Immunotherapy for SMARCB1-Deficient Sarcomas: Current Evidence and Future Developments
Abstract
:1. Introduction
2. SMARCB1
2.1. SMARCB1 Structure and Functions
2.2. SMARCB1 Alteration in Cancers
3. SMARCB1 Deficiency and Anti-Tumor Immunity
3.1. SMARCB1 Deficiency and Tumor Cell Immunogenicity
3.2. SMARCB1-Deficient Tumors’ Immune Microenvironment
3.2.1. Tumor-Infiltrating Lymphocytes (TILs)
3.2.2. Tertiary Lymphoid Structure (TLS)
3.2.3. Myeloid Populations
3.2.4. Immune Checkpoint Inhibitors
4. Clinical Efficacy of Immune Therapies in SMARCB1-Defective Tumors
4.1. Anti-PD(L)-1 Therapy as a Monotherapy
4.2. Anti-PD-(L)1 Therapy in Combination
4.2.1. Dual ICI Combination
4.2.2. Anti-Angiogenic Agents and ICI
4.2.3. Epigenetic Modulators and ICI Combinations
5. Perspectives and Future Directions
5.1. SMARCB1: A Role Which Is still Unclear in Modulating Tumor Immunogenicity
5.2. Improving Patient Selection for Immune Checkpoint Inhibitors
5.3. Other Immunotherapeutic Approaches
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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SMARCB1-Deficient Mesenchymal Malignant Tumors | SMARCB1-Deficient Non-Mesenchymal Malignant Tumors |
---|---|
Extrarenal malignant rhabdoid tumor | Atypical teratoid rhabdoid tumor |
Epithelioid sarcoma | Cribriform neuroepithelial tumor |
Poorly differentiated chordoma | Renal medullary carcinoma |
Epithelioid MPNST 1 | SMARCB1-deficient sinonasal carcinoma |
Myoepithelial carcinoma | SMARCB1-deficient carcinoma of the GI tract |
Myxoid extraskeletal chondrosarcoma |
Reference | NCT Identifier/ Trial Name | Study Design | Study Description | Number of Patients | Specific Histotype | Best Response | Duration of Best Response |
---|---|---|---|---|---|---|---|
Paoluzzi, 2016 | Retrospective series | Nivolumab in relapsed metastatic/unresectable sarcomas | 2 | ES | 1 PR | 3.8 mth | |
1 PD | |||||||
Blay, 2019 | NCT03012620/ AcSé | Phase II | Pembrolizumab for patients with selected rare cancer types | 1 | MRT | PR | NA |
Georger, 2020 | NCT02541604/ iMATRIX | Phase I/II | Atezolizumab in children and young adults with refractory or relapsed solid tumors, with known or expected PD-L1 expression | 3 | MRT | PR | NA |
Georger, 2020 | NCT02332668 | Phase I/II | Pembrolizumab in pediatric patients with PD-L1-positive, advanced, relapsed, or refractory solid tumor | 2 | MRT | 1 PR | 17.8 mth |
1 PD | |||||||
1 | ES | PR | 11.8 mth | ||||
Forrest, 2020 | Case report | Pembrolizumab | 1 | ES | SD | 12 mth | |
Nivolumab Pembrolizumab | 1 | PDC | PR | 9 mth | |||
1 | MRT | SD | 15 wk |
Reference | NCT Identifier/Trial Name | Study Design | Study Description | Number of Patients | Specific Histotype | Best Response | Duration of Best Response |
---|---|---|---|---|---|---|---|
D’Angelo, 2018 | NCT02500797/ Alliance A091401 | Phase II | Nivolumab with or without ipilimumab treatment for metastatic sarcoma | 1 | ES | 0 | |
Wilky, 2019 | NCT02636725 | Phase II | Axitinib + pembrolizumab in advanced sarcoma | 1 | ES | PR | 24 wk |
Martin-Broto, 2020 | NCT03277924 | Phase Ib/II | Nivolumab and sunitinib combination in advanced soft tissue sarcomas | 7 | ES | SD | 17 mth |
D’Angelo, 2017 | NCT01643278 | Phase Ib | Combined KIT and CTLA-4 Blockade in patients with Refractory GIST and other advanced Sarcomas: Ipilimumab + dasatinib | 1 | ES | SD | 16 wk |
Pecora, 2020 | Case report | Nivolumab + ipilumab | 1 | ES | Complete response | NA |
NCT Identifier/ Study Name | Drugs | Clinical Trial Phase | Population | Estimated Enrollment | Primary Completion Date | Location |
---|---|---|---|---|---|---|
NCT04741438/ RAR-Immune | Nivolumab + Ipilimumab | III | Metastatic or unresectable advanced sarcoma of rare subtype including ES and chordoma | 96 | February 2025 | Centre Léon Bérard, Lyon, France |
NCT04416568 | Nivolumab + Ipilimumab | II | Relapsed or refractory INI1-negative cancers in children and young adults from 6 months to 30 years | 45 | October 2023 | Dana-Farber Cancer Institute, United States, Massachusetts |
NCT04705818/ CAIRE | Durvalumab + Tazemetostat | II | Distinct cohorts of solid tumors including soft-tissue sarcoma and metastatic solid tumor with positive interferon gamma signature and/or presence of TLS | 173 | October 2022 | Multiple French Cancer Institute |
NCT04095208/ CONGRATS | Nivolumab + Relatlimab | II | Advanced non-resectable/metastatic soft tissue sarcoma with high-level of tertiary lymphoid structures | 67 | March 2022 | Multiple French Cancer Institute |
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Ngo, C.; Postel-Vinay, S. Immunotherapy for SMARCB1-Deficient Sarcomas: Current Evidence and Future Developments. Biomedicines 2022, 10, 650. https://doi.org/10.3390/biomedicines10030650
Ngo C, Postel-Vinay S. Immunotherapy for SMARCB1-Deficient Sarcomas: Current Evidence and Future Developments. Biomedicines. 2022; 10(3):650. https://doi.org/10.3390/biomedicines10030650
Chicago/Turabian StyleNgo, Carine, and Sophie Postel-Vinay. 2022. "Immunotherapy for SMARCB1-Deficient Sarcomas: Current Evidence and Future Developments" Biomedicines 10, no. 3: 650. https://doi.org/10.3390/biomedicines10030650