Development of an Orthotopic HPV16-Dependent Base of Tongue Tumor Model in MHC-Humanized Mice
Christoph SchifflersSamantha ZottnickJonas D. FörsterSebastian KruseRuwen YangHendrik WiethoffMatthias BozzaKarin Hoppe‐SeylerMathias HeikenwälderRichard P. HarbottleCarine MichielsAngelika B. Riemer
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Abstract:
Head and neck squamous cell carcinomas (HNSCC) caused by infections with high-risk human papillomaviruses (HPV) are responsible for an increasing number of head and neck cancers, particularly in the oropharynx. Despite the significant biological differences between HPV-driven and HPV-negative HNSCC, treatment strategies are similar and not HPV targeted. HPV-driven HNSCC are known to be more sensitive to treatment, particularly to radiotherapy, which is at least partially due to HPV-induced immunogenicity. The development of novel therapeutic strategies that are specific for HPV-driven cancers requires tumor models that reflect as closely as possible the characteristics and complexity of human tumors and their response to treatment. Current HPV-positive cancer models lack one or more hallmarks of their human counterpart. This study presents the development of a new HPV16 oncoprotein-dependent tumor model in MHC-humanized mice, modeling the major biologic features of HPV-driven tumors and presenting HLA-A2-restricted HPV16 epitopes. Furthermore, this model was developed to be orthotopic (base of tongue). Thus, it also reflects the correct tumor microenvironment of HPV-driven HNSCC. The cancer cells are implanted in a manner that allows the exact control of the anatomical location of the developing tumor, thereby homogenizing tumor growth. In conclusion, the new model is suited to study HPV16-specific therapeutic vaccinations and other immunotherapies, as well as tumor-targeted interventions, such as surgery or radiotherapy, or a combination of all these modalities.Keywords:
Humanized mouse
Tumor immunology
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The author studied comparatively the immunogenicity of the vaccines prepared of 38 virulent Ps. aeruginosa strains belonging to different serological types. It was demonstrated that the immunogenicity of killed vaccines varied within a wide range--from the absoulte protective effect to its complete absence. The culture medium on which the initial culture was grown and the method of its detoxication produced practically no influence on the immunogenicity of the vaccines. Immunogenicity of Ps. aeruginosa vaccines apparently had no relationship with the serological type of the strains.
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This chapter contains sections titled: Introduction Immune Mechanisms Factors Influencing Immunogenicity Detection Biological and Clinical Consequences A Risk-based Approach of Immunogenicity Examples Conclusions References
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This chapter contains sections titled: Introduction Basis of Therapeutic Protein Immunogenicity Tools for Immunogenicity Screening Approaches for Risk Assessment and Minimization Case Study and Clinical Experience Preclinical and Clinical Immunogenicity Assessment Strategy Conclusions Acknowledgment References
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This chapter contains sections titled: Introduction Immunogenicity of Therapeutic Proteins Immune Mechanisms Related to Protein Immunogenicity Aggregates and Immunogenicity Conclusions References
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This chapter contains sections titled: Introduction How the Immune System Responds to Protein Therapeutics Risk Factors for Inducing Immunogenicity Methods for Identifying an Immune Response Strategic Approach for Monitoring Immunogenicity Consequences of an Immune Response to a Therapeutic Protein Nonclinical Immunogenicity Testing Summary
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Nearly all therapeutic proteins induce antibodies in patients. However this immunogenicity has been neglected in the use of these products, even though the antibodies may have severe consequences. During the last few years, progress has been made in understanding why patients do not tolerate these protein therapeutic products and also how to manage the problem of immunogenicity.
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Immunogenicity of biological products can occur pre-clinically and clinically when products elicit immune responses in animals or humans receiving the products. This is a concern for manufacturers, regulatory agencies and clinicians as immune responses can result in effects on product effectiveness and safety. The clinical sequelae of immunogenicity range from no effects to serious, life-threatening syndromes. However, although many biological products are immunogenic to some extent, it is quite rare that immunogenicity leads to serious adverse events. Whilst there are methods to detect immunogenicity, they currently rely on detecting the humoral rather than the cellular response of the immune system. The design and validation of assays such as immuno-assays and bio-assays are critical for a meaningful assessment of immunogenicity. There are a growing number of computational and laboratory-based methods for the prediction of immunogenicity, as well as methods to reduce potential immunogenicity and these may lead to less immunogenic biological products in future.
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Abstract An antigen refers to a molecule that is able to bind to the cells of the immune system. If an antigen can also stimulate an immune response, it is termed an immunogen. Immunogenicity is a measure of this ability to activate the immune response: that is, the B and T cells underlying humoral and cell‐mediated immunity. Understanding the concept of immunogenicity is therefore vital in understanding the field of immunology as a whole. The determinants of immunogenicity are complex, but much research has been conducted in this area in the context of vaccination and protein therapeutics, where understanding immunogenicity is of key clinical significance. While obtaining accurate measures of immunogenicity is difficult, a range of techniques to both predict the immunogenicity of a substance and to measure immunogenicity based on B and T cell activation have been developed. Key Concepts Immunogenicity is defined as the ability of a substance to elicit an adaptive immune response. The immunogenicity of a substance depends on multiple factors relating to the properties of the substance itself, the biological system, and how the substance is delivered to the biological system. Immunogenicity is necessary for our body to respond to and destroy pathogens, as well as to remove tumourogenic and dying cells. Understanding immunogenicity is important for pharmaceutical development, where it is sometimes necessary to either increase (vaccination) or decrease (protein therapeutics) the immunogenicity of a product. Experimental model systems, and more recently, computational tools, are being developed to predict immunogenicity. Immunogenicity can be measured empirically by assessing the numbers of activated T or B cells, or antibody levels during a response to the substance.
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