Poster abstracts

Poster number 67 submitted by Siddhi Nath Paudel

Oncolytic Virotherapy in Murine MPNSTs: Making Cold Tumors Hot

Siddhi N. Paudel (Graduate Program in Molecular, Cellular and Developmental Biology, The Ohio State University, Columbus, OH, USA), Brian Hutzen (Center for Childhood Cancer and Blood Disorders, The Abigail Wexner Research Institute at Nationwide Childrens Hospital, 575 Childrens Crossroad, Columbus, OH, 43215, USA), Chun-Yu Chen (Center for Childhood Cancer and Blood Disorders, The Abigail Wexner Research Institute at Nationwide Childrens Hospital, 575 Childrens Crossroad, Columbus, OH, 43215, USA), Timothy P. Cripe (Center for Childhood Cancer and Blood Disorders, The Abigail Wexner Research Institute at Nationwide Childrens Hospital, 575 Childrens Crossroad, Columbus, OH, 43215, USA)

Abstract:
Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are an aggressive form of soft tissue sarcoma[1]. Surgical resection is the mainstay of therapy for MPNST, but the recurrence rate after the resection is as high as 65% and chemotherapy is generally ineffective[2]. A promising alternative is rationally targeted immunotherapy to augment natural antitumor immune responses in MPNST. We previously demonstrated that human MPNSTs have T cell infiltration in almost half of the patient samples tested, but the degree of infiltration was low and varied widely across individual tumors[3]. Herein we show that intratumoral injection of safely attenuated herpes simplex viruses enhances T cell infiltration in a syngeneic mouse model of MPNST. We treated the mouse model of MPNST with a three intratumoral doses of one of three oncolytic herpes simplex virus constructs (HSV1716, T-VEC and C134) and compared the relative frequency of immune cells present in the tumor microenvironment using flow cytometry. The frequency of T cells (both CD4 and CD8) increased significantly after treatment with each of the three viruses by day 11 after virus injection. We also observed a small but significant T cell response against a known tumor-associated endogenous retrovirus antigen, envelope glycoprotein 70 (gp70), expressed nearly universally in murine cancer cell lines but transcriptionally silent in normal tissues. Following these promising results, we examined the relative therapeutic efficacy of HSV1716, T-VEC and C134 against MPNST tumors established in immunocompetent mice. HSV1716 and C134 had a marginal, but statistically significant increase in overall survival relative to the vehicle control group (p=0.009 and p=0.01 respectively). T-VEC failed to show any survival advantage. Our results suggest that oncolytic herpes virotherapy may be an effective treatment strategy to enhance T cell infiltration in MPNST and warrants further study in combination with other immunotherapeutic platforms.

References:
1. Ducatman, B.S., et al., Malignant peripheral nerve sheath tumors. A clinicopathologic study of 120 cases. Cancer, 1986. 57(10): p. 2006-21.
2. Watson, K.L., et al., Patterns of recurrence and survival in sporadic, neurofibromatosis Type 1-associated, and radiation-associated malignant peripheral nerve sheath tumors. Journal of neurosurgery, 2017. 126(1): p. 319-329.
3. Haworth, K.B., et al., Immune profiling of NF1-associated tumors reveals histologic subtype distinctions and heterogeneity: implications for immunotherapy. Oncotarget, 2017. 8(47): p. 82037-82048.

Keywords: Malignant Peripheral Nerve Sheath Tumors, Oncolytic Virus, Immunotherapy