IMMUNOSARC: A collaborative Spanish (GEIS) and Italian (ISG) sarcoma groups phase I/II trial of sunitinib plus nivolumab in advanced soft tissue and bone sarcomas: Results of the phase II- soft-tissue sarcoma cohort

Broto, Javier Martín; Hindi, Nadia; Grignani, Giovanni; Trufero, Javier Martínez; Redondo, Andrés; Valverde, Claudia; Pousa, Antonio López; Stacchiotti, Silvia; Palmerini, Emanuela; Álava, Enrique de; Moura, David Silva; Vega, Herminia Pérez; Collini, Paola; Otero, Irene; Ledesma, Patrico; Marchesi, Emanuela; D’Ambrosio, Lorenzo; Lopez-Martin, Jose A.

doi:10.1093/annonc/mdz283.002

Cited by 13 publications

(10 citation statements)

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“…The clinical efficacy and tolerability of TKIs and checkpoint inhibitors in softtissue sarcomas was demonstrated (8,27), with a better overall response rate and progression-free survival in alveolar sarcomas. Only recently, have the results of a nivolumab and sunitinib combination in patients with bone sarcoma been presented, with an objective response in dedifferentiated chondrosarcomas and bone sarcomas (12). These findings are in line with recently published results of clinical trials in kidney cancer, demonstrating superior progression-free survival and overall survival for an anti-VEGFR and anti-PD-L1 combinatorial approach both over sunitinib (28)(29)(30) and checkpoint inhibitor monotherapy (31).…”

Section: Discussionsupporting

confidence: 67%

“…Sunitinib is a small molecule receptor tyrosine kinase (RTK) inhibitor that blocks signaling of multiple RTKs, including vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors (9), with pre-clinical evidence of activity in metastasizing osteosarcomas (10). Sunitinib is approved by the Food and Drug Administration for the treatment of patients with gastrointestinal stromal tumors (11) and has been examined in combination with nivolumab in selected soft tissue sarcomas such as alveolar sarcomas or dedifferentiated bone chondrosarcomas (8,12). Sunitinib may exert immunostimulatory activity through the modulation of a ratio of immunostimulatory versus immunoregulatory cells.…”

Section: Introductionmentioning

confidence: 99%

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Sunitinib Exerts In Vitro Immunomodulatory Activity on Sarcomas via Dendritic Cells and Synergizes With PD-1 Blockade

et al. 2021

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BackgroundHigh-grade sarcomas are a heterogeneous group of aggressive tumors arising in bone and soft tissues. After relapse, treatment options are limited. The multi-targeted receptor tyrosine kinase inhibitors (TKIs) sunitinib and inhibitor of PD-1 (anti-PD-1) nivolumab have shown antitumor activity in selected subtypes. In this study, we examine the role of TKIs and PD-1 based therapy in in vitro cocultures of sarcoma.MethodsThe human osteosarcoma (SaOS-2) and synovial sarcoma (SYO-1) cell lines were treated with sunitinib. After cell death and proliferation assessment, expression of PD-L1 was analyzed by flow cytometry. Sunitinib-treated sarcoma cells were cocultured with dendritic cells (DCs), and the phenotype of mature DCs was determined by flow cytometry. Mature DCs were cultured with autologous T cells. PD-1 expression on T cells, their proliferation, T regulatory cell (Tregs) induction and IFN-γ production, before and after nivolumab exposure, were analyzed.ResultsAlong with its anti-proliferative and direct pro-apoptotic effect on sarcoma cell lines, sunitinib prompted PD-L1 upregulation on sarcoma cells. Interestingly, sunitinib-treated sarcoma cells drive DCs to full maturation and increase their capacity to induce sarcoma-reactive T cells to produce IFN-γ. Conversely, no effect on T cell proliferation and T cell subpopulation composition was observed. Moreover, both bone and synovial sarcoma cell lines induced Tregs through DCs but sunitinib treatment completely abrogated Treg induction. Finally, sarcoma cell lines induced PD-1 upregulation on both effector T cells and Tregs when loaded into DCs, providing a rationale for using PD-1 blockade. Indeed, PD-1 blockade by nivolumab synergized with sunitinib in inducing IFN-γ-producing effector T cells.ConclusionsTaken together, our in vitro data indicate that the treatment of sarcoma cells with sunitinib can exert significant changes on immune cell subsets toward immune activation, leading to DC-based cross-priming of IFN-γ-producing effector T cells and reduced Treg induction. PD-1 blockade with nivolumab has a synergistic effect with sunitinib, supporting the use of TKI and anti-PD-1 approach in sarcomas, and perhaps in other cancers. DC-targeted drugs, including toll-like receptor 3 inhibitors and CD47 inhibitors, are under development and our preclinical model might help to better design their clinical application.

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Section: Discussionsupporting

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Sunitinib Exerts In Vitro Immunomodulatory Activity on Sarcomas via Dendritic Cells and Synergizes With PD-1 Blockade

et al. 2021

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“…Promising results were observed with an overall and progression free survival of 77% and 50%, respectively, at 6 months (NCT03277924). 208 Chimeric antigen receptor T (CAR-T) adaptive cell therapy involves the isolation of a patient's own T-cells and modifying them to express a CAR that recognizes a specific tumor antigen and then reinjecting them into the patient. 209 Recognition of the tumor cells by the CAR activates T-cell proliferation and elimination of the tumor cells.…”

Section: Immunotherapymentioning

confidence: 99%

Molecular mechanisms underpinning sarcomas and implications for current and future therapy

Damerell

Pepper

Prince

2021

Sig Transduct Target Ther

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Sarcomas are complex mesenchymal neoplasms with a poor prognosis. Their clinical management is highly challenging due to their heterogeneity and insensitivity to current treatments. Although there have been advances in understanding specific genomic alterations and genetic mutations driving sarcomagenesis, the underlying molecular mechanisms, which are likely to be unique for each sarcoma subtype, are not fully understood. This is in part due to a lack of consensus on the cells of origin, but there is now mounting evidence that they originate from mesenchymal stromal/stem cells (MSCs). To identify novel treatment strategies for sarcomas, research in recent years has adopted a mechanism-based search for molecular markers for targeted therapy which has included recapitulating sarcomagenesis using in vitro and in vivo MSC models. This review provides a comprehensive up to date overview of the molecular mechanisms that underpin sarcomagenesis, the contribution of MSCs to modelling sarcomagenesis in vivo, as well as novel topics such as the role of epithelial-to-mesenchymal-transition (EMT)/mesenchymal-to-epithelial-transition (MET) plasticity, exosomes, and microRNAs in sarcomagenesis. It also reviews current therapeutic options including ongoing pre-clinical and clinical studies for targeted sarcoma therapy and discusses new therapeutic avenues such as targeting recently identified molecular pathways and key transcription factors.

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“…A comprehensive clinico-genomic evaluation of this tumor type is currently being evaluated in the Angiosarcoma Project, a patient-partnered research with 338 angiosarcoma patients registered over 18 months. [54] Whole exome sequencing of 47 samples revealed a higher than expected rate of mutually exclusive mutations in Wilky et al [71] ( Broto et al [70] (2019) AS, angiosarcoma; ASPS, alveolar soft part sarcoma; CR, complete response; CCS, clear cell sarcoma; CSF1R, colony-stimulating factor-1 receptor; ES, epithelioid sarcoma; mOS, median overall survival; mPFS, median progression-free survival; NR, not reached; ORR, objective response rate; PD-1, programmed cell death-1; PDGFR, platelet-derived growth factor receptors; Ph, phase; PR, partial response; SFT, solitary fibrous tumor; SS, synovial sarcoma; UPS, undifferentiated pleomorphic sarcoma; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor TP53 (25%; 9/36) and KDR (22%; 8/36), with 82% of TP53 mutations detected in nonbreast angiosarcomas and 89% of KDR mutations found in breast angiosarcomas. PIK3CA was also one of the most frequently mutated genes (21%; 10/47) with nine of 10 found in primary breast samples and were previously described as hotspot mutations in other cancers but not previously related to angiosarcoma.…”

Section: Then Combination Of Antiangiogenic Agents and Icimentioning

confidence: 98%

“…[69] Results from the phase II trial in the advanced STS patients cohort were presented at ESMO 2019 confirming benefit derived from this active combination with 50% of patients free of disease progression at 6 months and mOS not reached at data cutoff. [70] Expansion study in six selected histologies are ongoing for further exploration of this combined immunomodulatory strategy (NCT03277924).…”

Section: Then Combination Of Antiangiogenic Agents and Icimentioning

confidence: 99%

When Molecular-Targeted Agents Meet Immunotherapy: The Opportunities for Soft Tissue Sarcoma

Wainsztein

Chen

2020

Journal of Immunotherapy and Precision Oncology

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Soft tissue sarcomas (STS) account for less than 1% of adult cancers with a median overall survival of 12 months in the metastatic setting. Although chemotherapy remains the standard of treatment for advanced disease, molecular targeted agents (MTAs) and immunotherapies are under intensive investigation in STS. The success of MTAs comes mainly from antiangiogenic agents in various STS subtypes, from colony-stimulating factor-1 receptor inhibitor in tenosynovial giant cell tumor and neurotrophic tropomyocin receptor kinase (NTRK) inhibitors while others, such as cyclin-dependent kinase (CDK)-4 inhibitors, remain under evaluation. In advanced STS the activity of single-agent immunotherapy was not paradigm-changing as in other tumor types. A better understanding of tumor microenvironment, the immunogenic properties of MTAs, and finding an optimal treatment combination to improve patients outcomes became a central topic of research and discussion. Furthermore, the development and incorporation of transcriptomic profiling-based classification will allow identification, refined patient selection, and guided-treatment assignment. This article reviewed recent advances in STS treatment in MTAs and immunotherapy, strategies to overcome resistance, and outcomes of combination treatments in different STS subtypes. Promising preliminary results from combination strategies have shed light on STS treatment. The increasing understanding of this heterogeneous group of tumors and its microenvironment biology may help develop and guide treatment strategies with MTA and immunotherapies, alone or in combination, in a tailored way based on predictive and validated biomarkers and tumor molecular profiling in this new coming era.

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IMMUNOSARC: A collaborative Spanish (GEIS) and Italian (ISG) sarcoma groups phase I/II trial of sunitinib plus nivolumab in advanced soft tissue and bone sarcomas: Results of the phase II- soft-tissue sarcoma cohort

Cited by 13 publications

References 0 publications

Sunitinib Exerts In Vitro Immunomodulatory Activity on Sarcomas via Dendritic Cells and Synergizes With PD-1 Blockade

Sunitinib Exerts In Vitro Immunomodulatory Activity on Sarcomas via Dendritic Cells and Synergizes With PD-1 Blockade

Molecular mechanisms underpinning sarcomas and implications for current and future therapy

When Molecular-Targeted Agents Meet Immunotherapy: The Opportunities for Soft Tissue Sarcoma

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