ORCID Profile
0000-0002-4290-6674
Current Organisation
Brigham and Women's Hospital
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Publisher: Informa UK Limited
Date: 30-12-2022
Publisher: SAGE Publications
Date: 09-08-2022
DOI: 10.1177/17479541221118423
Abstract: Historically, research that has aimed to understand the determinants of road cycling performance has focused primarily on the physiological characteristics of successful performers. To date, little research has been conducted on the tactical strategies that underpin successful road cycling, especially from a qualitative perspective. This study reports the practices of seven high-performing Australian cyclists and coaches to inform how they prepare for competition, the tactical decisions they make during and reflective practices they use following a road cycling competition. Inductive qualitative one-on-one semi-structured interviews were conducted using open-ended questions via an online meeting platform. A robust thematic analysis of the interviews was undertaken resulting in the establishment of themes aligned with pre-race, in-race and reflection upon tactical decision making. Prior to the race, themes related to the specificity of training, planning of a race strategy and use of training data emerged from the interviews. During the race, themes of the cyclist’s role within a team, in-race communication and race craft were established. Post-race, a theme related to the reflective practice implemented by each participant was evident. These results and discussion provide novel insights into the process of developing, implementing and reflecting upon tactical decision making used in high-level road cycling. This information is valuable for teams and governing bodies to inform and enhance coaching development and practice within the sport of road cycling.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 04-01-2023
DOI: 10.1126/SCITRANSLMED.ABO4778
Abstract: The administration of inactivated tumor cells is known to induce a potent antitumor immune response however, the efficacy of such an approach is limited by its inability to kill tumor cells before inducing the immune responses. Unlike inactivated tumor cells, living tumor cells have the ability to track and target tumors. Here, we developed a bifunctional whole cancer cell–based therapeutic with direct tumor killing and immunostimulatory roles. We repurposed the tumor cells from interferon-β (IFN-β) sensitive to resistant using CRISPR-Cas9 by knocking out the IFN-β–specific receptor and subsequently engineered them to release immunomodulatory agents IFN-β and granulocyte-macrophage colony-stimulating factor. These engineered therapeutic tumor cells (ThTCs) eliminated established glioblastoma tumors in mice by inducing caspase-mediated cancer cell apoptosis, down-regulating cancer-associated fibroblast-expressed platelet-derived growth factor receptor β, and activating antitumor immune cell trafficking and antigen-specific T cell activation signaling. This mechanism-based efficacy of ThTCs translated into a survival benefit and long-term immunity in primary, recurrent, and metastatic cancer models in immunocompetent and humanized mice. The incorporation of a double kill-switch comprising herpes simplex virus–1 thymidine kinase and rapamycin-activated caspase 9 in ThTCs ensured the safety of our approach. Arming naturally neoantigen-rich tumor cells with bifunctional therapeutics represents a promising cell-based immunotherapy for solid tumors and establishes a road map toward clinical translation.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 31-05-2023
DOI: 10.1126/SCITRANSLMED.ADE8732
Abstract: Oncolytic virus therapy has shown activity against primary melanomas however, its efficacy in brain metastases remains challenging, mainly because of the delivery and immunosuppressive nature of tumors in the brain. To address this challenge, we first established PTEN-deficient melanoma brain metastasis mouse models and characterized them to be more immunosuppressive compared with primary melanoma, mimicking the clinical settings. Next, we developed an allogeneic twin stem cell (TSC) system composed of two tumor-targeting stem cell (SC) populations. One SC was loaded with oncolytic herpes simplex virus (oHSV), and the other SC was CRISPR-Cas9 gene-edited to knock out nectin 1 (N1) receptor (N1 KO ) to acquire resistance to oHSV and release immunomodulators, such as granulocyte-macrophage colony-stimulating factor (GM-CSF). Using mouse models of brain metastatic BRAF V600E /PTEN −/− and BRAF V600E/wt /PTEN −/− mutant melanomas, we show that locoregional delivery of TSCs releasing oHSV and GM-CSF (TSC-G) activated dendritic cell– and T cell–mediated immune responses. In addition, our strategy exhibited greater therapeutic efficacy when compared with the existing oncolytic viral therapeutic approaches. Moreover, the TSCs composed of SC-oHSV and SC N1KO –releasing GM-CSF and single-chain variable fragment anti–PD-1 (TSC-G/P) had therapeutic efficacy in both syngeneic and patient-derived humanized mouse models of leptomeningeal metastasis. Our findings provide a promising allogeneic SC-based immunotherapeutic strategy against melanomas in the CNS and a road map toward clinical translation.
No related grants have been discovered for Mathew O'Grady.