Preclinical cancer models play a vital role in oncology research aiding in the understanding of tumorigenesis and answering key experimental questions. Advances are needed to identify the best therapeutic and diagnostic strategies. Although traditional chemotherapy based on broad mechanisms (e.g. inducing DNA damage in cancer cells) and radiotherapy are still effective treatment methods, they are aggressive and usually lead to severe side effects. Newer therapies take a more targeted approach, specifically inhibiting molecules that drive tumor growth.
However, even in the case of more targeted agents the duration of the clinical benefits is short-lived because of the rapid acquisition of drug resistance. As the design of anticancer agents has evolved, the processes, methods and equipment used to aid the fight against cancer have too, leading to the resurgence of immunotherapy as a powerful way of fighting cancer.
The concept of immunotherapy focuses on the ability of an individual patient’s immune system to eliminate or control cancer. There are several regulatory issues surrounding the development of immunotherapy, the most palpable being the issue between the balance of the higher costs of many immunotherapies vs. other therapies. Immunotherapy in combination with other therapies is perceived to be a more effective alternative to the current standard of care.
Current situation in oncology therapy research
Current treatments of cancer include chemotherapy and radiotherapy. Chemotherapy is successful at killing rapidly dividing cells and controlling the growth of the cancer, but also has the ability to cause damage to healthy cells. Radiotherapy uses ionizing radiation to damage the DNA of cancerous tissue. This form of treatment is highly dependent on the tumor cell type, with some cancers being radioresistant. While both methods of treatment are effective, they are associated with severe side effects and are vulnerable to the emergence of treatment resistance.
The ideal treatment for any disease is one that can cure or prevent it from spreading with the least impact on the patient’s quality of life. For a long time, researchers have looked into ways of taking advantage of the immune system to fight cancer. This can be done either through the stimulation of a robust immune-based anticancer response by vaccination or by attempting to inhibit factors that are currently blocking that response. Only in recent years, with a better understanding of the mechanism of action of immune cells, has progress started to be made in the application of immunotherapy to cancer patients, reducing side effects while increasing the efficacy of administered active compounds.
Recent advances in research have shown that certain mechanisms of immune suppression by cancer cells can be reversed, resulting in the reactivation of the immune system to recognize the tumor cells and kill them. This can result in a more durable response because it induces immunological memory: the ability of the immune system to recognize cancer cells and remember to fight them. Example treatments include cell-based therapies and antibody therapies.
Cell-based therapies, also known as “cancer vaccines,” involve the isolation of immune cells from the blood or tumor of a cancer patient. Immune cells specific for the tumor will be activated, grown ex vivo and returned to the patient, where they provoke an immune response against the cancer.
Antibody therapies, however, are currently the most successful form of immunotherapy. Cancer cell surface receptors are common targets for antibody therapy. The antibody can bind to the receptor and initiate destruction of the cancer cell. Although this treatment is typically completed within a few months, the stimulated immune response can accomplish disease control for extended periods and some patients can be considered cured of cancer. This contrasts with traditional therapies, which are limited by the emergence of drug resistance. Treatment combination strategies with radiotherapy and chemo- or immunotherapy have been developed to overcome drug resistance. The use of an innovative platform for image guided micro-irradiation (IGMI) at the preclinical stage of drug development will improve the ability of predicting success of these combination approaches in clinical trials.
Although immunotherapy research is fast-moving, researchers are still looking into how to maximize the benefits from immunotherapeutic agents, as cancer is a complex disease with extremely diverse histopathology and heterogeneous pathogenic mechanisms. Although immunotherapy appears to be a promising treatment option for cancer patients, it is unclear as to why some patients benefit from these treatments and others do not. There is, therefore, a distinct need for more accurate research models.
Why are preclinical research models compulsory?
Developing effective immunotherapeutic drug treatments requires patient-relevant models with which to screen potential candidates. Moreover, due to the huge diversity and complexity of cancer, large collections of surrogate models are compulsory.
At present, syngenic and genetically engineered mouse models (GEMM) with functional murine immunity are among the best models available for immunotherapy studies that focus on understanding the mechanism of action of new immunotherapeutics. However GEMM and syngenics are of little use when it comes to testing anticancer agents that target human-specific components. To fill this gap, humanized mice models, in which the deficient murine immune system has been substituted by a functional human counterpart, have been developed.
Another important aspect regarding the use of preclinical cancer models is the necessity to perform large-scale studies to screen for candidate compounds or identify the population of patients that will most likely benefit from a certain treatment regimen. Using surrogate models to mimic the human clinical trials settings is proving to be the next step forward. Mouse clinical trials not only allow large-scale screening of candidate compounds, but also enable surrogate trials to be run in tandem with human clinical trials. PDX models, which are derived directly from human cancers with primary tumor cells grafted directly into the animal model from the patient for clinical testing, can be used in human surrogate trials and are at the forefront of personalized medicine research, enabling the identification of the right compound for the appropriate patient population before new drugs are tested in the clinic.
A variation of this is to offer co-clinical mouse-human trials where the same treatment regiment is carried out on human tumors grown in mice avatars, while the patient is enrolled in a clinical study. Not surprisingly, this approach has more substantial cost implications and some time drawbacks for patients, and is still not available for application on a large scale. PDX models express their greatest potential by being used as a tool to improve the successes of translating novel drugs and therapies into the clinic in prospective studies.
Shift toward combination therapies
Combination therapies are needed, as cancer can be driven by more than one target gene and even the most targeted anticancer agent can have short-lived clinical benefits due the rapid acquisition of drug resistance. Combination therapies, using different agents or chemotherapy and radiotherapy simultaneously, are required to prevent the occurrence of drug resistance and produce a stronger anticancer effect. For example, epidermal growth factor receptor (EGFR) inhibitors are used to treat cancers that display an aberrant activation of this receptor. Recent data suggest that a course of radiotherapy can sensitize tumor cells to EGFR inhibitors, leading to a greater tumor inhibition and overcoming the issue of drug resistance.
The development of drugs that inhibit tumor-growth promoting pathways, alongside the translation of antitumor immunity concepts into immunotherapies, suggests possibilities for therapeutic synergy with combination treatment. A strong foundation has been established to advance the crafting of both preclinical and early-stage patient investigations to determine the best ways to integrate targeted agents and immunotherapy.
The use of IGMI on PDX models in preclinical testing has made it possible to assess the effectiveness of drug-radiation combination therapies. Radiation therapy has evolved and modern-day treatments exploit multiple lower-intensity beams, angled to meet at the tumor site, ensuring the full dosage is delivered to the cancerous tissue while causing the least damage to the surrounding healthy tissues. The newly developed IGMI platform closely mimics contemporary human radiotherapy treatment, facilitating the evaluation of potential radiosensitizers (i.e drugs that make tumor cells more sensitive to radiotherapy) for cancer treatment in preclinical settings.
Combination therapies offer great promise for boosting responses to immunotherapy, but the appropriate timing, dosage and sequencing of these agents is crucial to the success of combinatorial approaches, hence the importance of testing the clinical strategy before application on human patients using the most relevant preclinical models.
Conclusion
The oncology research community today is seeking better ways to offer to a wider cross-section of patients an improved quality of life and potential cures. There is a strong need to have tools available which can significantly improve the qualification of candidates at a much earlier stage in the drug discovery process. PDX, GEMM and syngeneic models can all contribute by different means to move the most promising compounds to the clinic and reduce drug attrition rates by selecting the best clinical strategy.
Immunotherapy is rapidly developing with striking results. It can potentially transform cancer treatment and perhaps provide cures for cancer types that historically had very poor prognosis. Unlike systemic chemotherapy, immunotherapy works by potentiating a patient’s own immune response, sparing normal tissues and potentially reducing off-target side effects. Immunotherapy allows treatment responses to last longer by inducing immune cells memory and potentially curing cancer types that were believed to be untreatable. Combining immunology with traditional anticancer agents solves the challenge of drug resistance and enables a stronger anti-cancer effect.
Laurie Heilmann is senior vice president of global strategy of Crown Bioscience and has extensive experience in sales, marketing, emerging business development, with multifaceted experience in the life-science industry that includes medical devices, software and Phase 1-4 clinical research. She has led teams to meet FDA and sponsor requirements and negotiated alliance partner agreements in the United States, Europe as well as India and Asia. Crown Bioscience is a drug discovery and development service company providing translational platforms and drug discovery solutions for its biotech and pharmaceutical partners in the dedicated therapeutic areas of oncology and metabolic disease.
