As our understanding of oncology continues to grow, so does the opportunity to develop novel treatments that more effectively treat a range of cancers. Over the past few decades, more treatment pathways have begun to emerge for exploration — particularly those that target or recruit the immune system. But while such immunotherapies hold promise during their preclinical phases, many are still failing to deliver the same efficacy and safety during clinical trials.
A more relevant preclinical model may hold the key to more efficacious treatments by better representing the human system under study. Humanized mouse models, for example, can recapitulate complex interactions that occur in humans between the immune system and the disease. As such, they can more precisely represent how a disease is likely to respond to treatment during a clinical trial.
So, how can humanized mouse models support the development of novel cancer treatments? We explore five applications below.
Immune checkpoint inhibitors (ICP)
Checkpoint proteins, which are made up of immune system cells such as T cells, prevent the immune system from attacking cancer cells. A novel treatment approach — ICP immunotherapies — hinders checkpoint proteins, thereby enabling the immune system to act upon cancer cells.
To determine whether a treatment is working effectively, preclinical models must be able to recapitulate complex interactions involving the immune system. By employing humanized mouse models for ICP investigations, scientists can examine both the effectiveness and underlying mechanisms in a single experiment. Additionally, researchers can analyze tumor-infiltrating leukocytes (TILs) following tumor dissociation using humanized mice, providing further valuable insights.
Chimeric antigen receptor (CAR)-T studies
CARs work by recognizing and binding to antigens on cancer cells, causing inflammation and destroying them in certain diseases such as blood cancer. In CAR-T cell therapy, T cells are collected from the patient and re-engineered to produce CARs on their surface. Once the cells multiply, they are reinfused back into the patient, helping the immune system to attack the cancer cells.
For a preclinical model to be predictive of clinical trials, it must recreate the human immune system. CAR-T therapies can be modelled in humanized mice by extracting T cells from their spleens and engineering them to possess the same characteristics as regular human T cells. These modified CAR-T cells are subsequently reintroduced into animals derived from the same CD34+ donors, allowing researchers to examine their potential for cancer treatment.
By modelling CAR-T therapies in humanized mice, scientists can explore the longevity, effectiveness, and immune-related safety of these treatments within the framework of a fully functional human immune system, providing a deeper understanding of such therapies.
Cytokine-based immunotherapies
Cytokines are a critical group of proteins that boost the immune system. Such proteins can be tailored to treat cancer by either interfering with cancer cell growth and chemical production, or by immune system stimulation. Preclinical models must therefore be able to reproduce these key interactions to determine efficacy.
Humanized mice models hold immense promise in the assessment of cytokine-based immunotherapies. Recent research investigated the therapeutic effectiveness of an antibody IL-12 fusion protein (NHS-IL-12) in a CD34+ humanized mouse model that was injected with human rhabdomyosarcoma cells. The therapy exhibited a remarkable enhancement in survival rates and a reduction in tumor volume, showing the utility of these models in preclinical studies for cytokine-based therapies.
Oncolytic viruses
Oncolytic viruses can infect and directly destroy cancer cells by replicating in them and causing cell lysis. Once the virus kills the cells, tumor-associated antigens and other cancerous materials are released, thereby triggering an immune response. Oncolytic viruses can also be genetically engineered to deliver therapeutic payloads that further enhance immune responses.
To better understand how potential treatments work, preclinical models must be able to monitor the immune response. Humanized mouse models serve as valuable tools in this respect, enabling researchers to explore the effectiveness of oncolytic viruses in treating cancers.
Antibody-dependent cellular cytotoxicity (ADCC)
ADCC is a cell-mediated immune defense mechanism in which effector cells induce lysis of target cancer cells. NK cell activation plays a crucial role in ADCC, and so a preclinical model must be able to recapitulate NK cell function to be predictive of clinical studies.
Humanized mice can undergo NK cell enhancement, making them an ideal model for studying ADCC. In an in-house study, researchers subcutaneously injected A431 melanoma cells into hIL15-boosted mice. Here, bi-specific antibodies that target the tumor were administered at varying doses. The models were able to demonstrate that NK cells facilitated complete regression of the tumor at a high dose.
A versatile model for your immuno-oncology studies
Humanized mouse models offer deeper insights than traditional mouse models during preclinical studies, significantly enhancing the chances of success in subsequent clinical trials and supporting the development of safe and effective treatments. These models prove particularly invaluable in immuno-oncology research, shedding light on various treatment areas such as CAR-T and oncolytic virus therapies.
By incorporating advanced humanized mouse models into preclinical investigations, your laboratory can make informed decisions that enable the advancement of the most promising drug candidates, enabling you to bring a safe and efficacious product to the market faster.
To learn more about humanized mouse models and how to incorporate them into your preclinical studies, download our guide today.