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Protecting Tumors by Preventing Human Papilloma Virus Antigen Presentation: Insights from Emerging Bioinformatics Algorithms.

ABSTRACT: Recent developments in bioinformatics technologies have led to advances in our understanding of how oncogenic viruses such as the human papilloma virus drive cancer progression and evade the host immune system. Here, we focus our review on understanding how these emerging bioinformatics technologies influence our understanding of how human papilloma virus (HPV) drives immune escape in cancers of the head and neck, and how these new informatics approaches may be generally applicable to other virally driven cancers. Indeed, these tools enable researchers to put existing data from genome wide association studies, in which high risk alleles have been identified, in the context of our current understanding of cellular processes regulating neoantigen presentation. In the future, these new bioinformatics approaches are highly likely to influence precision medicine-based decision making for the use of immunotherapies in virally driven cancers.

SUBMITTER: Gensterblum-Miller E

PROVIDER: S-EPMC6826432 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Protecting Tumors by Preventing Human Papilloma Virus Antigen Presentation: Insights from Emerging Bioinformatics Algorithms.

Gensterblum-Miller Elizabeth E Brenner J Chad JC

Cancers 20191012 10

Recent developments in bioinformatics technologies have led to advances in our understanding of how oncogenic viruses such as the human papilloma virus drive cancer progression and evade the host immune system. Here, we focus our review on understanding how these emerging bioinformatics technologies influence our understanding of how human papilloma virus (HPV) drives immune escape in cancers of the head and neck, and how these new informatics approaches may be generally applicable to other vira ...[more]

PMID: 31614809

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Project description:Immune checkpoint blockade (ICB) is a clinically proven concept to treat cancer. Still, a majority of patients with cancer including those with poorly immune infiltrated 'cold' tumors are resistant to currently available ICB therapies. Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is one of few clinically validated targets for ICB, but toxicities linked to efficacy in approved αCTLA-4 regimens have restricted their use and precluded full therapeutic dosing. At a mechanistic level, accumulating preclinical and clinical data indicate dual mechanisms for αCTLA-4; ICB and regulatory T cell (Treg) depletion are both thought to contribute efficacy and toxicity in available, systemic, αCTLA-4 regimens. Accordingly, strategies to deliver highly effective, yet safe αCTLA-4 therapies have been lacking. Here we assess and identify spatially restricted exposure to a novel strongly Treg-depleting, checkpoint-blocking, vectorized αCTLA-4, as a highly efficacious and potentially safe strategy to target CTLA-4. A novel human IgG1 CTLA-4 antibody (4-E03) was identified using function-first screening for monoclonal antibodies (mAbs) and targets associated with superior Treg-depleting activity. A tumor-selective oncolytic vaccinia vector was then engineered to encode this novel, strongly Treg-depleting, checkpoint-blocking, αCTLA-4 antibody or a matching surrogate antibody, and Granulocyte-macrophage colony-stimulating factor (GM-CSF) (VVGM-αCTLA-4). The identified 4-E03 antibody showed significantly stronger Treg depletion, but equipotent checkpoint blockade, compared with clinically validated αCTLA-4 ipilimumab against CTLA-4-expressing Treg cells in a humanized mouse model in vivo. Intratumoral administration of VVGM-αCTLA-4 achieved tumor-restricted CTLA-4 receptor saturation and Treg depletion, which elicited antigen cross-presentation and stronger systemic expansion of tumor-specific CD8+ T cells and antitumor immunity compared with systemic αCTLA-4 antibody therapy. Efficacy correlated with FcγR-mediated intratumoral Treg depletion. Remarkably, in a clinically relevant mouse model resistant to systemic ICB, intratumoral VVGM-αCTLA-4 synergized with αPD-1 to reject cold tumors. Our findings demonstrate in vivo proof of concept for spatial restriction of Treg depletion-optimized immune checkpoint blocking, vectorized αCTLA-4 as a highly effective and safe strategy to target CTLA-4. A clinical trial evaluating intratumoral VVGM-αhCTLA-4 (BT-001) alone and in combination with αPD-1 in metastatic or advanced solid tumors has commenced.

Dataset Information

Protecting Tumors by Preventing Human Papilloma Virus Antigen Presentation: Insights from Emerging Bioinformatics Algorithms.

Publications

Protecting Tumors by Preventing Human Papilloma Virus Antigen Presentation: Insights from Emerging Bioinformatics Algorithms.

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