Characterization of recombinant gorilla adenovirus HPV therapeutic vaccine PRGN-2009

Pellom, Samuel T.; Rumfield, Claire Smalley; Morillon, Y. Maurice; Roller, Nicholas; Poppe, Lisa K.; Brough, Douglas E.; Sabzevari, Helen; Schlom, Jeffrey; Jochéms, Caroline

doi:10.1172/jci.insight.141912

Cited by 13 publications

(6 citation statements)

References 43 publications

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“…Human papillomavirus (HPV)-oncogenesis being associated with the constitutive expression of HPV proteins E6 and E7 in tumors, many clinical trials have investigated the efficacy of therapeutic vaccines targeting E6 and E7, but none has led to approval for clinical use so far ( 83 ). However, a novel therapeutic gorilla adenovirus HPV vaccine, PRGN-2009, has shown promise when tested in PBMC-humanized NSG mice bearing human HPV16 + cervical tumors as it reduced tumor growth and increased CD8 + and CD4 + T cell levels in the TME, supporting its use in clinical trials ( 84 ) ( Figure 2D ).…”

Section: Humanized Mouse Models In Cancer Immunotherapy Researchmentioning

confidence: 99%

Humanized Mice as a Valuable Pre-Clinical Model for Cancer Immunotherapy Research

et al. 2021

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Immunotherapy with checkpoint inhibitors opened new horizons in cancer treatment. Clinical trials for novel immunotherapies or unexplored combination regimens either need years of development or are simply impossible to perform like is the case in cancer patients with limited life expectancy. Thus, the need for preclinical models that rapidly and safely allow for a better understanding of underlying mechanisms, drug kinetics and toxicity leading to the selection of the best regimen to be translated into the clinic, is of high importance. Humanized mice that can bear both human immune system and human tumors, are increasingly used in recent preclinical immunotherapy studies and represent a remarkably unprecedented tool in this field. In this review, we describe, summarize, and discuss the recent advances of humanized mouse models used for cancer immunotherapy research and the challenges faced during their establishment. We also highlight the lack of preclinical studies using this model for radiotherapy-based research and argue that it can be a great asset to understand and answer many open questions around radiation therapy such as its presumed associated “abscopal effect”.

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Section: Humanized Mouse Models In Cancer Immunotherapy Researchmentioning

confidence: 99%

Humanized Mice as a Valuable Pre-Clinical Model for Cancer Immunotherapy Research

et al. 2021

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“…These characteristics subjected to use the non-human Ads as a vector for gene therapy and recombinant vaccine development so as to overcome the pre-existing antibodies that exists against human adenoviral vectors. There are numerous non-human adenoviral vectors that have used for recombinant vaccine development and gene therapy such as gorilla adenovirus vector (GC-46), chimpanzee adenoviral vectors (ChAdOx1 nCoV-19, ChAd1, ChAd2, ChAd3, ChAd5, ChAd6, ChAd7, and ChAd68); bovine adenoviral vectors; fowl adenoviral vectors; canine adenoviral vectors, ovine adenoviral vectors; porcine adenoviral vectors ( 36 – 40 ).…”

Section: General Information On Adenovirusesmentioning

confidence: 99%

“…The study revealed that PRGN-2009 treatment reduced tumor volume and increased CD8+ and CD4+ T cells in the tumor microenvironment of humanized mice bearing the human cervical tumor SiHa. The PRGN-2009 monotherapy in the syngeneic TC-1 model also reduced tumor volumes and weights, generated high levels of HPV16 E6–specific T cells, and increased multifunctional CD8+ and CD4+ T cells in the tumor microenvironment ( 40 ).…”

Section: Application Of Adenoviruses In Cancer Therapymentioning

confidence: 99%

“…Non-human adenoviruses have been used to overcome the challenge of preexisting human adenoviral immunity. The commonly used nonhuman adenovirus vectors include gorilla adenovirus and chimpanzee-derived adenovirus vector (ChAd) ( 40 ). Several chimpanzee adenoviral vector-based vaccines, such as ChAd7 for Ebola virus, ChAd6 for rabies, and ChAd6, ChAd7, and ChAd9 for malaria, have shown high efficacy in animal models ( 216 ).…”

Section: Challenges and Solutions Of Using Adenoviral Vectors In Canc...mentioning

confidence: 99%

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Role of Adenoviruses in Cancer Therapy

Tseha

2022

Front. Oncol.

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Cancer is one of the leading causes of death in the world, which is the second after heart diseases. Adenoviruses (Ads) have become the promise of new therapeutic strategy for cancer treatment. The objective of this review is to discuss current advances in the applications of adenoviral vectors in cancer therapy. Adenoviral vectors can be engineered in different ways so as to change the tumor microenvironment from cold tumor to hot tumor, including; 1. by modifying Ads to deliver transgenes that codes for tumor suppressor gene (p53) and other proteins whose expression result in cell cycle arrest 2. Ads can also be modified to express tumor specific antigens, cytokines, and other immune-modulatory molecules. The other strategy to use Ads in cancer therapy is to use oncolytic adenoviruses, which directly kills tumor cells. Gendicine and Advexin are replication-defective recombinant human p53 adenoviral vectors that have been shown to be effective against several types of cancer. Gendicine was approved for treatment of squamous cell carcinoma of the head and neck by the Chinese Food and Drug Administration (FDA) agency in 2003 as a first-ever gene therapy product. Oncorine and ONYX-015 are oncolytic adenoviral vectors that have been shown to be effective against some types of cancer. The Chiness FDA agency has also approved Oncorin for the treatment of head and neck cancer. Ads that were engineered to express immune-stimulatory cytokines and other immune-modulatory molecules such as TNF-α, IL-2, BiTE, CD40L, 4-1BBL, GM-CSF, and IFN have shown promising outcome in treatment of cancer. Ads can also improve therapeutic efficacy of immune checkpoint inhibitors and adoptive cell therapy (Chimeric Antigen Receptor T Cells). In addition, different replication-deficient adenoviral vectors (Ad5-CEA, Ad5-PSA, Ad-E6E7, ChAdOx1–MVA and Ad-transduced Dendritic cells) that were tested as anticancer vaccines have been demonstrated to induce strong antitumor immune response. However, the use of adenoviral vectors in gene therapy is limited by several factors such as pre-existing immunity to adenoviral vectors and high immunogenicity of the viruses. Thus, innovative strategies must be continually developed so as to overcome the obstacles of using adenoviral vectors in gene therapy.

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“…HPV is a small, nonenveloped double-stranded DNA virus [ 8 ]. Among the high-risk HPV types, HPV16 and HPV18 are major viral carcinogens, accounting for the development of up to nearly 5% of the total cancer incidence worldwide [ 9 , 10 ]. HPV E6 and E7 are two major oncoproteins encoded by HPV 16 and 18 [ 11 ], which have been shown to promote tumorigenesis by inducing cell immortality and migration, changing the cell cycle, controlling apoptosis, and fostering avoidance of host immune surveillance [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

HPV16 E6 enhances the radiosensitivity in HPV-positive human head and neck squamous cell carcinoma by regulating the miR-27a-3p/SMG1 axis

Long

Deng

et al. 2021

Infect Agents Cancer

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Background Head and neck squamous cell carcinoma (HNSCC) is the 6th most common malignant cancer type worldwide. Radiosensitivity has been shown to be significantly increased in patients with human papillomavirus (HPV)-positive HNSCC compared with HPV-negative patients. However, the clinical significance of HPV and its regulatory mechanisms in HNSCC are largely unknown. The aim of our study was to explore the regulatory mechanism of miR-27a-3p in the radiosensitivity of HPV-positive HNSCC cells. Methods E6-overexpressing and E6-knockdown HNSCC cell lines were generated and the transfection efficiencies were evaluated by quantitative real-time PCR (RT-qPCR) and western blotting. The expression of miR-27a-3p and DiGeorge syndrome critical region 8 (DGCR8) was examined by RT-qPCR after transfection with E6 overexpressing plasmid or E6 siRNA. The effects of miR-27a-3p on the radiosensitivity of HNSCC cells were explored by a colony formation and TUNEL staining assays. Bioinformatic tools and luciferase reporter assays were used to identify that SMG1 is the direct target of miR-27a-3p. Furthermore, the effect of E6 overexpression on the regulation of the miR-27a-3p/SMG1 axis was investigated. Results In our study, we found overexpression of HPV E6 upregulated the expression of DGCR8 and miR-27a-3p in HNSCC cells. We next confirmed that DGCR8 positively regulated the expression of miR-27a-3p in HNSCC cells. The luciferase reporter gene results verified that miR-27a-3p targeted the 3’UTR of SMG1 mRNA. MiR-27a-3p mimics transfection resulted in a decrease in SMG1 expression and miR-27a-3p inhibitor transfection increased SMG1 expression. Apoptotic activity of HNSCC cells was significantly increased in miR-27a-3p mimics HNSCC cells compared with control HNSCC cells. After treatment with 4 Gy irradiation, UM-SCC47 cells transfected with miR-27a-3p inhibitor or SMG1 overexpressing plasmid formed more colonies than the corresponding control cells. Furthermore, the rescue experiments demonstrated that HPV16 E6 improved the radiosensitivity of HNSCC cells by targeting miR-27a-3p/SMG1. Conclusion Our study demonstrated that HPV16 E6 activated the DGCR8/miR-27a-3p/SMG1 axis to enhance the radiosensitivity. Our findings might provide a novel therapeutic target to improve the response of HNSCC to radiotherapy.

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Characterization of recombinant gorilla adenovirus HPV therapeutic vaccine PRGN-2009

Cited by 13 publications

References 43 publications

Humanized Mice as a Valuable Pre-Clinical Model for Cancer Immunotherapy Research

Humanized Mice as a Valuable Pre-Clinical Model for Cancer Immunotherapy Research

Role of Adenoviruses in Cancer Therapy

HPV16 E6 enhances the radiosensitivity in HPV-positive human head and neck squamous cell carcinoma by regulating the miR-27a-3p/SMG1 axis

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