BIOMEDICAL SCIENCES GRADUATE PROGRAM SPRING 2018

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1 THE OHIO STATE UNIVERSITY BIOMEDICAL SCIENCES GRADUATE PROGRAM SPRING 2018 Nicholas Denton PhD Candidate Modulation of tumor associated macrophages enhances oncolytic herpes virotherapy in preclinical models of Ewing sarcoma Meiling Hall 2:00 pm

2 VITA BS Biomedical Science, The Ohio State University 2013-present PhD Biomedical Sciences, The Ohio State University COMMITTEE MEMBERS Timothy Cripe, MD/PhD Balveen Kaur, PhD Kevin Cassady, PhD Deborah Parris, PhD

3 ABSTRACT Ewing sarcoma is a highly aggressive bone and soft tissue cancer that is found predominantly in adolescents and young adults. The aggressive progression of Ewing sarcoma is due in part to the infiltration and activation of pro-tumor M2-like macrophages. Within the traditional classifications of inflammatory M1-like macrophages and immune suppressive M2-like macrophages is a broad panel of non-canonical macrophage subtypes whose actions in tumor progression and tumor resistance to immunotherapy are unknown. Oncolytic virotherapy that selectively replicates in and destroys cancer cells is a promising option for treating Ewing sarcoma through both direct infection of the cancer cells and activation of the host antitumor immune response. The effect of M1-like and M2-like tumor macrophages on oncolytic virus therapy, however, is variable among solid tumors and is unknown in Ewing sarcoma. We observed high activity of M2-like macrophage subtypes M(IL4) and M(IL10) in Ewing sarcoma xenograft models that experience a macrophage-dependent restriction of oncolytic virus antitumor efficacy. Macrophage depletion with Clodrosome or trabectedin greatly enhanced oncolytic virus antitumor efficacy of Ewing sarcoma xenografts by increasing tumor stroma inflammatory activity and decreasing angiogenic and immune suppressive signaling molecules. Our data suggest that combination of trabectedin and oncolytic virus therapy warrants testing in the clinical setting of pediatric sarcoma treatment. The presence of M(IL4) and M(IL10) tumor macrophages may be a cellular biomarker for determining antitumor efficacy of trabectedin and oncolytic virus combination therapy in a wider panel of solid tumor types.

4 RECENT ABSTRACTS AND PRESENTATION Tumor Associated Macrophages Mitigate HSV Oncolytic Virus Efficacy presented in 18th Annual Meeting of the Translational Research Cancer Centers Consortium; Seven Springs, PA 2015 (oral presentation) Tumor Associated Macrophages Mitigate ohsv Efficacy in Ewings Sarcoma presented in 9th Annual Oncolytic Therapeutics Consortium; Boston, MA 2015 (poster presentation), 14th Annual Ohio State University Wexner Medical Center Trainee Research Day; Columbus, OH 2015 (poster presentation) Tumor Associated Macrophages Mitigate ohsv Efficacy in Ewings Sarcoma in part through TGFβ presented in 30th Annual Ohio State University Hayes Forum; Columbus, OH 2016 (oral presentation), and 19th Annual Meeting of American Society of Gene and Cell Therapy; Washington D.C., 2016 (oral presentation) Tumor Associated Macrophages in Oncolytic Virotherapy: Friend or Foe? presented in The Ohio State University 2016 Translational Therapeutics Retreat; Columbus, OH 2016 (poster presentation), and OSU Biomedical Sciences Program Annual Retreat, Columbus, OH 2016 (oral presentation) Modulation of Tumor Associated Macrophages Enhances Oncolytic Herpes Virotherapy in Preclinical Models of Ewing Sarcoma presented in International Oncolytic Virus Conference; Oxford, UK 2018 (oral presentation)

5 RECENT PUBLICATIONS Nicholas L. Denton, Chun-Yu Chen, Mark A. Currier, Brian Hutzen, Thomas Scott, Brooke Nartker, Jennifer L. Leddon, Pin-Yi Wang, Rachelle Snrivas, William R. Gions, Timothy P. Cripe. Modulation of Tumor Associated Macrophages Enhances Oncolytic Herpes Virotherapy in Preclinical Models of Ewing Sarcoma. Science Translational Medicine 2018 (submitted) Mary Frances Wedekind, Nicholas L Denton, Chun-Yu Chen, Timothy Cripe. Immunotherapy in Pediatric Cancer: A Review. Pediatric Drugs 2018 (submitted) Denton N.L., Chen C.Y., Scott T.R., and Cripe T.P. Tumor- Associated Macrophages in Oncolytic Vriotherapy: Friend or Foe? Biomedicines 2016, 4(3), 13; doi: /biomedicines Friedman G.K., Beierle E.A., Gillespie G.Y., Markert J.M., Waters A.M., Chen C.Y., Denton N.L., Haworth K.B., Hutzen B., Leddon J.L., Streby K.A., Wang P.Y., Cripe T.P. Pediatric cancer gone viral part II: potential clinical application of oncolytic herpes simplex virus-1 in children. Mol Ther- Oncolytics 2015 (2). Cripe T.P., Chen C.Y., Denton N.L., Haworth K.B., Hutzen B., Leddon J.L., Streby K.A., Wang P.Y., Markert J.M., Waters A.M., Gillespie G.Y., Beierle E.A., Friedman G.K. Pediatric cancer gone viral part I: the potential of oncolytic virotherapy in children. Mol Ther- Oncolytics 2015 (2). Jennifer Leddon, Chun-Yu Chen, Mark Currier, Pin-Yi Wang, Francesza Jung, Nicholas Denton, Kevin Cripe, Kellie Haworth, Michael Arnold, Amy Gross, Timothy Eubank, William Goins, Joseph Glorioso, Justus Cohn, Paola Grandi, David Hildeman, Timothy Cripe. Oncolytic HSV Virotherapy in Murine Sarcomas Differentially Triggers an Antitumor T Cell Response in the Absence of Virus Permissivity. Mol Ther- Oncolytics 2015 (1).

6 AWARDS AND HONORS NIH F31 Predoctoral Fellowship- NIH funded for the remainder of PhD research training ( ) OSU Graduate Student Council Career Development Grant- travel award for career development (2016) OSU Hayes Graduate Research Forum- 2nd place for presentation in Professional Health Sciences (2016) Pelotonia Graduate Fellowship- funded for two full years of cancer research at NCH ( ) OSU Ray Travel Award- travel award for research achievement and service to the community (2015) 14th Annual OSUWMC Trainee Research Day- travel award for outstanding research presentation (2015) Nationwide Children s Hospital Graduate Student Research Award- funded for full year of research at NCH ( ) Alex s Lemonade Stand POST Fellowship- summer research training award (2014)

7 FUTURE PLANS I have upcoming interviews for postdoctoral fellowships investigating cancer immunotherapy in Columbus and the NCI. My long term plans are to become the principle investigator of my own cancer immunotherapy laboratory and support the sciences through the education and training of younger scientists in addition to my own research.

8 [This must be the first line on Page 8] Biomedical Sciences Graduate Program 1170 Graves Hall 333 W. 10 th Avenue Columbus, Ohio 43210