Successful treatment of refractory leiomyosarcoma with the PD-1 inhibitor nivolumab

Heine, Annkristin; Kristiansen, G.; Schild, Hans H.; Brossart, Peter

doi:10.1093/annonc/mdw243

Cited by 17 publications

(12 citation statements)

References 5 publications

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“…In a phase 2 study evaluating the activity of nivolumab alone or in association with pazopanib [91], one response in an epithelioid sarcoma patient was recorded in the group treated with the combination, but no signs of activity in STS for the drug as a single agent were reported. Despite an anecdotal response reported, nivolumab as a single agent failed to demonstrate antitumor activity in a phase 2 study on 12 patients with advanced uterine leiomyosarcoma [92, 93]. Nevertheless, the value of immunotherapy in STS is still largely unexplored.…”

Section: Second and Further Lines In Stsmentioning

confidence: 99%

Systemic treatment in advanced soft tissue sarcoma: what is standard, what is new

Frezza

Stacchiotti

Gronchi

2017

BMC Med

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For metastatic soft tissue sarcoma (STS) patients not eligible for surgery, systemic treatments, including standard chemotherapy and newer biological compounds, still play the most relevant role in the management of the disease. An anthracycline and alkylating agent combination has formed the cornerstone of chemotherapy in STS for more than 30 years, with its value over that of administration of anthracycline as a single agent still being debated. Efforts have been made to improve the activity and minimise the toxicity of the combination, as well as to explore the upfront efficacy of agents known to be active in sarcoma and to develop new biological compounds. Nevertheless, beyond the first line, evidence for medical treatment in STS is less robust and all the more driven by histology. Thus, the introduction of kinases and small molecule inhibitors in the treatment armamentarium for STS is a major achievement in this setting. Preliminary data on immunotherapy are also available and discussed in this review.

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Section: Second and Further Lines In Stsmentioning

confidence: 99%

Systemic treatment in advanced soft tissue sarcoma: what is standard, what is new

Frezza

Stacchiotti

Gronchi

2017

BMC Med

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“… 37 , 38 Furthermore, a successful treatment of refractory and metastatic PD-L1 positive LMS has been recently reported. 39 It highlights the potential efficacy of such agents in selected advanced LMS and the challenge of identifying predictive biomarkers. Among possible biomarkers, the immune profile of the tumor or immunoscore, i.e.…”

Section: Discussionmentioning

confidence: 99%

Increased infiltration of M2-macrophages, T-cells and PD-L1 expression in high grade leiomyosarcomas supports immunotherapeutic strategies

et al. 2017

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Background: Immunotherapy may be a rational strategy in leiomyosarcoma (LMS), a tumor known for its genomic complexity. As a prerequisite for therapeutic applications, we characterized the immune microenvironment in LMS, as well as its prognostic value. Methods: CD163+ macrophages, CD3+ T-cells, PD-L1/PD-L2 and HLA class I expression (HCA2, HC10 and β2m) were evaluated using immunohistochemistry in primary tumors (n = 75), local relapses (n = 6) and metastases (n = 19) of 87 LMS patients, as well as in benign leiomyomas (n = 7). Correlation with clinicopathological parameters and survival analyses were assessed. Effect of LMS cells on macrophage differentiation was investigated using coculture of CD14+ monocytes with LMS cell lines or their conditioned media (CM). Results: 58% and 52% of the tumors were highly infiltrated with CD163+ macrophages and T-cells, respectively, with HLA class I expression observed in almost all tumors and PD-L1 expression in 30%. PD-L2 expression was also detected in some PD-L1+ tumors. All these immune markers correlated with high tumor grade but only CD163 associated with overall survival (p = 0.003) and disease-specific survival (p = 0.041). In vitro, CD163 was upregulated in the presence of LMS cells producing M-CSF, suggesting that this tumor drives macrophages towards the M2 phenotype. Conclusion: The clinical significance of M2 macrophages, possibly induced by LMS cell-secreted factors, suggests that 2/3 of high-grade LMS patients might benefit from macrophage-targeting agents. Furthermore, PD-L1 expression together with high T-cell infiltrate and HLA class I expression in around 30% of high grade LMS reflects an active immune microenvironment potentially responsive to immune checkpoint inhibitors.

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“…A different anti-PDL1 antibody, nivolumab, was shown to be an effective treatment for one patient with refractory LMS, who had already undergone surgery and multiple rounds of radiation and chemotherapy. 115 Furthermore, Paoluzzi et al reported a retrospective study of 24 STS patients treated with nivolumab: seven were diagnosed with LMS, three of whom had stable disease after eight cycles of treatment. 112 However, the response to pembrolizumab was dramatically different in different individual tumors in a single ULMS patient.…”

Section: Leiomyosarcomamentioning

confidence: 99%

A review of soft-tissue sarcomas: translation of biological advances into treatment measures

Hoang¹,

Acevedo²,

Mann³

et al. 2018

CMAR

113

176

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Soft-tissue sarcomas are rare malignant tumors arising from connective tissues and have an overall incidence of about five per 100,000 per year. While this diverse family of malignancies comprises over 100 histological subtypes and many molecular aberrations are prevalent within specific sarcomas, very few are therapeutically targeted. Instead of utilizing molecular signatures, first-line sarcoma treatment options are still limited to traditional surgery and chemotherapy, and many of the latter remain largely ineffective and are plagued by disease resistance. Currently, the mechanism of sarcoma oncogenesis remains largely unknown, thus necessitating a better understanding of pathogenesis. Although substantial progress has not occurred with molecularly targeted therapies over the past 30 years, increased knowledge about sarcoma biology could lead to new and more effective treatment strategies to move the field forward. Here, we discuss biological advances in the core molecular determinants in some of the most common soft-tissue sarcomas – liposarcoma, angiosarcoma, leiomyosarcoma, rhabdomyosarcoma, Ewing’s sarcoma, and synovial sarcoma – with an emphasis on emerging genomic and molecular pathway targets and immunotherapeutic treatment strategies to combat this confounding disease.

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Successful treatment of refractory leiomyosarcoma with the PD-1 inhibitor nivolumab

Cited by 17 publications

References 5 publications

Systemic treatment in advanced soft tissue sarcoma: what is standard, what is new

Systemic treatment in advanced soft tissue sarcoma: what is standard, what is new

Increased infiltration of M2-macrophages, T-cells and PD-L1 expression in high grade leiomyosarcomas supports immunotherapeutic strategies

A review of soft-tissue sarcomas: translation of biological advances into treatment measures

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