The quest for effective immunotherapies against malignant peripheral nerve sheath tumors: Is there hope?

Paudel, Siddhi N.; Hutzen, Brian; Cripe, Timothy P.

doi:10.1016/j.omto.2023.07.008

Cited by 3 publications

(2 citation statements)

References 82 publications

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“…Immunosuppressive mechanisms within the tumor microenvironment limit the effectiveness of viroimmunotherapy ( 7 ). In MPNST, three primary immunosuppressive mechanisms have been identified: dysregulated cytokine/chemokine expression, infiltration of regulatory immune cells, and the presence of immune checkpoint molecules ( 12 ). To identify the most effective approach for leveraging viroimmunotherapy in MPNST, we screened three combination viroimmunotherapy regimens targeting these mechanisms in murine tumors.…”

Section: Resultsmentioning

confidence: 99%

“…Emerging evidence suggests that the tumor microenvironment plays a pivotal role in modulating the response to immunotherapies ( 10 , 11 ). MPNST are characterized by an abundance of immunosuppressive myeloid cells as well as tumor-promoting cytokines/chemokines, and dysregulated expression of programmed death-ligand 1 (PD-L1) checkpoint ligands ( 12 ). These factors can impede the effectiveness of immune-based strategies ( 13 – 15 ).…”

Section: Introductionmentioning

confidence: 99%

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Myelomodulatory treatments augment the therapeutic benefit of oncolytic viroimmunotherapy in murine models of malignant peripheral nerve sheath tumors

Paudel,

Hutzen,

Miller

et al. 2024

Front. Immunol.

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IntroductionMalignant peripheral nerve sheath tumors (MPNST) pose a significant therapeutic challenge due to high recurrence rates after surgical resection and a largely ineffective response to traditional chemotherapy. An alternative treatment strategy is oncolytic viroimmunotherapy, which can elicit a durable and systemic antitumor immune response and is Food and Drug Administration (FDA)-approved for the treatment of melanoma. Unfortunately, only a subset of patients responds completely, underscoring the need to address barriers hindering viroimmunotherapy effectiveness. MethodsHere we investigated the therapeutic utility of targeting key components of the MPNST immunosuppressive microenvironment to enhance viroimmunotherapy’s antitumor efficacy in three murine models, one of which showed more immunogenic characteristics than the others. ResultsMyelomodulatory therapy with pexidartinib, a small molecule inhibitor of CSF1R tyrosine kinase, and the oncolytic herpes simplex virus T-VEC exhibited the most significant increase in median survival time in the highly immunogenic model. Additionally, targeting myeloid cells with the myelomodulatory therapy trabectedin, a small molecule activator of caspase-8 dependent apoptosis, augmented the survival benefit of T-VEC in a less immunogenic MPNST model. However, tumor regressions or shrinkages were not observed. Depletion experiments confirmed that the enhanced survival benefit relied on a T cell response. Furthermore, flow cytometry analysis following combination viroimmunotherapy revealed decreased M2 macrophages and myeloid-derived suppressor cells and increased tumor-specific gp70+ CD8 T cells within the tumor microenvironment. DiscussionIn summary, our findings provide compelling evidence for the potential to leverage viroimmunotherapy with myeloid cell targeting against MPNST and warrant further investigation.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Myelomodulatory treatments augment the therapeutic benefit of oncolytic viroimmunotherapy in murine models of malignant peripheral nerve sheath tumors

Paudel,

Hutzen,

Miller

et al. 2024

Front. Immunol.

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The Multimodality Management of Malignant Peripheral Nerve Sheath Tumours

Seres,

Hameed,

McCabe

et al. 2024

Cancers

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Malignant peripheral nerve sheath tumours (MPNST) are aggressive sarcomas that have nerve sheath differentiation and can present at any anatomical site. They can arise from precursor neurofibroma in the context of neurofibromatosis type 1 (NF1) or as de novo and sporadic tumours in the absence of an underlying genetic predisposition. The primary therapeutic approach is most often radical surgery, with non-surgical modalities playing an important role, especially in locally advanced or metastatic cases. The aim of multimodality approaches is to optimize both local and systemic control while keeping to a minimum acute and late treatment morbidity. Advances in the understanding of the underlying biology of MPNSTs in both sporadic and NF-1-related contexts are essential for the management and implementation of novel therapeutic approaches.

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Rare primary intrapulmonary malignant peripheral nerve sheath tumor showing significant response to sintilimab: A case report and literature review

Chen,

Zhu

et al. 2024

Oncol Lett

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The quest for effective immunotherapies against malignant peripheral nerve sheath tumors: Is there hope?

Cited by 3 publications

References 82 publications

Myelomodulatory treatments augment the therapeutic benefit of oncolytic viroimmunotherapy in murine models of malignant peripheral nerve sheath tumors

Myelomodulatory treatments augment the therapeutic benefit of oncolytic viroimmunotherapy in murine models of malignant peripheral nerve sheath tumors

The Multimodality Management of Malignant Peripheral Nerve Sheath Tumours

Rare primary intrapulmonary malignant peripheral nerve sheath tumor showing significant response to sintilimab: A case report and literature review

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