The Evolving Role of Mouse Models in Immunotherapy

Pre-clinical models have been criticized for some of their limitations, but Marcus Bosenberg, MD, PhD, confirms their current relevance and clinical applicability.

In his laboratory, Bosenberg, an associate professor of Dermatology and Pathology, Yale University, co-leader of the Genomics, Genetics, and Epigenetics Program of the Yale Cancer Center, and co-director of the SPORE program for skin cancer, and colleagues have developed several mouse models to study the effect of immunotherapy agents on the treatment of melanoma.

In an interview with Targeted Oncology, Bosenberg discussed the utility and history of mouse models, the efficacy and future of immunotherapies, and next-generation sequencing.

TARGETED ONCOLOGY:What role do mouse models play in immunotherapy research?

Bosenberg:

There's obviously a great amount of interest in immunotherapies, and we’ve had a great deal of success. One of the ideas is that some of the models, including mouse models, could be very useful for figuring out the next generation of combination therapies and what roads to take from here. The idea behind this workshop is to review the current state of the art of mouse models, which are used to test new immunotherapies and old, and what the future directions are for those models. This way, we'll be better able to tell which immunotherapies will work well with humans, and which will not.

TARGETED ONCOLOGY:Where are we now with immunotherapy and mouse models?

Bosenberg:

There are 2 main types of models, one of which are models that are entirely in mice. These are mice that have an intact immune system, and you can graft in tumors where the mouse is like the human equivalent; it's just that there's no human tissue in them at all. Some people have criticized those because they don't have any human tissue in them, and they've been trying to build a humanized mouse model. This typically involves trying to put the human immune system into mice, then using human cancer cells, and seeing how that immune reaction works in mice.

It's very difficult to do. A lot of progress has been made in this area, but one of the tasks of the workshop is to explain these humanized mouse models and how they compare to mouse models.

TARGETED ONCOLOGY:What about non-mouse models? What are the options there?

Bosenberg:

There are a number of models. For instance, it turns out dogs have a very high rate of getting melanoma. There might be more dog melanomas than human melanomas in the United States. Utilizing a spontaneous model of melanoma in a dog, you can do clinical trials or look at dogs with melanoma to see if immunotherapies could work in them. The problem has been that it takes a whole lot of infrastructure to make that work, which has happened in the mouse research field. In the dog research field, it hasn't happened yet for immunotherapies, though it could. That would be another example of a non-mouse vertebrae animal model for development.

TARGETED ONCOLOGY:Are there non-animal models being used?

Bosenberg:

Other ways to study immunotherapies and determine what might happen next involves studying humans. For example, we can try to get biopsy specimens from humans, get peripheral blood and try to follow the immune reaction, and now with the really spectacular advances in DNA sequencing, it's much more successful than it has been in the past. There are limitations, though, because if you want to know about the components that are required for an immune system to work, you can't really do that experiment in patients. That's where the mouse models tend to be very helpful, because you can say that one component of the immune system—for instance, T lymphocytes—are absolutely required for a particular immune reaction. In humans, you can't really take away their T lymphocytes. It's not ethical to do those kinds of things.

We also do as much as we can in the dish, in vitro experiments, where you can take lymphocytes from a patient and determine if they can react with tumor cells. This has developed into some pretty exciting immunotherapies where you take lymphocytes from a patient, expand them outside their body, and then you transfer them back into the patient, and you can see some pretty good antitumor immune responses in those settings. There are only a few centers that can do that because there are a lot of elements required for that. You can also study the lymphocytes during a process called adoptive cell transfer.

TARGETED ONCOLOGY:Do you think next-generation sequencing needs to be able to gather more information at this point?

Bosenberg:

It's exciting because the techniques for this area are really evolving rapidly. Oncologists look to see how many types of lymphocytes are in a particular tumor, and it turns out that lymphocytes change their DNA to react with one certain antigen; and so you can follow how many T cells have that particular DNA makeup. It's called a repertoire of T cells, and that's commonly being done.

A second big area for next-generation sequencing analysis is looking at the different subtypes of cells. There's a technique called single-cell RNA sequencing in which you take each individual cell and you see what it's making, and that allows you to classify and understand the cells much more precisely than we could in the past.

One last approach that’s very exciting: when you take the mutations that are in a patient's tumor, you can sometimes predict whether or not any of those mutations will result in a change of sequence that will be recognized by the immune system. Five years ago, that technique barely worked at all, but now it's working better, and the more information we get, the more we can accurately predict in patients.