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Advancing Immunotherapy against Malignant Peripheral Nerve Sheath Tumors: Development of Myelolytic Viroimmunotherapy and Chlorotoxin Bispecific Engagers as a Therapeutic Strategy to Leverage the Antitumor T Cell Response

Paudel, Siddhi Nath
http://orcid.org/0000-0001-7339-0888
http://rave.ohiolink.edu/etdc/view?acc_num=osu168960951098127

Abstract Details

2023, Doctor of Philosophy, Ohio State University, Molecular, Cellular and Developmental Biology.
Malignant Peripheral Nerve Sheath Tumor (MPNST) is an aggressive subtype of soft tissue sarcoma characterized by poor prognosis, limited response to traditional chemotherapy, and high rates of post-surgical recurrence. Immune-based therapies have emerged as a promising avenue for tumor treatment due to their ability to induce durable and safe clinical responses. Unleashing T cell responses is crucial for engaging the immune system and generating targeted long-lasting therapeutic effect. To address the pressing need for novel therapeutic strategies, we have developed two immune-based approaches aimed at harnessing the antitumor potential of T cells and enhancing their efficacy against MPNST. Firstly, we engineered a chlorotoxin bispecific T cell engager, designed to target MPNST cells through chlorotoxin and redirect T cells via CD3 (Chapter 2). Co-culturing the chlorotoxin bispecific T cell engager with the human MPNST-derived cell line S426TY and peripheral blood mononuclear cells led to a substantial reduction in tumor cell viability and activation of T cells. These results indicate that the chlorotoxin bispecific T cell engager effectively directed the cytotoxic activity of T cells towards MPNST cells. Secondly, we investigated the therapeutic utility of combining T-VEC oncolytic viroimmunotherapy with myelolytic treatments (Trabectedin or Pexidartinib) in murine models (Chapter 3). Our study demonstrated that this rational combination significantly improved survival in weakly-immunogenic mouse models with varying levels of immunogenicity. Notably, the enhanced efficacy of the combination of T-VEC and Trabectedin was attributed to enhanced antitumor T cell response. In summary, our findings provide compelling evidence for the potential of myelolytic viroimmunotherapy and chlorotoxin bispecific T cell engagers as effective therapeutic approaches against MPNST. These results underscore the significance of investigating T cell-based strategies for the treatment of MPNST and warrant further exploration.
Timothy Cripe (Advisor)
132 p.
Oncology; Therapy
Malignant Peripheral Nerve Sheath Tumor; Immunotherapy; Oncolytic Virus; Myeloid Cell Targeting; Trabectedin; T-VEC; MPNST Immunotherapy; Chlorotoxin; Bispecific Engagers; Myelolytic Treatments; T cells; Pexidartinib; Macrophage Targeting; Myeloid-derived Suppressor Cells; MDSC; gp70; MPNST therapy; Nerve Sheath Tumor

Recommended Citations

Citations

  • Paudel, S. N. (2023). Advancing Immunotherapy against Malignant Peripheral Nerve Sheath Tumors: Development of Myelolytic Viroimmunotherapy and Chlorotoxin Bispecific Engagers as a Therapeutic Strategy to Leverage the Antitumor T Cell Response [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu168960951098127

    APA Style (7th edition)

  • Paudel, Siddhi Nath. Advancing Immunotherapy against Malignant Peripheral Nerve Sheath Tumors: Development of Myelolytic Viroimmunotherapy and Chlorotoxin Bispecific Engagers as a Therapeutic Strategy to Leverage the Antitumor T Cell Response . 2023. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu168960951098127.

    MLA Style (8th edition)

  • Paudel, Siddhi Nath. "Advancing Immunotherapy against Malignant Peripheral Nerve Sheath Tumors: Development of Myelolytic Viroimmunotherapy and Chlorotoxin Bispecific Engagers as a Therapeutic Strategy to Leverage the Antitumor T Cell Response ." Doctoral dissertation, Ohio State University, 2023. http://rave.ohiolink.edu/etdc/view?acc_num=osu168960951098127

    Chicago Manual of Style (17th edition)

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This open access ETD is published by The Ohio State University and OhioLINK.