Dataset Information

Tailoring an Intravenously Injectable Oncolytic Virus for Augmenting Radiotherapy

ABSTRACT: Oncolytic viruses (OVs) combined with radiotherapy (RT) have shown promise in clinical trials but remain limited by unsatisfactory efficacy. Key challenges include poor intravenous delivery, insufficient RT-induced DNA damage, and suboptimal anti-tumor immune responses. Herein, we developed a novel oncolytic adenovirus (AD) formulation, RadioOnco (AD@PSSP), which incorporates multifunctional polyethyleneimine (PEI)-selenium-PEG (PSSP) to enhance intravenous delivery, viral infectivity, immune response and the efficacy of radiotherapy. The PEGylation shields the virus from rapid clearance, while the ROS-responsive Se-Se bond enables targeted delivery at tumor sites following RT. The exposed PEI enhanced infectivity of AD through electrostatic interactions, consequently augmenting DNA damage after RT via inhibiting the expression of DNA-repair proteins, such as CHEK1 and CDK1. Furthermore, AD-PEI can capture and deliver the RT-induced tumor-released antigens to lymph nodes, thereby activating robust anti-tumor immune responses. Our data from diverse animal models have shown that RadioOnco exhibits unique characteristics, including reversing RT resistance, ability for distant killing, and long-term memory retention, all of which are crucial for addressing metastasis and recurrence in clinical RT. In summary, we have devised an intravenously injectable OVs with synergistic effects in conjunction with RT, achieved through the surface modification of a multifunctional material.

ORGANISM(S): Homo Sapiens Mus Musculus

SUBMITTER: Funan Liu

PROVIDER: PXD060493 | iProX | Sun Feb 02 00:00:00 GMT 2025

REPOSITORIES: iProX

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Tailoring an intravenously injectable oncolytic virus for augmenting radiotherapy.

Xu Chen C Chen Liting L Liu Guangna G Xu Jiaqi J Lv Wei W Gao Xiaoyu X Xu Peijun P Tang Ming M Wang Yaohe Y Zhao Xiao X Nie Guangjun G Cheng Keman K Liu Funan F

Cell reports. Medicine 20250414 5

Oncolytic viruses (OVs) combined with radiotherapy (RT) show promise but are limited by challenges such as poor intravenous delivery and insufficient RT-induced DNA damage. In this study, an oncolytic adenovirus (AD) formulation, RadioOnco (AD@PSSP), is developed to improve delivery, infectivity, immune response, and RT efficacy. The multifunctional polyethylenimine (PEI)-selenium-polyethylene glycol (PEG) (PSSP) enhances intravenous delivery, shields the virus from rapid clearance, and enables ...[more]

PMID: 40233744

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Project description:Accumulating data support the concept that ionizing radiation therapy (RT) has the potential to convert the tumor into an in situ, individualized vaccine; however this potential is rarely realized by RT alone. Transforming growth factor β (TGFβ) is an immunosuppressive cytokine that is activated by RT and inhibits the antigen-presenting function of dendritic cells and the differentiation of effector CD8+ T cells. Here we tested the hypothesis that TGFβ hinders the ability of RT to promote anti-tumor immunity. Development of tumor-specific immunity was examined in a pre-clinical model of metastatic breast cancer. Mice bearing established 4T1 mouse mammary carcinoma treated with pan-isoform specific TGFβ neutralizing antibody, 1D11, showed significantly improved control of the irradiated tumor and non-irradiated metastases, but no effect in the absence of RT. Notably, whole tumor transcriptional analysis demonstrated the selective upregulation of genes associated with immune-mediated rejection only in tumors of mice treated with RT+TGFβ blockade. Mice treated with RT+TGFβ blockade exhibited cross-priming of CD8+ T cells producing IFNγ in response to three tumor-specific antigens in tumor-draining lymph nodes, which was not evident for single modality treatment. Analysis of the immune infiltrate in mouse tumors showed a significant increase in CD4+ and CD8+ T cells only in mice treated with the combination of RT+TGFβ blockade. Depletion of CD4+ or CD8+ T cells abrogated the therapeutic benefit of RT+TGFβ blockade. These data identify TGFβ as a master inhibitor of the ability of RT to generate an in situ tumor vaccine, which supports testing inhibition of TGFβ during radiotherapy to promote therapeutically effective anti-tumor immunity. We used genome-wide microarray to depict main biological processes responsibles for the therapeutic benefit of the combination ofTGF-beta blockade and local radiotherapy. To gain a more comprehensice protrait of the effects of RT and TGFbeta blockade on gene expressionin tumors, we collected 4T1 tumors 4 days after completion of RT. Three tumors from each group were then subjected to RNA extraction and hybridization on affymetrix array.

Dataset Information

Tailoring an Intravenously Injectable Oncolytic Virus for Augmenting Radiotherapy

Publications

Tailoring an intravenously injectable oncolytic virus for augmenting radiotherapy.

Similar Datasets

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