Syngeneic vs. Humanized Models: How to Choose the Right Model for Immuno-Oncology Research

Hello and welcome to CrownCast. I'm your host, Michelle Dawn Mooney. Immuno-oncology research depends on choosing models that can answer the right biological questions and generate data that meaningfully informs the next development decision. But with a growing range of model types, tumor settings and immune mechanisms to consider, selecting the most appropriate approach can be complex. In this episode, we explore how syngeneic tumor models support preclinical immunotherapy research. Our guest, Chris Dillon, Executive Director of In Vivo at Crown Bioscience's San Diego site, discusses the importance of quality model selection and translational relevance in building studies that deliver actionable results. You'll hear how immune cell profiles can inform model choice, how engineered models can help investigate tumor antigens, receptors and resistance mechanisms, and how orthotopic models can provide a more biologically relevant tumor microenvironment. Chris also explains when syngeneic models may be the right choice and when humanized models may be more appropriate. Whether you are evaluating a new immunotherapy, investigating resistance or planning an in vivo study, this conversation offers practical perspective on using the right model to move your research forward. Let's get into it. My name is Chris Dillon. I'm the Executive Director in charge of in vivo at the San Diego site. How does Crown Bioscience ensure consistency and translational relevance in its syngeneic tumor models? At Crown, we look to drive the best quality work. And with that constant focus on quality starts with our training program. And so we have a highly skilled trainer who works together with all of our research associates to train them on particular techniques, to evaluate the quality of the work that's done in those techniques and ensure that when, particularly in the context of syngeneics, when those tumors are implanted, that we're seeing consistent growth over time, that they're in the right shape, there's consistent growth and they respond to treatment as expected when we do positive controls. Ensuring translational relevance in syngeneic models starts with ensuring that we're asking the right question and choosing the right model that can address the question that needs to be asked. And so different syngeneic models can recruit different immune cells into them and so knowing what the downstream purpose of the data is useful for us to choose the right model. And then when we have the right model done in a quality fashion, then what we use as positive controls or standard of care controls to understand what the effects we're seeing relative to these translationally relevant treatments. How are syngeneic models engineered to study specific IO mechanisms or tumor drivers? So various syngeneic models are derived from different organs within the animal from where the tumor first originated and because of that there are mechanisms that these tumors use to recruit certain types of immune cells and these have been well characterized in the field and so we know that certain tumors can recruit more T cells, certain tumors might recruit more B cells and we then select these models based on what needs to be recruited and what questions we're asking. So another way that we would leverage understanding specific mechanisms or drivers is that here at Crown we have a highly skilled in vitro group that can engineer or change the cells that allow us to ask certain questions and so we can express a certain tumor antigen, we can express an activating or inhibitory receptor and, when these tumors are then implanted and a client's therapy is used, these engineered cells then respond differently and may better model the translational environment of the patients that we're looking to treat. How can syngeneic resistance models be developed and applied to evaluate second line therapies or rational IO combination strategies? One of the most challenging aspects of, treatment in patients is they often become resistant to the particular therapy. So we want to understand the mechanisms of which that resistance occurs and then translate that back into preclinical models that we can use to evaluate new therapies going forward. So there are a couple ways for us to model that, one is to do an active treatment in vivo with a therapy and develop that resistance in that setting and then take those tumors and pass it to another animal for the treatment with the new therapeutic. There's also an approach that you can take that is an engineered model where there's a known mechanism, perhaps a mutation that has been found in patients that are undergoing this therapy and then we take that mutation, put it back in our syngeneic model and then implant that model into the mouse and then treat the mouse with the new therapy going forward. And that will let us know whether we're engaging or bypassing the mechanism of resistance. How are metastatic or systemic syngeneic models established? There are many mechanisms by which, or many approaches by which we can establish syngeneic tumor models in mice. One, if we want to model a systemic or liquid tumor, these tumor cells get injected into the bloodstream. If we want a general idea about how a particular treatment might affect tumor growth and control that tumor growth, we often implant syngeneic tumor cells on the flank of an animal and measure the tumor growth in that setting. One of the more powerful approaches, moving forward, it's something that we're well set up to do in San Diego is to engineer lines that have tags that we can follow them once they're implanted in vivo. And then for these lines that we have tagged and can visualize, we implant into the organ that they originally were derived from. So for instance, if we have a liver tumor, we can implant that tagged tumor into the liver of the animal and then it can have the appropriate tumor microenvironment that we can then track and the advantage of these orthotopic models as these are called are that you can get a immune response that more reflects the response in the organ, more naturally. How do syngeneic models compare to humanized models for evaluating immune responses and when should each be used? So we have two main systems that we can use to look at immune therapy responses in animals. We've been talking about syngeneic models and these are tumors that are derived from mice that then go back into mice. And these are valuable models because they capture the entirety of the immune system. All the different parts together. T cells, B cells, macrophages, dendritic cells, NK cells, neutrophils. And so it models the entirety of the system. There are other cases where humanized models might be more appropriate and this is where we bring human immune cells into a mouse and use that to look at a tumor response and there are various ways of doing this. They can take just T cells or you could take stem cells and put those in a mouse and in these settings, often, the development of the immune system is not quite as robust as it would be in a mouse model by itself. And so you would use these humanized models in particular settings. For example, if you have a human biologic that's specific to human, you would need to work in a humanized model. If you have an agent that you can use with either mouse or human tissues, then we would typically go to a syngeneic because we want to see this complete immune response that you wouldn't necessarily see in humanized mice. And that brings us to the end of this episode. We explored how syngeneic models can support preclinical immunotherapy research from selecting models based on the biological question and immune profile to using engineered and orthotopic approaches to investigate tumor biology and treatment resistance. And as Chris highlighted, translational relevance starts with the right model applied with consistent quality and a clear understanding of the decisions the data needs to support. Whether evaluating an immunotherapy, studying resistance mechanisms, or comparing treatment approaches, thoughtful model selection can help generate more meaningful and actionable insights. Thank you to Chris for sharing his expertise, and thank you to everyone for listening. If you would like to hear more engaging conversations like the one you heard today, we invite you to subscribe to the podcast available on Spotify, YouTube and Apple Music. And you can also visit www.crownbio.com for more information there. I've been your host, Michelle Dawn Mooney. Thanks again for joining us. We hope to connect with you on another podcast soon.