: How has research in cancer immunotherapy changed in the past decade and how have the technological developments contributed to this evolution?
MS: The past decade has witnessed a revolution in oncology with the development of new immunotherapies. It's a massive shift. The success of checkpoint inhibitor drugs paved the way for investment in other immuno-oncology categories such as cell-based therapies, as well as trials of combinations of immunotherapies along with traditional chemotherapeutics. There's just been this massive influx of research in this area. In terms of preclinical development to support immunotherapy research, we have also seen a massive shift. Evaluation of an immune-modulating drug requires an in vivo system with immune cells. Prior to the rise of immunotherapies, most oncology drugs were tested in simple mouse xenograft systems, in which an immunodeficient mouse was engrafted with a human tumor cell line. But an immunodeficient mouse isn't an appropriate model for testing an immuno-modulating drug. That left the field with two options: syngeneic tumor models and humanized immune system models. Mouse syngeneic tumor models aren't new—they were developed in the early 1900s—but they had taken a back seat to xenograft models until recently. Syngeneic models have a competent immune system, but both the tumor and immune cells are mouse in origin, and they don't always adequately model the human condition. Humanized immune system models are newer, but enable researchers to study both human tumors and human immune cells in an in vivo system. In particular, humanized immune system mice are great tools to investigate mechanistic questions and provide insight into how these drugs work.
: What are some of the biggest hurdles/challenges facing researchers in this field and do you think they are being adequately addressed?
MS: Translational models are always a challenge. Many immunotherapies are species-specific biologics, with insufficient cross-reactivity to the mouse version of the human target. That means researchers must either develop a surrogate drug that targets the mouse (or other preclinical species) version of the protein or use gene-editing techniques to humanize the target protein in a mouse. That latter approach is being used quite widely, and Taconic has leveraged our advanced genetic engineering expertise toward this end. We can replace a mouse gene with the human homologue—including both exons and introns—to create genetically humanized immuno-oncology mouse models that express the full diversity of alternate transcripts for studying human therapeutic targets such as checkpoint inhibitor receptors. Other advanced solutions include partial humanization of single targets (e.g. receptor extracellular domains) or complete humanization of multiple targets (e.g. receptors and cognate ligands).
Another major challenge in this field is on the regulatory end. Immunotherapies have a whole new set of potential side effects and toxicities, and the regulatory authorities currently don't have great tools to assess safety of these new therapies prior to approval. Rodent models are already being used to understand the underlying mechanisms of immunotherapy side effects, and certain rodent models may eventually be shown to reliably predict the safety or toxicity of immunotherapies. These models will become the much-needed tools for regulatory evaluation of immunotherapies.
: Are there technological solutions that are currently being developed that you are excited about?
MS: Humanized mice have become critical tools for assessing immunotherapies because you can use them to study the interaction between the tumor and immune system. Some of the limitations of these models have been around the types of human cells thath engraft and differentiate. The basic models such as the huNOG and huPBMC-NOG have been primarily considered T cell models. With interest in the role of NK cells and myeloid cells in immuno-oncology, the field has needed humanized models that recapitulate those compartments. That's where next-generation models come in. Mice that express human cytokines can bias development of the human immune cells toward NK or myeloid fractions. That permits study of drugs with ADCC mechanisms or of myeloid-derived suppressor cells and tumor-associated macrophages.
: What are some of the new trends that you are seeing in this field? Will existing technology keep up with those trends?
MS: I think one of the most exciting trends right now is looking at the interaction between microbiome and response to immunotherapies. It's been shown that the gut microbiome differs between checkpoint inhibitor responders and non-responders. The next step is to take that knowledge and use it to modulate response to immunotherapies. The potential of a microbiome therapy which could improve immunotherapy response rates is tremendously exciting. The microbiome field has been primarily descriptive to this point. We can identify lots of areas in which the microbiota appears to be associated with a disease state, but getting to the next step of affecting a health outcome has been a challenge. There are various preclinical tools available for microbiome research, but these systems can be quite complex; there are not standard assays available to just plug and play. For example, you can start with germ-free mice and associate them with patient-derived microbiota, but you may need to assess how well the associated mice recapitulate the starting microbiota as not all species will successfully transfer to the new host. Microbiome can affect the results of all sorts of preclinical studies, as for example, mice sourced from different vendors or even different production locations from a single vendor may perform differently. It's important to be thinking about this even just from a reproducibility standpoint.
: Are there gaps in current technology offerings for cancer immunotherapy? How do they relate to lack of instrumentation, technical know-how, data deluge, translational issues?
MS: History is littered with molecules that cured cancer in a mouse but were not effective in humans. That's where we see genetically humanized and humanized immune system mice as so important in improving the translational impact of preclinical research. We have curated a portfolio of relevant products and services designed to address many of the challenges faced by immuno-oncology researchers. One example would be our Jh mouse, which allows researchers to address the challenge of immunogenicity. Biologics can induce an immune response in the host, including development of anti-drug antibodies (ADA). Anti-drug antibodies can reduce the efficacy of a biologic drug in several ways, for example by decreasing half-life of the drug, directly blocking the biological activity of the drug, or even causing anaphylaxis. ADA can prevent determination of efficacy of a biologic drug.
Many immuno-oncology therapies are humanized or fully human antibodies. Although species difference in epitopes can limit use of these drugs in preclinical mouse systems, there may be sufficient cross-reactivity with the mouse epitopes to permit testing of these drugs in syngeneic tumor models. However, these humanized therapeutics may be at higher risk of developing ADA reactions in the mouse host. One solution to this problem is to perform the syngeneic tumor study in a mouse strain that lacks ADA-producing B cells. The Jh mouse lacks B cells, but retains other immune cell types. For drugs that are immunogenic in wild type mice, the Jh mouse provides a system in which to evaluate immunotherapy efficacy without the interference of anti-drug antibodies.
: As a technology/service provider how are you impacting the progress in this field? What can you do more/better and what will help to make this happen?
MS: We have been privileged to work with a lot of really great scientists across pharma and biotech. They are experts in immuno-oncology, but they aren't necessarily mouse model experts. That's where our field application scientists come in. We are able to consult with researchers and help them identify the most appropriate mouse model for their field. In many cases, we have jointly identified unmet needs and then worked together collaboratively to generate data to fill that gap which benefits the entire field.
: If you could change one thing to drive progress in this field what would that be?
MS: Despite increasing collaboration between commercial and academic researchers, the differences in their respective research goals is limiting to research model progression. Generally speaking, academic science incentivizes novelty, whereas commercial research is empowered by models that offer scalability, reproducibility, and overall consistency. Academic researchers working to establish novel (publishable) models have little to no incentive to ensure their models offer practical utility to common commercial drug development work. This is a problem. We’re on the right path toward a solution though. Academic and commercial researchers are increasingly working together, particularly on therapeutic research efforts. Through developing a shared understanding of the distinctions in academic vs. commercial research model applications, rodent models with both novel and practical utility will increasingly be developed, thereby driving progress in the field.
Author Bio: Mike earned a bachelors’ degree from the University of Iowa, and Ph.D. in cell and molecular biology from the Baylor College of Medicine in Houston, Texas. At Baylor, Mike worked with Dr. Brendan Lee, investigating the immune response to systemically administered viral mediated gene therapies to treat inborn errors of metabolism. He followed with a postdoctoral fellowship at the University of Chicago with Dr. Albert Bendelac where he worked to define the earliest molecular and epigenetic signals of Natural Killer T cell lineage commitment. Mike published fifteen peer reviewed manuscripts in the fields of airway biology, immunity to viral gene therapies, and developmental immunology. In addition to his scientific training, Mike holds a Master’s of Business Administration from the Questrom School of Business at Boston University. Since joining Taconic, Mike held positions in scientific marketing and product management, focused on aspects of competitive intelligence, business analytics, market forecasting and new product launch. He is currently the Vice President, Commercial Product Strategy, responsible for all commercial products.