Humans are supra-organisms co-evolved with microbial communities (Prokaryotic and Eukaryotic), named the microbiome. These microbiomes supply essential ecosystem services that play critical roles in human health. A loss of indigenous microbes through modern lifestyles leads to microbial extinctions, associated with many diseases and epidemics. This narrative review conforms a complete guide to the human holobiont—comprising the host and all its symbiont populations- summarizes the latest and most significant research findings in human microbiome. It pretends to be a comprehensive resource in the field, describing all human body niches and their dominant microbial taxa while discussing common perturbations on microbial homeostasis, impacts of urbanization and restoration and humanitarian efforts to preserve good microbes from extinction.
Oncolytic viruses are a promising experimental treatment for solid tumors. Recently, several phase 1 clinical trials have reported encouraging therapeutic effects of oncolytic viruses in adult and pediatric patients with malignant gliomas. To further improve the therapeutic outcome of viroimmunotherapy, we have developed Delta-24-RGDOX (DNX-2440), a replication competent adenovirus encompassing the T-cell activator OX40L in the genetic backbone of Delta-24-RGD. We have previously reported the effect of Delta-24-RGDOX in murine brain tumors supporting the translation of this new agent to treat patients with recurrent malignant gliomas (NCT03714334). In the work presented here, we have tested the therapeutic effect of Delta-24-RGDOX in murine syngeneic models of breast (4T1), gastric (M12) and lung cancer (LLC and CMT 167). We found that Delta-24-RGDOX infected all cancer cell lines efficiently. In addition, infection of cells was followed by the expression of the ectopic ligand in vitro and in vivo. Because the elicitation of an anti-tumor immunity is part of the mechanisms underlying the therapeutic effect of oncolytic viruses, we examined whether infection of tumors led to the reshaping of the tumor microenvironment. We observed that Delta-24-RGDOX infection was followed by increased frequencies of tumor infiltrating lymphocytes, particularly CD8+ T cells and NK cells. In addition, the CD8+/CD4+ ratio was increased in Delta-24-RGDOX-treated tumor versus PBS-treated tumors. Interestingly, abscopal modifications were observed in breast cancer brain metastases with increased frequency of CD8+ T cells at the distal, untreated site. Delta-24-RGDOX treatment induced an anti-cancer effect in orthotopically implanted breast cancer and subcutaneously implanted lung and gastric tumors, as well as in metastatic niches. In summary, our data showed that treatment of solid tumors with Delta-24-RGDOX induces robust remodeling of the tumor microenvironment and produces anti-tumor effects leading to decrease in tumor volume, along with a delay in the development and in the reduction of the number of metastases. These data suggest that Delta-24-RGDOX should be tested in the clinical setting in patients with metastatic breast, gastric and lung cancers. Citation Format: Arie C. Van Wieren, Sagar Sahoni, Teresa Nguyen, Ashley Ossimetha, Yisel Rivera-Molina, Hong Jiang, Dong Ho Shin, Debora Kim, Xuejun Fan, Yanhua Yi, Natalie M. Melendez-Vazquez, Filipa Godoy-Vitorino, Joy Gumin, Frederick F. Lang, Marta M. Alonso, Juan Fueyo, Candelaria Gomez-Manzano. Viroimmunotherapy for solid tumors results in local and abscopal anti-cancer effects and the remodeling of tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3565.
Gastric cancer is the third leading cause of cancer-related mortality worldwide, and current standard-of-care treatment allows for a 5-year survival rate of 20%. Newer treatments against solid tumors include an oncolytic adenovirus armed with T-cell activator OX40L, named Delta-24-RGDOX, which expresses the positive immune checkpoint OX-40L. While studies have revealed the interaction between the gut microbiome and immunotherapy agents, it’s still unknown how the gut microbiome might influence viroimmunotherapy efficacy. We hypothesized that the gut microbiota plays an important role in modulating the virus-driven anti-tumor response. To test this hypothesis, immunocompetent C57BL/6 mice were subcutaneously implanted M12Luc gastric cancer cells and were administered PBS (control) or Delta-24-RGDOX by intratumoral injections. Mice fecal pellets were collected at three different time points: (1) before tumor implantation, (2) after tumor establishment, and (3) 14 days after the first dose of the treatment. Genomic DNA was isolated with the QIAGEN DNeasy Powersoil Kit from fecal pellets of cancer-bearing mice (n=60), and the V4 region of the 16S ribosomal RNA gene (prokaryotes) was sequenced using the Illumina platform. Data was deposited in QIITA for quality assessment, followed by microbial community analysis using the taxonomic reference database SILVA and the downstream platforms QIIME2 and R with a rarefaction depth of 9,187 reads per sample. We found significant differences in the gut microbiome community structure of viroimmunotherapy-treated mice compared to controls (ANOSIM p-value=0.025). No differences in gut diversity were observed, although control animals tended to show higher richness (Kruskal-Wallis p-value>0.05). Of interest, the bacterial composition of responders to the viroimmunotherapy had a decrease in Actinobacteria and an increase of Patescibacteria. Additionally, responders had higher levels of butyrate-producer bacteria such as Ruminococcaceae and Clostridium sensu stricto. These findings suggest that butyrate producers may be important in regulating host gut homeostasis associated with the clinical efficacy of Delta-24-RGDOX, suggesting possible benefits of microbiota modulation in patient survival. This project was sponsored by a pilot award within The University of Puerto Rico/University of Texas MD Anderson Cancer Center (MDACC) Partnership for Excellence in Cancer Research Grant (2U54CA096297-16). Citation Format: Natalie M. Melendez-Vazquez, Sagar Sohoni, Arie Van Wieren, Juan Fueyo, Candelaria Gomez-Manzano, Filipa Godoy-Vitorino. Changes in the gut microbiota associated with oncolytic virotherapy efficacy in a gastric cancer murine model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5894.
Malignant gliomas are devastating diseases that require new and more effective treatments. To improve clinical outcomes, our laboratories have developed an oncolytic adenovirus armed with the T-cell activator OX40L, named Delta-24-RGDOX. Here, we evaluated changes to gut microbiome in glioma bearing mice treated with viroimmunotherapy. GL261 glioblastoma cells were implanted in the brain of immunocompetent C57BL/6 mice. Then mice were treated with intratumoral injections of control (PBS) or a combination of Delta-24-RGDOX and Indoximod, an inhibitor of the immune modulator IDO. The combined immunotherapy prolonged mice overall survival with the production of long-term survivors (>100 days). We also performed a similar set of experiments in mice with depleted CD4+ T cell. Genomic DNA was isolated with the Powerlyzer kit from fecal pellets collected from glioma-bearing mice (n=15), followed by sequencing of the 16S ribosomal RNA V4 region (prokaryotes) and ITS-2 region (for fungi) using the Illumina platform. Data was analyzed at first and deposited in Qiita, the taxonomic reference was the SILVA database, and community analyses were performed in QIIME and R with a rarefaction depth of 27,000 reads for 16S and 500 reads for ITS. We found significant differences in the gut microbiome community structure of viroimmunotherapy-treated animals compared to those with depleted CD4+ T cells and controls which shared similarities (PERMANOVA p<0.001). The highest gut diversity was observed in viroimmunotherapy in animals in which the T cell populations were not depleted which also corresponded to long-term survivors (KW p=0.006). The gut bacterial community structure of viroimmunotherapy-treated animals without T-cell depletion showed an increase in Actinobacteria compared to control-treated mice and those with shorter survival. In fact, we found significantly higher amounts of Bifidobacterium and Lactobacillus in the viroimmunotherapy-treated mice while Moryella were more dominant in the control groups (WRST p<0.05). We did not find significant differences in structure nor diversity of the fungal communities which were dominated by Ascomycota with Alternaria and Fusarium. However, control-treated animals had higher amounts of Aspergillus while Trichoderma were increased in viroimmunotherapy-treated mice.Our data suggests that bacterial communities play an important role in modulating viroimmunotherapy against glioma in immunocompetent animal glioma models. Importantly, increase in Bifidobacterium and Lactobacillus was associated with a better response to the therapy, likely strengthening antitumor immunity and raising efficacy in viroimmunotherapy-treated mice. This reveals the benefits of gut microbiome therapeutics in positively influencing the final clinical outcome of viroimmunotherapy. Sponsored by NCI's 2U54CA096297-16. Citation Format: Candelaria Gomez-Manzano, Natalie M. Melendez-Vazquez, Teresa Nguyen, Ashley Ossimetha, Hong Jiang, Juan Fueyo, Filipa Godoy-Vitorino. Gut microbiome changes are associated with the efficacy of Delta-24-RGDOX viroimmunotherapy against malignant glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 927.
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