activating Your Immune System to Fight Disease
SUNDAY, AUGUST 25, 2019
Kansas City Convention Center
301 W 13th St. 2100 Entrance, Room 2103 A
Kansas City, MO
WELCOME AND INTRODUCTIONS
Dennis Ridenour, BioNexus KC
ArtiCell® Forte: The First Allogeneic Stem Cell Based Veterinary Medicine for Equine
More recently, in search for treatment alternatives, cell-based therapies are being investigated because of their biological nature and regenerative potential. Intra-articular application of mesenchymal stem cells (MSCs) improves cartilage healing supported by in vitro observations having demonstrated that chondrogenic induced MSCs produce cartilage-specific substances, such as aggrecan, glycosaminoglycans, and collagen type II, which may aid cartilage repair. In 2019, the European Medicines Agency has approved the first chondrogenic induced stem cell based veterinary medicine for the intra-articular treatment of mild to moderate recurrent lameness due to non-infectious joint inflammation in lower limb joints of horses. To develop ArtiCell® Forte, it was of utmost importance to understand the importance of the tissue sources of the stem cells but also the selection of donor horses to assure the generation of a relevant clinical effect based on immunogenic and chondroprotective properties. Based on the MUMS requirements applicable for this product in the EU, the safety and efficacy of the product was tested: 75 adult horses with early signs of degenerative fetlock joint disease were enrolled in a randomized, multicenter, double-blinded, and placebo-controlled study conducted in Belgium. Fifty animals were injected intra-articularly with ArtiCell® Forte (IVP), and 25 horses were injected with 0.9% NaCl (saline) solution. From week 3 to 18 after treatment, lameness scores (P < 0.001), flexion test responses (P < 0.034), and joint effusion scores (P < 0.001) were remarkably superior in IVP-treated horses. Besides nasal discharge in both treatment groups, no adverse events were observed. On long-term follow-up (1 year), significantly more ArtiCell® Forte treated horses were working at training level or were returned to their previous level of work (P < 0.001).
Klaus Hellmann, KLIFOVET AG
Tammie Wahaus, ELIAS Animal Health, TVAX Biomedical
Autologous Activated T cell Therapy for Osteosarcoma of Companion Dogs
Canine osteosarcoma (OSA) is an aggressively metastatic primary bone malignancy with frequent chemotherapy failure. We hypothesized that dogs with OSA would be safely treated with autologous vaccination, adoptive T cell transfer (ACT) of ex vivo-activated T cells and low dose human interleukin-2 (IL-2) resulting in improved survival compared to carboplatin.
Jeffrey Bryan, DVM, PhD, University of Missouri
(Dr. Bryan will be presenting his research in conjunction with Elias Animal Health technology)
Immunotherapeutic Approaches in Canine Lymphoma
It is estimated that one in four pet dogs in the United States will develop cancer during their life-time. Lymphoma is one of the most common malignancies diagnosed in pet dogs, and non-Hodgkin’s lymphoma predominates. Similar to humans, standard of care for this disease in dogs includes multi-agent, CHOP-based chemotherapy. This has been shown to induce remission and prolong life. However, the median survival time for treated dogs is less than 1 year. Immunotherapy is a promising approach for improving outcomes in this disease. Various immunotherapeutic options are currently under investigation for the treatment of canine lymphoma. Anti-CD20, and others, monoclonal antibodies have been developed, but the clinical outcomes have been equivocal. Vaccines currently undergoing investigation include a xenogeneic DNA vaccine targeting CD20, a telomerase reverse transcriptase-based vaccine, and an autologous heat shock protein peptide chaperone-based vaccine. Additionally, T-cell based therapies have been developed with ongoing evaluation in canines. These include CAR T-cells targeting CD20, as well as autologous, activated, T-cell therapies. These various immunotherapeutic strategies will be discussed, including the results of a recent study assessing adoptive T-cell based therapy for the treatment of canine B-cell lymphoma.
Mary Lynn Higginbotham, DVM, MS, DACVIM, Kansas State University
Importance of Neoantigen Affinity for Determining the Effectiveness of Immunotherapy in Lung Carcinomas
Lung cancer patients with activating EGFR mutations tend to have poor response to immunotherapy, but not all activating mutation driven lung cancers. This study examined the relationship between differential agretopicity index (DAI), mutational burden (MB), and survival with mutated BRAF or EGFR genes in lung carcinomas (LUAD). The findings of the study describe a model for more robust antitumor immune response to immunotherapy in BRAF positive tumors compared to EGFR positive tumors. There is a strong relationship with DAI and higher mortality rate with BRAF positive tumors and no such relationship for EGFR positive tumors. Therefore, DAI is only important in determining patient outcome for select gene mutations.
Katrina Case, Pembroke Hill High School
Autologous Approaches to Cancer Immunotherapy in the Veterinary Market
Immunotherapy directs a patient’s own immune system to initiate robust and specific anti-tumor activity, and is fundamentally changing what it means to fight cancer. Tissue vaccines consist of material harvested directly from a patient’s own tumor, including cancer cells that present a rich assortment of tumor-associated antigens (TAAs) unique to in vivo growth, as well as extracellular matrix, fibroblasts, inflammatory cells and blood vessels. The collected tissue is deactivated and combined with an adjuvant, matrix immune modulator (MIM) that stimulates a Th1 mediated immune response. We will discuss the preclinical data, safety, efficacy and complementary approaches that Torigen is implementing in the immuno-oncology space.
Ashley Kalinauskas, Torigen Pharmaceuticals
Novel Therapeutic Bovine Ultralong Antibodies
Innovative solutions are required to address some of the most challenging human and animal diseases for which traditional methods have failed to produce effective countermeasures. A neutralizing B-cell epitope is the fundamental unit targeted by a neutralizing antibody to confer protection. However, some pathogens, such as Human Immunodeficiency Virus [HIV] and Porcine Reproductive and Respiratory Disease Syndrome [PRRSV], have a high mutation rate, such that the virus can escape antibody recognition. However, some rare epitopes are required for crucial function, and are thus not easily mutable. These epitopes are highly conserved among disparate strains and thus, they are targets for generating cross-protective neutralizing antibodies. These epitopes are often hidden, masked, or only exposed when needed. Identification of such epitopes is critical if prophylactics/therapeutic approaches to these challenging viruses are to succeed. We have found that the cow antibody repertoire has evolved unique structural and genetic features that may help us identify and understand neutralizing epitopes on viruses. Notably, we have demonstrated that immunization of cows with well-ordered HIV gp120 antigen or whole PRRS virus elicited potent broadly neutralizing antibodies. Overall, this approach will enable mapping of clinically relevant pathogen epitopes for development of contemporary prophylactics and or therapeutics.
Waithaka Mwangi, Kansas State University
Therapeutic Strategies for Spinal Muscular Atrophy
Spinal Muscular Atrophy (SMA) is the leading genetic cause of infantile death worldwide. SMA is caused by homozygous loss of the SMN1. With the recent clinical success of SMA therapeutics and the FDA approval of two novel therapeutics, the path towards second-generation compounds has been laid out by these early successes. To address the breadth and complexity of the SMA patient population, additional therapeutics are needed. To this end, we are examining a targeted series of SMA modifying genes, including Stathmin-1, to provide biological understanding and to develop novel therapeutic targets. The discovery of new pathways in combination with SMN-dependent strategies will hopefully begin to address the needs of all SMA patients.
Chris Lorson, PhD, University of Missouri
MONDAY, AUGUST 26, 2019
WELCOME AND INTRODUCTIONS
Mark Nichols, PhD University of Missouri – Kansas City
Harnessing Natural and Engineered Properties of NKT cells for Adoptive Cancer Immunotherapy
NKT cells are attractive carriers of chimeric antigen receptors (CAR) due to their inherent antitumor properties and preferential localization to tumor sites. Unlike conventional T cells, NKT cells are non-alloreactive and could be used as off-the-shelf therapies without the risk for graft-versus-host disease. However, low frequency of NKT cells in human peripheral blood presents a fundamental challenge for clinical development of NKT cell-based therapeutics. To address this limitation, we have developed the current good manufacturing practice (cGMP) protocol for rapid generation of large numbers of NKT and CAR-NKT cells from leukapheresis products. This technology has enabled the initiation of first-in-human CAR-NKT clinical trial in children with neuroblastoma.
Leonid Metelitsa, MD, PhD, Texas Children’s Hospital
State of the Industry for Advanced Therapies
The revolution in cell therapy began with the use of autologous cord blood cells for hematopoietic and immunologic reconstitution in patients with disorders affecting the
hematopoietic system. Most recently, genetically modified cell therapies such as Yescarta® and Kymriah™ are proving the power that human cells have to treat disease in truly transformative ways. However, the translation of preclinical promise of efficacy to the reality of clinical efficacy is particularly challenging and expensive. These transformative therapies must be affordable and accessible in order to be truly transformative. The challenges faced in the development of these advanced therapies encompass all aspects of product development. Manufacturing is expensive and must exceed pace of both nonclinical and clinical development. Demonstration of proof-of-concept in traditional nonclinical studies is constrained by species specificity. Demonstration of clinical benefit may need to rely on biomarkers that need to be validated in patient populations that are limited. With the recent plethora of updated and final guidance documents issued by the FDA, perhaps the least challenging aspect of product
development will be regulatory submissions. Regardless of these challenges the landscape for regenerative medicines is expanding, with clinical trials encompassing indications in oncology to lymphatic diseases. While only a few advanced therapy products have received full FDA approval to date, there are thousands that are at various stages of development.
Debra Aub Webster, PhD, Cardinal Health
Orion BioScience and the Development of ‘Soluble Antigen Arrays’ for Antigen Specific Treatment of Autoimmune Diseases
Orion is currently developing our ‘Soluble Antigen Array’ or ‘SAgA’ technology for the treatment of autoimmune diseases such as Type-1 diabetes, neuromyelitis optica, and myasthenia gravis. SAgAs combine both molecular and physical properties to produce a SOLUBLE and FLEXIBLE, antigen specific, multivaltent array. SAgAs leverage lessons learned across antigen specific immunotherapy approaches and are able to more efficiently drive the antigen specific restoration of peripheral tolerance through the induction of T and B cell anergy. By achieving activity in the lymphatics SAgAs also help promote regulatory bystander suppression through increased levels of antigen specific Tr1 type Tregs, IL-10 production, and an increase in traditional Tregs within the lymph and spleen. A further benefit of this antigen specific activity is an enhanced safety profile which will ultimately lead to our ability to treat patients earlier in their disease, as well as the many pediatric patients in a disease like Type-1 diabetes. These results have translated in our multiple in vivo efficacy, and safety/toxicity studies. Currently completed studies with SAgAs have shown an almost complete suppression of disease progression with no observed adverse events.
Joshua Sestak, PhD, Orion BioSciences
CAR-T: Continuation in a Revolution of Cancer Therapeutics
Joseph McGuirk, DO, University of Kansas Medical Center
Providers and Payers: Hurdles to the Adoption of Advanced Therapies in Oncology
In 2011, ipilimumab altered the treatment paradigm of metastatic melanoma patients by becoming the first immunotherapy to demonstrate prolonged survival among afflicted patients. Now, nearly 10 years later, providers and payers are challenged with determining how to preferentially sequence, in the case of BRAF-mutated melanoma, immunotherapy and targeted therapies. As excitement around advanced therapies continues to build, the challenges of expanding access to these products remain significant due to adoption, costs, and logistical considerations. The FDA is currently anticipating nearly 20 cell and gene therapy approvals by 2025 with almost 300 targeted therapies currently in development. While the potential clinical impact of these advanced therapies continues to evolve, an effective response to overcome the barriers to access will require coordination between providers, payers, and manufacturers.
Eli Phillips, Jr., PharmD, Cardinal Health
NextGen Now – The Future of ATMP Facilities
ATMP processes have fallen back on manual operations to accommodate the patient specific scale, but what will these facilities look like in five years? The race for process closure and automated solutions has already begun. Don’t miss out as CRB discusses what will drive the industry to reduced operating costs, more efficient staff utilization and improved reliability and product reproducibility.
Clinical Pediatric Chimeric Antigen Receptor T-cell Experience in the KC Region
Chimeric Antigen Receptor, or CAR, technology was conceived in the 1980’s as a potential immunotherapeutic strategy to be used in oncologic and autoimmune/inflammatory disease. However, the first CAR therapy was not approved by the FDA until 2017 following clinical trials demonstrating impressive response rates and remission durations for patients with B-cell leukemias and lymphomas. CARs are molecules, in the case of cancer immunotherapy, that redirect the cellular cytotoxicity of an immune cell to a target other than its natural target. As one of the most exciting advances in the treatment of relapsed/refractory hematologic malignancies, CAR technology allows the redirection of T-lymphocyte cytotoxicity from that of its native T-cell receptor, toward a cancer cell. The impressive efficacy and safety of CAR T-cells in these malignancies has caused research in the field to boom. And this “living drug,” has encouraged renewed interest in immunotherapies in general, raising hopes for treatments of life threatening illnesses that are more efficacious and have fewer early and late toxic effects. We will discuss the rationale for CAR therapy in cancer and review the experience in the Kansas City region over the last 5 to 10 years in the field. We will also discuss some future directions and opportunities for regional collaboration in the field of cell based immunotherapy.
Doug Myers, MD, Children’s Mercy
Immune Profiling Reveals Antigen Spreading after HER2 CAR T-cell Therapy in Sarcoma
Chimeric Antigen Receptor (CAR) T cells combine the specificity of an antibody with the functionality of T cells. A phase I study testing CAR T cells targeting human epidermal growth factor receptor 2 (HER2) is currently ongoing for patients with advanced HER2 positive sarcoma (NCT00902044). In this trial, multiple infusions of HER2 CAR T-cells in a child with refractory alveolar rhabdomyosarcoma (RMS) metastatic to the bone marrow, induced a complete response (CR) that was durable. The objective clinical benefit observed in the patient was investigated to identify involvement of broader host immune responses that may have contributed to tumor elimination. Following the CAR T-cell infusion, we observed remodeling of the T-cell receptor (TCR) repertoire in the peripheral blood and bone marrow metastatic sites. Additionally, evaluation of the CAR T-cell induced endogenous humoral immune response identified autoantibody generation against proteins involved in oncogenic signaling pathways in rhabdomyosarcoma.
Sujith Joseph, PhD, Baylor College of Medicine
Discovery of Anti-PD-L1 Peptides for Cancer Immunotherapy
Immunotherapy using checkpoint inhibitors, especially PD-1/PD-L1 inhibitors, has now evolved into the most promising therapy for cancer patients. However, most of these inhibitors are monoclonal antibodies, and their large size may limit their tumor penetration, leading to suboptimal efficacy. As a result, there has been a growing interest in developing low-molecular-weight checkpoint inhibitors. Here, we discover peptide-based anti-PD-L1 inhibitors to block the PD-1/PD-L1 interaction. These peptides exhibit high affinity and specificity to human PD-L1 as well as PD-L1-positive human cancer cells. Molecular docking studies indicate that the CLP002 peptide specifically binds to PD-L1 at the site where PD-L1 interacts with PD-1. The CLP002 peptide inhibits tumor growth and increases survival of CT26 tumor-bearing mice, suggesting that the CLP002 peptide represents a promising low-molecular-weight checkpoint inhibitor for cancer immunotherapy.
Kun Cheng, PhD, University of Missouri – Kansas City
NBAF Operational Stand Up Status
The National Bio and Agro-Defense Facility (NBAF) will be the premier center of scientific excellence for the study of transboundary, emerging, and zoonotic animal diseases (those transmitted between animals and humans) that threaten U.S. agriculture economy, food supply, and public health. This state-of-the-art facility will be a national asset that helps protect our nation’s agriculture and its citizens against the threat and potential impact of serious animal diseases. NBAF will ultimately replace the existing Plum Island Animal Disease Center (PIADC) and all its essential functions, as well as provide additional capabilities for early development of veterinary medical countermeasures. Once NBAF becomes fully operational, it will provide several “firsts” for the U.S., including a maximum containment large animal Biosafety Level (BSL) 4 facility to study particularly dangerous zoonotic agents in large animals and a Biologics Development Module (BDM) to enhance and expedite the transition from research to commercially viable countermeasures. This will place NBAF at the nexus of the biodefense and agro-defense domains and establish NBAF as a leader among biocontainment laboratories.
Diana Whipple, USDA, ARS National Animal Disease Center
Patricia Glas, PhD, USDA, National Bio and Agro Defense Facility
USDA Science Programs at the National Bio and Agro Defense Facility (NBAF)
The National Bio and Agro-Defense Facility (NBAF) is a new 574,000 square foot biocontainment laboratory facility in Manhattan, KS that will provide state-of-the-art infrastructure for developing vaccines, performing diagnostics, and developing countermeasures against large animal foreign animal diseases (FADs) and zoonotic diseases. USDA Agricultural Research Service (ARS) researchers at NBAF will work to deliver scientific information and countermeasures to protect U.S. agriculture and combat threats to public health from foreign animal diseases that exist in animals but can infect humans. The USDA Animal and Plant Health Inspection Service (APHIS) Foreign Animal Disease Diagnostic Laboratory (FADDL) protects U.S. livestock from foreign and emerging diseases by conducting diagnostic testing of suspicious animal health situations and training veterinarians in the detection of high consequence animal diseases. This session will highlight the current and expanded research and diagnostic programs by ARS and APHIS.
Roxann Brooks Motroni, DVM, PhD, USDA, Agricultural Research Service
Kimberly Dodd, DVM, PhD, USDA Animal and Plant Health Inspection Service
USDA Biological Development Module at the National Bio and Agro Defense Facility (NBAF)
Current facilities at the Plum Island Animal Disease Center (PIADC) do not have the dedicated specialized space needed to support the early development and technology transfer of veterinary medical countermeasures (MCM). This is a major gap as the incentive for pharmaceutical companies to develop and manufacture MCM for foreign animal diseases (FAD) is limited since there is a very limited market for these products in the United States. There is therefore a critical need to mitigate the risks associated with developing MCM to incentivize pharmaceutical companies to invest in their development, registration, stockpiling, and distribution. To address this need, the United States Department of Agriculture (USDA) initiated plans for a Biological Development Module (BDM) at the National Bio and Agro Defense Facility (NBAF). This session will highlight some of the features of BDM, including staffing needs.
Cyril Gay, DVM, PhD, USDA
Research at the Biosecurity Research Institute at Kansas State University
The BRI is a unique biosafety level-3 (BSL-3) and BSL-3Ag facility where scientists and their teams work on pathogens that contaminate food or infect livestock, people, and plants. An arthropod containment level-3 insectary enables research with mosquito vectors. Researchers at the BRI are from many different departments with projects sponsored by several federal agencies and industry partners. The ongoing projects on Wheat blast began in 2009. Research on food-borne pathogens and agents that infect livestock, including zoonotic pathogens that can also infect humans, include studies to evaluate diagnostics and vaccines. With its interdisciplinary research, education and training programs, the BRI is playing a key role in conducting research on transboundary animal diseases that are priorities for the National Bio and Agro-Defense Facility (NBAF), and in developing a scientific workforce qualified to work at the facility. The BRI is the first and only non-federal facility to be approved to conduct research on classical swine fever virus (CSFV) and African swine fever virus (ASFV) – both pathogens that are designated as priorities for NBAF. A vaccine to protect swine from CSFV infection has been licensed, and has been modified for expression in plants to allow oral vaccination. With the largest group of researchers in the U.S. dedicated to working on ASFV, the groups are working on diagnostics, vaccines, basic virology, swine host genetics and pathway analysis. The research has not only increased our understanding of the viruses but also identified potential routes by which these could be introduced into the United States. Other NBAF-priority pathogens being studied at the BRI are Japanese encephalitis virus and Rift Valley fever virus (RVFV). Studies on JEV have included work on mosquito vectors and the first ever U.S. studies on swine, whilst collaborative research between K-State and U.S.D.A.-ARS scientists on RVFV have included the first U.S. studies on wildlife (white tailed deer). The highly productive research has resulted in 12 publications on CSFV, 19 on ASFV, 7 on JEV and 26 on RVFV. Pat Roberts Hall, where the BRI is located, is also the home of the National Agricultural Biosecurity Center (NABC), whose staff work with agencies including the Department of Homeland Security and FEMA, to deliver training and to develop response capabilities to combat foreign animal disease threats to the United States.
Stephen Higgs, PhD, Kansas State University
Transboundary Animal Disease Fellowship and High Containment Training Opportunities at the Biosecurity Research Institute at Kansas State University
The Department of Homeland Security Science and Technology sponsored training program is focused on training researchers to work in the high containment environment on transboundary animal diseases. This program is conducted at the Biosecurity Research Institute at Kansas State University. Successful outcomes include the development of a Transboundary Animal Disease Fellowship program which selected and trained three cohorts of highly qualified PhD, DVM, MS and MPH students to safely work on these important diseases. We have also developed a Graduate Certificate in Agricultural Biosecurity Research which is available through Kansas State University and is based on the graduate level courses developed and presented for this program.
Dana Vanlandingham, PhD, Kansas State University