Immunotherapy has taken a center stage in cancer treatment. Novel approaches in cancer immunotherapy have been explored in recent years, including immune checkpoint antibodies, adoptive transfer of CAR (chimeric antigen receptor) T cells and TCR (T cell receptor) T cells, NK (natural killer) cells, T cell engagers, oncolytic viruses, and vaccines. Some of these therapies are already in the clinic, with others in development. However, results are showing that not all patients respond to treatment or resistance can develop. As the available therapies increase, there needs to be a better understanding of why they work for some patients but not others, how to prioritize this evaluation, and how to potentially combine them for better results.
Having translational models to advance what is seen in the laboratory to patient outcomes is the key to bettering cancer immunotherapy. Animal models have been highly instrumental in this endeavor, and humanized mouse models in particular have shown great promise in moving these therapies forward.
Clinical development of immune checkpoint blockers has become a focal point in anti-tumor therapy. Although there has been some early evidence of sustained responses and survival advantages in multiple tumor types, most patients do not benefit from treatment. Therefore, it has become increasingly important to identify and develop biomarkers that will produce more predictable responses in cancer patients.
Potential predictive biomarkers have been studied from tumor cells, cells within the tumor microenvironment, as well as expanding to circulating and host systemic markers. By using high-throughput sequencing and microarray technology, additional potential biomarkers have been identified.
Being able to test potential predictive biomarkers in in-vivo systems to better translate results to the clinic is highly needed. Promising candidates for this endeavor include humanized immune system (HIS) mice, which are mice that contain human immune cells and that are engrafted with human tumors.
Humanized mouse models are generally created by engraftment of mice with a human tumor, also known as a patient-derived xenograft (PDX) mouse. This is done on immunodeficient mice, or mice with little or no mouse immune system, but that contain human immune cells. They allow scientists to investigate how the human immune system functions during a wide range of diseases, including but not limited to cancer.
Humanized mouse models of immune checkpoint genes have become available in recent years. Included in the most popular mouse models for immunotherapy research are the PD1 and PD-L1 humanized models. PD-1 is a checkpoint protein on T cells. Upon binding to its ligand PD-L1, it acts as an “off switch” by keeping the T cells from attacking other healthy cells in the body. Some cancer cells have adapted to express large amounts of PD-L1 on their cell membrane. When they bind to T-cells, they trick the T-cell into leaving them alone, thereby evading an immune attack. Monoclonal antibody therapy has been developed that targets either PD-1 or PD-L1, blocking its binding and thus leading to a boost in the immune response against the cancer cells. The PD-1/PD-L1 checkpoint system has been shown in the clinic to be a promising target for immune checkpoint inhibitor drugs for certain cancer types, such as lung cancer, melanoma, and lymphoma, with more being added as research continues.
Although monoclonal therapy against PD1/PD-L1 has shown some early results, much research and development is still needed to make targeting this system effective in more patients. Combinatorial therapies have begun to be studied, with CTLA-4 being a primary target. CTLA-4 is another protein found on T-cells that helps keep the body’s immune responses in check. When CTLA-4 is bound to another protein called B7, it helps keep the T cells from killing cancer cells. Immune checkpoint inhibitor drugs can be used to block CTLA-4, thereby allowing the T-cells to kill the cancer cells. Early research in mouse models showed significant antitumor activity in mouse colorectal tumors by concurrent blockage of the CTLA-4 and PD-1 system. Expanding to the clinic, this combination therapy has shown promising results for treatment in additional cancer types including melanoma, metastatic sarcoma, and renal-cell carcinoma, to name a few.
In the case of cancer immunotherapy, humanized immune checkpoint mice can be used to better understand the mechanism of action of immune-oncology drugs that can be used in the clinic, help prioritize immunotherapies and test combinatorial approaches. Outcomes in humanized mice could help predictive responses in humans, shorten translation of new drugs to the clinic, and provide personalized treatment in the event of relapse.
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