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      H 2O 2-Inactivated Salmonella typhimurium RE88 Strain as a New Cancer Vaccine Carrier: Evaluation in a Mouse Model of Cancer

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          Abstract

          Purpose

          This study aimed to describe a novel cancer vaccine developed using H 2O 2-inactivated Salmonella typhimurium RE88 [with deletions of AroA (the first enzyme in the aromatic amino acid biosynthesis pathway) and DNA adenine methylase] as the carrier.

          Methods

          The pVLT33 plasmid was used to engineer an RE88 strain induced to express ovalbumin (OVA) by isopropylthiogalactoside (RE88-pVLT33-OVA). The immune responses and anticancer effects of H 2O 2-inactivated RE88-pVLT33-OVA were compared with those of non-inactivated RE88-pVLT33-OVA and OVA (positive control) in mice carrying OVA-expressing tumors (EG7-OVA) cells.

          Results

          Anti-ovalbumin IgG (immunoglobulin G) titer following vaccination with H 2O 2-inactivated RE88-pVLT33-OVA was higher for subcutaneous than for intragastric vaccination. When subcutaneous administration was used, H 2O 2-inactivated RE88-pVLT33-OVA (2 × 10 9 CFU (colony forming units)/mouse) achieved an anti-ovalbumin IgG titer higher than that for the same dose of RE88-pVLT33-OVA and comparable to that for 10 µg ovalbumin (positive control). The binding of mouse serum antibodies to EG7-OVA cells was stronger for H 2O 2-inactivated RE88-pVLT33-OVA (2 × 10 9 CFU/mouse) than for 10 µg ovalbumin. Furthermore, subcutaneous vaccination with H 2O 2-inactivated RE88-pVLT33-OVA (2 × 10 9 CFU/mouse) induced greater activation of splenic T cells and more extensive tumor infiltration with CD4 +/CD8 + T cells compared with 10 µg ovalbumin (positive control). The mice vaccinated subcutaneously with H 2O 2-inactivated RE88-pVLT33-OVA at a dose of 2 × 10 8 or 6 × 10 8 CFU/mouse had smaller tumors compared with mice in the negative control groups. Tumor weight in mice vaccinated with H 2O 2-inactivated RE88-pVLT33-OVA at a dose of 2 × 10 9 CFU/mouse was significantly lower than that in both negative control groups ( P < 0.05) and decreased with the increasing dose of H 2O 2-inactivated RE88-pVLT33-OVA. H 2O 2-inactivated RE88-pVLT33-OVA was potentially safer than the non-inactivated strain, could carry exogenous antigens, and had specific epitopes that could be exploited as natural adjuvants to facilitate the induction of cellular and humoral immune responses.

          Conclusion

          It was anticipated that H 2O 2-inactivated RE88-pVLT33-OVA could be used as a novel delivery system for new cancer vaccines.

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          Most cited references 34

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          Somatic mutations have the potential to encode "non-self" immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade.
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            Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer.

            Immune checkpoint inhibitors, which unleash a patient's own T cells to kill tumors, are revolutionizing cancer treatment. To unravel the genomic determinants of response to this therapy, we used whole-exome sequencing of non-small cell lung cancers treated with pembrolizumab, an antibody targeting programmed cell death-1 (PD-1). In two independent cohorts, higher nonsynonymous mutation burden in tumors was associated with improved objective response, durable clinical benefit, and progression-free survival. Efficacy also correlated with the molecular smoking signature, higher neoantigen burden, and DNA repair pathway mutations; each factor was also associated with mutation burden. In one responder, neoantigen-specific CD8+ T cell responses paralleled tumor regression, suggesting that anti-PD-1 therapy enhances neoantigen-specific T cell reactivity. Our results suggest that the genomic landscape of lung cancers shapes response to anti-PD-1 therapy. Copyright © 2015, American Association for the Advancement of Science.
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              Genomic correlates of response to CTLA-4 blockade in metastatic melanoma.

              Monoclonal antibodies directed against cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), such as ipilimumab, yield considerable clinical benefit for patients with metastatic melanoma by inhibiting immune checkpoint activity, but clinical predictors of response to these therapies remain incompletely characterized. To investigate the roles of tumor-specific neoantigens and alterations in the tumor microenvironment in the response to ipilimumab, we analyzed whole exomes from pretreatment melanoma tumor biopsies and matching germline tissue samples from 110 patients. For 40 of these patients, we also obtained and analyzed transcriptome data from the pretreatment tumor samples. Overall mutational load, neoantigen load, and expression of cytolytic markers in the immune microenvironment were significantly associated with clinical benefit. However, no recurrent neoantigen peptide sequences predicted responder patient populations. Thus, detailed integrated molecular characterization of large patient cohorts may be needed to identify robust determinants of response and resistance to immune checkpoint inhibitors.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                dddt
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                15 January 2021
                2021
                : 15
                : 209-222
                Affiliations
                [1 ]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center , Chengdu, People’s Republic of China
                [2 ]Department of Laboratory Medicine, Clinical Medical College and the First Affiliated Hospital of Chengdu Medical College , Chengdu, People’s Republic of China
                Author notes
                Correspondence: Li Yang State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center , No. 17, People’s South Road, Chengdu610041, People’s Republic of ChinaTel +86 18628182400 Email yl.tracy73@gmail.com
                [*]

                These authors contributed equally to this work

                Article
                282660
                10.2147/DDDT.S282660
                7815095
                © 2021 Fan et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 5, References: 34, Pages: 14
                Funding
                Funded by: the National Major Scientific and Technological Special Project for “Significant New Drugs Development;
                This study was supported by the National Major Scientific and Technological Special Project for “Significant New Drugs Development (2018ZX09733001 and 2018ZX09201018) and 1.3.5 project for disciplines of excellence,” West China Hospital, Sichuan University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Original Research

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