Immunotherapy for Sarcoma: A Work in Progress

Meyer, Christian F.

doi:10.1200/jco.21.01338

Cited by 8 publications

(8 citation statements)

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“…Sarcoma is a type of mesenchymal neoplasm exhibiting distinct prognosis, clinical behavior and treatment options ( 1 , 28 , 29 ). Sarcoma is regarded as a formidable type of malignancy to treat, as conventional chemotherapies have yielded frustratingly slow progress, while immunotherapy remains an investigational approach, making sarcoma one of the most difficult tumors to treat ( 4 ). Due to its rarity and histologic heterogeneity, the understanding of sarcoma biology is also relatively limited, compared with that of common epithelial cancers ( 1 ).…”

Section: Discussionmentioning

confidence: 99%

“…Sarcomas are rare cancers predominantly derived from embryonic mesoderm, accounting for approximately 1% of human malignancies, which primarily affect younger patients and are difficult to treat ( 1 – 3 ). The histologic and molecular diversity, coupled with limited access to specialized sarcoma centers, often leads to erroneous therapeutic plans ( 4 ). Currently, localized sarcomas are typically treated with surgery, and chemotherapy or targeted therapy is employed for metastatic disease ( 2 ), while immunotherapy for sarcoma remains largely investigational ( 2 , 4 , 5 ).…”

Section: Introductionmentioning

confidence: 99%

“…The histologic and molecular diversity, coupled with limited access to specialized sarcoma centers, often leads to erroneous therapeutic plans ( 4 ). Currently, localized sarcomas are typically treated with surgery, and chemotherapy or targeted therapy is employed for metastatic disease ( 2 ), while immunotherapy for sarcoma remains largely investigational ( 2 , 4 , 5 ). Despite numerous clinical trials exploring various chemotherapy regimens, the progression-free survival rates range from 3 to 7 months, with an overall survival (OS) of 12 to 18 months ( 6 , 7 ).…”

Section: Introductionmentioning

confidence: 99%

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miR-939-3p induces sarcoma proliferation and poor prognosis via suppressing BATF2

Xu,

Huang,

Lei

et al. 2024

Front. Oncol.

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BackgroundSarcoma is a rare and aggressive malignancy with poor prognosis, in which oncogene activation and tumor suppressor inactivation are involved. Accumulated studies suggested basic leucine zipper transcription factor ATF-like 2 (BATF2) as a candidate tumor suppressor, but its specific role and mechanism in sarcoma remain unclear.MethodsThe expression levels of BATF2 and miR-939-3p were evaluated by using human sarcoma samples, cell lines and xenograft mouse models. Bioinformatics analysis, qPCR, Western blot, cell proliferation assay, overexpression plasmid construction, point mutation and dual luciferase reporter assay were utilized to investigate the role and mechanism of miR-939-3p in sarcoma.ResultsIn this study, we demonstrated that the expression of BATF2 was downregulated in human sarcoma tissues and cell lines. The downregulation of BATF2 was negatively associated with the prognosis of sarcoma patients. Subsequent bioinformatic prediction and experimental validations showed that BATF2 expression was reduced by microRNA (miR)-939-3p mimic and increased by miR-939-3p inhibitor. Additionally, miR-939-3p was upregulated in sarcoma tissues and cells, correlating with a poor prognosis of sarcoma patients. Moreover, miR-939-3p overexpression suppressed sarcoma cell proliferation, which was significantly attenuated by the restoration of BATF2, while siRNA-mediated knockdown of BATF2 aggravated the miR-939-3p-induced promotion of sarcoma cell proliferation. Further computational algorithms and dual-luciferase reporter assays demonstrated that miR-939-3p repressed BATF2 expression via directly binding to its 3’ untranslated region (3’ UTR).ConclusionCollectively, these findings identified miR-939-3p as a novel regulator of BATF2, as well as a prognostic biomarker in sarcoma, and revealed that suppressing miR-939-3p or inducing BATF2 expression may serve as a promising therapeutic strategy against sarcoma.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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miR-939-3p induces sarcoma proliferation and poor prognosis via suppressing BATF2

Xu,

Huang,

Lei

et al. 2024

Front. Oncol.

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“…Immunotherapy for sarcoma has been studied for many years and achieved good results, which is an important supplement to chemotherapy [ 205 , 206 ]. As mentioned above, ferroptosis can affect can affect tumor-related immune effects in TME.…”

Section: Progress Of Research On Ferroptosis In Sarcoma Treatmentmentioning

confidence: 99%

Harnessing ferroptosis for enhanced sarcoma treatment: mechanisms, progress and prospects

Zeng,

Zhang,

Lin

et al. 2024

Exp Hematol Oncol

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Sarcoma is a malignant tumor that originates from mesenchymal tissue. The common treatment for sarcoma is surgery supplemented with radiotherapy and chemotherapy. However, patients have a 5-year survival rate of only approximately 60%, and sarcoma cells are highly resistant to chemotherapy. Ferroptosis is an iron-dependent nonapoptotic type of regulated programmed cell death that is closely related to the pathophysiological processes underlying tumorigenesis, neurological diseases and other conditions. Moreover, ferroptosis is mediated via multiple regulatory pathways that may be targets for disease therapy. Recent studies have shown that the induction of ferroptosis is an effective way to kill sarcoma cells and reduce their resistance to chemotherapeutic drugs. Moreover, ferroptosis-related genes are related to the immune system, and their expression can be used to predict sarcoma prognosis. In this review, we describe the molecular mechanism underlying ferroptosis in detail, systematically summarize recent research progress with respect to ferroptosis application as a sarcoma treatment in various contexts, and point out gaps in the theoretical research on ferroptosis, challenges to its clinical application, potential resolutions of these challenges to promote ferroptosis as an efficient, reliable and novel method of clinical sarcoma treatment.

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“…The clinical application of programmed cell death protein 1 (PD-1) inhibitors has brought remarkable progress in treating various malignant diseases ( Khan et al, 2021 ). However, the response rate of PD-1 inhibitor monotherapy in STS is approximately 8% ( Roulleaux Dugage et al, 2021 ; Meyer, 2022 ). To improve the efficacy of immunotherapy, PD-1 inhibitors have been used in combination with chemotherapy and other therapies ( Dajsakdipon et al, 2022 ; Kerrison et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of sintilimab plus doxorubicin in advanced soft tissue sarcoma: A single-arm, phase II trial

et al. 2022

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Background: Chemoimmunotherapy is safe and efficacious in treating many types of malignant tumors. However, clinical data demonstrating the effect of this combination treatment in patients with metastatic soft tissue sarcoma (STS) are currently limited. This study evaluated the safety and efficacy of a programmed cell death protein 1 (PD-1) inhibitor plus doxorubicin in patients with advanced STS who failed previous systemic therapy.Methods: This was a single-center, single-arm, open-label phase II trial. Patients with unresectable or metastatic STS who had previously failed systemic therapy were enrolled. Patients received up to six cycles of doxorubicin and sintilimab (a PD-1 inhibitor), while sintilimab treatment continued for up to 2 years. Primary outcomes were objective response rate (ORR) and safety. Univariate Cox proportional hazards model was used to analyze the relationship between clinicopathological parameters and progression-free survival (PFS).Results: A total of 38 patients (20 men and 18 women) were enrolled in this study. The overall ORR was 39.5%, disease control rate was 71.1%, and the median PFS was 4.5 months [95% confidence interval (CI), 3.0–8.5 months]. The adverse events (AEs) associated with the combined treatment were mild, manageable, and well-tolerated. The most common grade 3 or higher AEs were hematologic, including leukopenia (21.1%), anemia (18.4%), and thrombocytopenia (18.4%). Patients with undifferentiated pleomorphic sarcoma (UPS) or dedifferentiated liposarcoma had a significantly longer PFS than those with other pathological subtypes [hazard ratio (HR) = 0.42, 95% CI 0.21–0.83; p = 0.013]. There was no significant difference in the median PFS between patients who had previously received anthracycline-based chemotherapy and those who had not (HR = 0.74, 95% CI 0.34–1.58, p = 0.43).Conclusion: Sintilimab plus doxorubicin is a safe and promising treatment for patients with advanced STS who have failed previous systemic therapy (including anthracycline-based chemotherapy). The efficacy of this combination therapy in UPS and dedifferentiated liposarcoma is superior to that in other sarcomas.Clinical Trial Registration:https://www.chictr.org.cn, registration number: ChiCTR1900027009.

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Immunotherapy for Sarcoma: A Work in Progress

Abstract: Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Cited by 8 publications

References 23 publications

miR-939-3p induces sarcoma proliferation and poor prognosis via suppressing BATF2

miR-939-3p induces sarcoma proliferation and poor prognosis via suppressing BATF2

Harnessing ferroptosis for enhanced sarcoma treatment: mechanisms, progress and prospects

Efficacy and safety of sintilimab plus doxorubicin in advanced soft tissue sarcoma: A single-arm, phase II trial

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