Capsid and Genome Modification Strategies to Reduce the Immunogenicity of Adenoviral Vectors

Adenovirus-based gene transfer vectors are the most frequently used vector type in gene therapy clinical trials to date, and they play an important role as genetic vaccine candidates during the ongoing SARS-CoV-2 pandemic. Immediately upon delivery, adenovirus-based vectors exhibit multiple complex vector-host interactions and induce innate and adaptive immune responses. This can severely limit their safety and efficacy, particularly after delivery through the blood stream. In this review article we summarize two strategies to modulate Ad vector-induced immune responses: extensive genomic and chemical capsid modifications. Both strategies have shown beneficial effects in a number of preclinical studies while potential synergistic effects warrant further investigations.

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Healthy Effects Exerted by Prebiotics, Probiotics, and Symbiotics with Special Reference to their Impact on the Immune System

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000112 ◽

2012 ◽

Vol 82 (3) ◽

pp. 200-208 ◽

Cited By ~ 23

Author(s):

Emilio Jirillo ◽

Felicita Jirillo ◽

Thea Magrone

Keyword(s):

Immune Responses ◽

Tumor Development ◽

The Elderly ◽

Adaptive Immune Responses ◽

Free Living ◽

Beneficial Effects ◽

Adaptive Immune ◽

Inflammatory Conditions ◽

Reduced Frequency ◽

Inflammatory Bowel

Pre-, pro-, and symbiotics are endowed with a broad spectrum of beneficial effects when administered to animals and humans. A series of experimental and clinical studies have clearly demonstrated that prebiotics, probiotics, or their combination are very effective in attenuating chronic inflammatory conditions such as inflammatory bowel disease or obesity. In addition, these natural products are able to prevent or arrest tumor development, acting on the intestinal microbiota as well as potentiating the immune response.Aging is characterized by a dramatic reduction of both innate and adaptive immune responses, the so-called immunosenescence. This leads to an increased incidence of infections, autoimmune diseases, and cancer in the elderly. Pre-, pro-, and symbiotic administration has been shown to ameliorate the immune response in aging. In particular, administration of a symbiotic to free-living elderly was able to potentiate the release of interleukin-8, thus increasing neutrophils in the host, perhaps explaining the reduced frequency of winter infections in the elderly.

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Progress in Adenoviral Capsid-Display Vaccines

Biomedicines ◽

10.3390/biomedicines6030081 ◽

2018 ◽

Vol 6 (3) ◽

pp. 81 ◽

Cited By ~ 8

Author(s):

Marija Vujadinovic ◽

Jort Vellinga

Keyword(s):

Immune Responses ◽

Adenoviral Vector ◽

Vaccine Development ◽

Adenoviral Vectors ◽

Manufacturing Costs ◽

Genetic Vaccine ◽

Immunogenic Peptides ◽

T Cell Immune Responses ◽

Protein Ix ◽

Capsid Display

Adenoviral vectored vaccines against infectious diseases are currently in clinical trials due to their capacity to induce potent antigen-specific B- and T-cell immune responses. Heterologous prime-boost vaccination with adenoviral vector and, for example, adjuvanted protein-based vaccines can further enhance antigen-specific immune responses. Although leading to potent immune responses, these heterologous prime-boost regimens may be complex and impact manufacturing costs limiting efficient implementation. Typically, adenoviral vectors are engineered to genetically encode a transgene in the E1 region and utilize the host cell machinery to express the encoded antigen and thereby induce immune responses. Similarly, adenoviral vectors can be engineered to display foreign immunogenic peptides on the capsid-surface by insertion of antigens in capsid proteins hexon, fiber and protein IX. The ability to use adenoviral vectors as antigen-display particles, with or without using the genetic vaccine function, greatly increases the versatility of the adenoviral vector for vaccine development. This review describes the application of adenoviral capsid antigen-display vaccine vectors by focusing on their distinct advantages and possible limitations in vaccine development.

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1019. Immune System Regulation of Transgene Expression in the Brain 2: Differential Increase of mRNAs Encoding for Interferon-Regulated, Chemokine, and T-Cell Genes during Either Innate Acute or Chronic Systemic Adaptive Immune Responses to First Generation Adenoviral Vectors

Molecular Therapy ◽

10.1016/j.ymthe.2004.06.964 ◽

2004 ◽

Vol 9 ◽

pp. S390-S391

Keyword(s):

Immune System ◽

Immune Responses ◽

Transgene Expression ◽

First Generation ◽

Adenoviral Vectors ◽

Adaptive Immune Responses ◽

Adaptive Immune ◽

Immune System Regulation ◽

Differential Increase ◽

The Brain

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Exploring the synergistic effects of cabozantinib (cabo) and a programmed cell death protein 1 (PD1) inhibitor in metastatic renal cell carcinoma (mRCC) with artificial intelligence (AI).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e16555 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e16555-e16555

Author(s):

Ignacio Duran ◽

Luis Costa ◽

Javier Puente ◽

Urbano Anido ◽

Lidia Martin ◽

...

Keyword(s):

Immune Responses ◽

Immune Evasion ◽

Synergistic Effects ◽

Holistic View ◽

Biological Targets ◽

Adaptive Immune ◽

Drug Actions ◽

Apoptotic Effects ◽

Cellular Components ◽

Cell Death Protein

e16555 Background: Nonclinical and clinical data suggest that cabo with a PD1 inhibitor provides synergistic antitumor activity in patients with mRCC, possibly by a cabo-induced switch to an immunopermissive tumor microenvironment. We used a complementary, unbiased, AI approach to gain a holistic view of the complex interplay between multiple pathways, cells and molecules and identify the mechanisms that may underpin this synergism. Methods: Biological targets associated with mRCC pathophysiology or drug actions were identified from proteomic, genomic and transcriptomic databases and literature. Using systems- and AI-based technology, the data were integrated using machine learning into mathematical models of the human mRCC protein network topology. The combined effects of cabo and a PD1 inhibitor on biological targets were simulated assuming target receptors were fully activated or fully inhibited. Relevant effects on known cancer processes (e.g. angiogenesis, metastasis, cell proliferation, immune evasion) were identified using artificial neural networks. Biologically plausible synergistic mechanisms were described with sampling methods. Results: Inhibition of VEGF/VEGFR and GAS6/TAMR axes by cabo enhanced the known effects of PD1 inhibitors on immune evasion mechanisms by modulating multiple humoral and cellular components of the innate and adaptive immune responses (Table). PD1 inhibitors further enhanced the anti-angiogenic and tumor pro-apoptotic effects of cabo by modulating pro- and anti-angiogenic factors and T cell cytotoxicity. Conclusions: These data provide a mechanistic rationale and further support for the beneficial combination of cabo and a PD1 inhibitor and may guide future nonclinical and clinical research.[Table: see text]

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Exploring the synergistic effects of cabozantinib (cabo) and a programmed cell death protein 1 (PD1) inhibitor in metastatic renal cell carcinoma (mRCC) with artificial intelligence (AI).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.336 ◽

2021 ◽

Vol 39 (6_suppl) ◽

pp. 336-336

Author(s):

Luis Costa ◽

Daniel Castellano ◽

Javier Puente ◽

Lidia Martin ◽

Urbano Anido ◽

...

Keyword(s):

Immune Responses ◽

Immune Evasion ◽

Synergistic Effects ◽

Holistic View ◽

Biological Targets ◽

Adaptive Immune ◽

Drug Actions ◽

Apoptotic Effects ◽

Cellular Components ◽

Cell Death Protein

336 Background: Nonclinical and clinical data suggest that cabo with a PD1 inhibitor provides synergistic antitumor activity in patients with mRCC, possibly by a cabo-induced switch to an immunopermissive tumor microenvironment. We used a complementary, unbiased, AI approach to gain a holistic view of the complex interplay between multiple pathways, cells and molecules and identify the mechanisms that may underpin this synergism. Methods: Biological targets associated with mRCC pathophysiology or drug actions were identified from proteomic, genomic and transcriptomic databases and literature. Using systems- and AI-based technology, the data were integrated using machine learning into mathematical models of the human mRCC protein network topology. The combined effects of cabo and a PD1 inhibitor on biological targets were simulated assuming target receptors were fully activated or fully inhibited. Relevant effects on known cancer processes (e.g. angiogenesis, metastasis, cell proliferation, immune evasion) were identified using artificial neural networks. Biologically plausible synergistic mechanisms were described with sampling methods. Results: Inhibition of VEGF/VEGFR and GAS6/TAMR axes by cabo enhanced the known effects of PD1 inhibitors on immune evasion mechanisms by modulating multiple humoral and cellular components of the innate and adaptive immune responses (Table). PD1 inhibitors further enhanced the anti-angiogenic and tumor pro-apoptotic effects of cabo by modulating pro- and anti-angiogenic factors and T cell cytotoxicity. Conclusions: These data provide a mechanistic rationale and further support for the beneficial combination of cabo and a PD1 inhibitor and may guide future nonclinical and clinical research. [Table: see text]

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Innate Immune Response to Adenoviral Vectors Is Mediated by both Toll-Like Receptor-Dependent and -Independent Pathways

Journal of Virology ◽

10.1128/jvi.02192-06 ◽

2007 ◽

Vol 81 (7) ◽

pp. 3170-3180 ◽

Cited By ~ 225

Author(s):

Jiangao Zhu ◽

Xiaopei Huang ◽

Yiping Yang

Keyword(s):

Gene Therapy ◽

Immune Response ◽

Immune Responses ◽

Innate Immune Response ◽

Adenoviral Vectors ◽

Innate Immune ◽

Type I ◽

Type I Ifn ◽

Adaptive Immune ◽

Type I Ifns

ABSTRACT Recombinant adenoviral vectors have been widely used for gene therapy applications and as vaccine vehicles for treating infectious diseases such as human immunodeficiency virus disease. The innate immune response to adenoviruses represents the most significant hurdle in clinical application of adenoviral vectors for gene therapy, but it is an attractive feature for vaccine development. How adenovirus activates innate immunity remains largely unknown. Here we showed that adenovirus elicited innate immune response through the induction of high levels of type I interferons (IFNs) by both plasmacytoid dendritic cells (pDCs) and non-pDCs such as conventional DCs and macrophages. The innate immune recognition of adenovirus by pDCs was mediated by Toll-like receptor 9 (TLR9) and was dependent on MyD88, whereas that by non-pDCs was TLR independent through cytosolic sensing of adenoviral DNA. Furthermore, type I IFNs were pivotal in innate and adaptive immune responses to adenovirus in vivo, and type I IFN blockade diminished immune responses, resulting in more stable transgene expression and reduction of inflammation. These findings indicate that adenovirus activates innate immunity by its DNA through TLR-dependent and -independent pathways in a cell type-specific fashion, and they highlight a critical role for type I IFNs in innate and adaptive immune responses to adenoviral vectors. Our results that suggest strategies to interfere with type I IFN pathway may improve the outcome of adenovirus-mediated gene therapy, whereas approaches to activate the type I IFN pathway may enhance vaccine potency.

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