Of Mice and Men
Originally developed by Leonard Shultz, Ph.D, and his group at the Jackson Laboratory, mice with elaborate immune system modifications such as the interleukin-2-receptor gamma-disabled mice developed at Jackson have allowed transplantation of human tumors. These explanted patient-derived human tumor models in mice may provide in vivo preclinical models that more accurately reflect tumor behavior and characteristics in patients, potentially according to some changing the cancer drug development landscape.
Currently, numerous tumor-specific PDTX models have been established. These tumor models retain biological stability when passaged in mice in terms of global gene expression patterns, mutational status, metastatic potential, drug responsiveness, and tumor architecture. These characteristics, say investigators, might provide significant improvements over standard cell-line xenograft models.
“The idea is that you can take human immune systems and put them in a mouse and make them functional. Then you can manipulate them as if you were manipulating little humans, so to speak, without ever putting patients at risk,” says Dale Greiner, Ph.D., of the University of Massachusetts Medical School.
Several laboratories supply tumor-specific PDTX mice including Jackson’s NOD scid IL2 receptor gamma chain knockout mice, also known as NSG mice, Oncodesign/Taconic’s Chi-Mice®. In particular, some investigators note, the development of NSG mice has allowed for even greater take rates (approaching 95–100%) for difficult to engraft tumors because in these animals, innate immunity is further impaired by blocking the maturation of natural killer (NK) T cells.
According to Susan Airhart, senior director of strategic alliances at Jackson Laboratories, “Pharma companies are embracing the concept of using these models. Most have internal programs of their own to develop these xenografts as well as outsourcing to CROs. Pharma also comes to us for access to our collection.”
Airhart told GEN, “Jackson scientists have developed diverse and representative patient-derived tumor xenograft models, with over 200 models established and another 200 in development. To build the models, Jackson used immunodeficient NOD scid IL2 receptor gamma chain knockout mice as the mouse host. In addition to the severe immunodeficiency (no functional B, T, or NK cells) and long life span, the NSG mice are resistant to estradiol toxicity, therefore supporting the engraftment of patient-derived estrogen-dependent breast cancer models.”
She added, “The model that we use is the NOD-SCID Interleukin 2 gamma chain knockout mouse, a highly engineered mouse and the most immune-deficient strain currently available today. NOD-SCID mice retain NK cells. This additional knockout takes out the NK cells, the last element of the immune system that would prevent human system immune engraftment in the mouse. It allows you to create patient-derived xenografts from tumors types that failed to grow in other immune-deficient strains.
“Another advantage of these models is that tumors grown in the mouse retain the higher-order structure they had in the patient. While over time, the human stroma is replaced by the mouse stroma, the relationship between the tumor cells and the stromal cells stays the same, and the xenograft tumor looks more like the tumor that you are trying to test.”
Airhart also emphasizes that PDTX model collections being developed today reflect the patients in the clinic today. “We have a library of new cancer models that more closely reflect the actual disease you are trying to treat today.”
But how well do these models recapitulate the behavior, and drug responsiveness of patient tumors? Some scientists caution that drift of stromal components of PDTX tumors from primarily human to primarily mouse may present a “relevant drawback” to of these models, given the importance of the tumor microenvironment in numerous aspects of cancer biology. This limitation is especially apparent in studies involving species-specific anticancer compounds that target the microenvironment, such as bevacizumab (an antibody that binds to VEGF) or agents that target the immune system, such as ipilimumab (an anti-CTLA-4 antibody).
Clearly, however, these models have provided information on the behavior of tumors in patients, recapitulating the biology and disease outcomes of the patient tumors from which they were derived—for example, maintaining their estrogen dependence and responsiveness through serial passages in mice, and metastasizing to sites similar to those observed in the original patients.
PDTX models can also facilitate analysis of the effects of drugs on patient-derived human tumors and potentially reinforce decision making about whether to proceed to clinical testing.