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Newly Characterized Murine Undifferentiated Sarcoma Models Sensitive to Virotherapy with Oncolytic HSV-1 M002
Eric K Ring1, Rong Li2, Blake P Moore1
1Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
Abstract:
Despite advances in conventional chemotherapy, surgical techniques, and radiation, outcomes for patients with relapsed, refractory, or metastatic soft tissue sarcomas are dismal. Survivors often suffer from lasting morbidity from current treatments. New targeted therapies with less toxicity, such as those that harness the immune system, and immunocompetent murine sarcoma models to test these therapies are greatly needed. We characterized two new serendipitous murine models of undifferentiated sarcoma (SARC-28 and SARC-45) and tested their sensitivity to virotherapy with oncolytic herpes simplex virus 1 (HSV-1). Both models expressed high levels of the primary HSV entry molecule nectin-1 (CD111) and were susceptible to killing by interleukin-12 (IL-12) producing HSV-1 M002 in vitro and in vivo. M002 resulted in a significant intratumoral increase in effector CD4+ and CD8+ T cells and activated monocytes, and a decrease in myeloid-derived suppressor cells (MDSCs) in immunocompetent mice. Compared to parent virus R3659 (no IL-12 production), M002 resulted in higher CD8:MDSC and CD8:T regulatory cell (Treg) ratios, suggesting that M002 creates a more favorable immune tumor microenvironment. These data provide support for clinical trials targeting sarcomas with oncolytic HSV-1. These models provide an exciting opportunity to explore combination therapies for soft tissue sarcomas that rely on an intact immune system to reach full therapeutic potential.
Insights
New murine sarcoma models show promise for testing oncolytic herpes simplex virus 1 (HSV-1) therapies. Virotherapy with interleukin-12 (IL-12) producing HSV-1 M002 effectively reduced tumors and improved the immune microenvironment in mice.
Area of Science:
- Oncology
- Immunotherapy
- Virology
Background:
- Outcomes for relapsed, refractory, or metastatic soft tissue sarcomas remain poor despite conventional treatments.
- There is a critical need for novel, less toxic targeted therapies, such as immunotherapies, and suitable preclinical models.
- New immunocompetent murine sarcoma models are essential for evaluating novel therapeutic strategies.
Purpose of the Study:
- To characterize two novel murine undifferentiated sarcoma models (SARC-28 and SARC-45).
- To evaluate the efficacy of oncolytic herpes simplex virus 1 (HSV-1) virotherapy in these models.
- To assess the impact of interleukin-12 (IL-12) producing HSV-1 (M002) on the tumor immune microenvironment.
Main Methods:
- Characterization of two new spontaneous murine sarcoma models (SARC-28 and SARC-45).
- In vitro and in vivo testing of oncolytic HSV-1 (M002) sensitivity and efficacy.
- Analysis of intratumoral immune cell populations (CD4+, CD8+ T cells, monocytes, MDSCs, Tregs) following M002 treatment.
Main Results:
- Both SARC-28 and SARC-45 models expressed high levels of the HSV entry receptor nectin-1 and were susceptible to M002 virotherapy.
- M002 treatment led to significant intratumoral increases in effector CD4+ and CD8+ T cells and activated monocytes, with a decrease in myeloid-derived suppressor cells (MDSCs).
- M002 demonstrated superior immune modulation compared to the parent virus, increasing CD8:MDSC and CD8:T regulatory cell (Treg) ratios, indicating a more favorable tumor immune microenvironment.
Conclusions:
- The characterized murine sarcoma models are valuable tools for studying immunotherapies.
- Oncolytic HSV-1 M002 shows significant therapeutic potential for soft tissue sarcomas by modulating the tumor immune microenvironment.
- These findings support the advancement of oncolytic HSV-1 therapies, including combination strategies, into clinical trials for soft tissue sarcomas.