Advertisement

The race to identify the next blockbuster oncology drug is no doubt a fast one.  With cancer immunotherapy becoming a major focus of oncology research over the past several years, that blockbuster drug will likely target the immune system.  In fact, some analysts predict that up to half of all cancer treatments will be immunomodulatory by 2023, and the industry is responding in kind by developing new tools that can be employed in this rapidly expanding field.

One tool oncology researchers are exploring is actually not new at all—the murine tumor model.  Allograft mouse tumor systems, otherwise known as syngeneic or syngenic models, were developed over 50 years ago as early in vivo models for oncology drug development.  However, as the industry moved towards therapies directed against human targets, syngeneic models drifted out of the drug discovery landscape, and were replaced by in vivo models which could express human targets, such as genetically engineered mouse models and human xenograft models. 

Now, with the success of new immunotherapy agents these “new” syngeneic models, which had been all but shelved for decades, have recently resumed center stage having been identified as reliable models for immunotherapy studies.   Because they retain intact immune systems, syngeneic mouse models are particularly relevant for studies of immunologically-based targeted therapies, either used alone or in combination with other drugs that modulate the immune system’s ability to seek out and destroy cancer cells.  

READ MORE: An Introduction To Immunotherapy And The Promise Of Tissue Phenomics

Immunotherapy research and successful clinical trials have identified a class of protein targets known as immune checkpoints, such as CTLA-4, PD-1, and PDL-1, which regulate T cell function and proliferation.  Acting as a brake by shutting down T cell immune responses, these checkpoints prevent the immune system from “going rogue.”  Click to Enlarge. Individual tumor growth curves for the CT26 tumor model showing the “all or none” phenomena. Tumor cells escape the immune system by exploiting these checkpoints, and it has been demonstrated that inhibitors of these checkpoint molecules can restore the balance, allowing the immune system to destroy tumors.  Agents directed against these immune checkpoint proteins, known as checkpoint inhibitors, have been the first immunotherapies approved for human clinical use.  Identifying and manipulating syngeneic models that are responsive to these immune checkpoint inhibitors are crucial to the development of not only next generation checkpoint inhibitor molecules, but also for combination strategies with currently approved drugs. 

As we gain information about the immunological makeup of these tumors and their responsiveness to checkpoint inhibitors, it is becoming clear that there is still a lot to learn. Beyond simply identifying these syngeneic tumor models as responsive to checkpoint inhibitors, the question then becomes how best to position these models for use in drug development.  To this end, some important considerations to best capitalize on model utility are emerging in the field:

Dose timing  

The timing of treatment is important.  In some cases, if a syngeneic tumor-bearing animal is dosed a few days after implant, the response can be very strong.  However, if the same treatment is delivered just a couple of days later, the tumor progresses as if the animal was not dosed at all.  Neither lack of response nor complete response is a desirable outcome in developing strategies for testing combination therapy.  Rather, the identification of conditions to produce a “moderate response” is required. 

In many cases, this moderate response manifests as a subset of tumors that will grow with the veracity of an untreated tumor while other tumors, treated in an identical manner, will completely disappear with treatment.  This “all or nothing” phenomenon is seen across several labs, but predicting how individual tumors will respond is currently elusive.  It is likely that populations of tumor infiltrating lymphocytes (TILs) and myeloid derived suppressor cells (MDSCs) are being modulated by these therapies and understanding the underlying mechanisms behind this modulation are key to predicting outcome.  For now, the goals of successful combination therapies are those outcomes that drive the number of tumors in a treatment group from no response to complete response.

Choice of antibody clone

There are multiple experimental antibodies against the checkpoint inhibitors, and specific clones of these antibodies behave very differently.  These responses can vary widely within the same tumor model from very little response to a virtual cure.  A study led by MD Anderson Cancer Center in Houston, Texas and published in 2013 in the Journal of Experimental Medicine linked the differences to the varying Fc regions, and the resulting differences in the Fc based signaling upon binding to the antibody to its epitope or target.  Depending on the timing of dose and which checkpoint inhibitor clone is chosen, the treatment outcomes can be vastly different even within the same tumor model.

Endpoints to determine activity 

With standard xenograft models, the gold standard for measuring activity is analysis of how the growth rate of a tumor changes with treatment.  Oftentimes, ex vivo biomarker assays are also employed to help understand the modulation of signaling pathways involved with treatment.  While these methods are also important in determining the success of immune-based therapies, a deeper understanding of the immune response to treatment can be particularly powerful.  To this end, the identification of immune cell populations (namely CD4+ and CD8+ effector cells, Tregs, and MDSC) present in the tumor, spleen, lymph nodes, and blood, and how these populations are altered with treatment can offer insight into mechanisms of tumor reduction.  Further, exploring Th1 and Th2 responses by ex vivo T cell activation assays can help further elucidate a therapy’s impact on the immune response and can guide the clinical experience.  Such assays to define tumor cell killing may also give insight into what defines the “all or nothing” trends seen. 

The race to immunology-based therapy for cancer is a sprint and a marathon.  The field is being propelled forward by researchers using these experimental models, but the work required to translate those findings to clinical success will take much longer.  Those who are able to exploit model systems, such as syngeneic tumors, and who can identify the next major variable associated with immunologically driven elimination of tumor cells, will be the runners that cross the finish line. Through those efforts, the promise of new immunotherapies can be realized.

 

About the author:

Sheri Barnes joined Charles River in 2009 and currently serves as Study Director at the Charles River Discovery Services site in North Carolina.  She holds a PhD in Cell and Developmental Biology from the University of North Carolina at Chapel Hill.  Sheri began her career in 2004 at CellzDirect, Inc., an in vitro drug metabolism CRO, where she provided sales and scientific support.  In 2007, she joined Piedmont Research Center as a Project Manager with a focus on in vivo oncology research.  She continued in this role through the integration with Charles River in 2009 and assumed the role of Study Director in 2014.  

Advertisement
Advertisement