Oncological researchers face a major hurdle in trying to model the complexity of the disease, which has led to genetically engineered rats and, most recently, humanized rat models for use in preclinical studies. Scientists have achieved this unique humanized model using a range of genetic engineering technologies, including transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeats (CRISPR). The goal is to create an immune system enough like that of humans that xenografts of the human immune system and tumors present in humans are viable. While such human models have been effectively established in mice, efforts are now concentrated on creating similar models in rats, pigs and other animals to further drive immuno-oncology developments.
A key to the future of immuno-oncology is the patient-derived xenograft (PDX), which researchers can use with animal models to figure out the best clinical decisions. In this case, the primary animal model is immunocompromised mice. PDX models have characteristics and genomic expression that are very similar to the tumors present in the patients from which they are derived. By studying how these models interact with potential drugs and techniques, clinicians can choose the best combination of therapies.
The humanized mouse model was developed by the Central Institute for Experimental Animals in Japan using a nonobese diabetic (NOD) animal with a spontaneous severe combined immune deficiency (scid) mutation. This combination causes an attenuation of the immune system. Then, transgenic expression of human growth factors causes the growth of both human innate and adaptive immune system cells, which in part replace the missing immune system in the mouse host. The resulting model has become one of the most important tools in pharmaceutical testing in the immuno-oncology industry.
The Development of a Humanized Rat Model for Immuno-Oncology
Since it is possible to purchase immunodeficient mice, they have become a staple in cancer immunotherapy research. Efforts to humanize a rat model have been largely headed by Hera BioLabs, which uses a double Rag2, interleukin-2 (IL2) knockout (scid) rat.
The rat has some key advantages over the humanized mouse model. For example, the pharmacokinetic characteristics are more favorable, and rats can handle intravenous dosing that is more intense. Since these animals are larger, blood samples can be of a greater volume and taken more frequently. Tissue samples can also be larger.
According to Hera, the company is currently in the optimization and validation stage of developing the humanized rat model, and it is using humanization of the rat liver to gauge future success. Next, the company will look at human-specific drug metabolism in the models to test for efficacy. If the liver works effectively, the next step will be to humanize the immune system. When this is accomplished, the humanized rat model may prove to be a key tool for testing interactions of immuno-oncological compounds and other drugs. Hera is on track to provide the first humanized rat model in the near future.
Potential Benefits of a Humanized Swine Model for Immuno-Oncology
Traditionally, smaller animal models have been used in cancer research because they have a much quicker turnaround time. However, larger animals can more effectively mirror the complexity of the human system. Surrogen is a gene-editing company that has recently refocused its efforts on developing a humanized swine model as a way to more effectively model complex diseases, such as cancer. Already, the company has produced pigs with Recklinghausen’s disease, or neurofibromatosis type 1 syndrome. This disease causes the growth of multiple benign tumors known as neurofibromas. The team wanted to create an animal that has some of the features of the disease that do not appear in mice, including external neurofibromas, which are a primary aspect of NF1 syndrome. When these features are present in larger mammals, researchers can test devices for disease treatment that would not be feasible to use with smaller animals.
Surrogen uses Ossabaw miniature pigs, which grow to about 180 to 200 pounds, a size that is similar to humans. The size factor is important in drug metabolism. Patients with NF1 tend to metabolize drugs differently than those in control populations, so the pigs could provide a better model for this metabolism than mice or rats.
Ultimately, Surrogen hopes to develop swine models for a number of different diseases, ranging from Alzheimer’s disease to cancer. Already, the team has created an immunodeficient pig model similar to the rodent model. However, it is important to trigger the right and relevant genetic changes, which is not simple, so more work must be done. Surrogen largely uses TALENS for its genetic engineering and has worked with bovine models, in addition to swine. The company is currently partnering with academic institutions and companies to speed up the development of its humanized models.