Highlights
- •Karyotypically complex pleomorphic sarcomas are the most likely to be immune hot.
- •Alveolar soft part sarcoma show response to immune checkpoint inhibitors.
- •Multiplexed and spatially resolved technologies can aid immune biomarker discovery.
- •Sarcoma subtype and/or biomarker specific Phase 3 trials are required.
Abstract
Keywords
Introduction
- Young R.J.
- Natukunda A.
- Litière S.
- Woll P.J.
- Wardelmann E.
- van der Graaf W.T.A.
- Mok T.S.K.
- Wu Y.
- Kudaba I.
- Kowalski D.M.
- Cho B.C.
- Turna H.Z.
- et al.
Markers of infiltration
T cell infiltration: CD3, CD4, CD8, FOXP3

- van Erp A.E.M.
- Versleijen-Jonkers Y.M.H.
- Hillebrandt-Roeffen M.H.S.
- van Houdt L.
- Gorris M.A.J.
- van Dam L.S.
- et al.
- van Erp A.E.M.
- Versleijen-Jonkers Y.M.H.
- Hillebrandt-Roeffen M.H.S.
- van Houdt L.
- Gorris M.A.J.
- van Dam L.S.
- et al.
- van Erp A.E.M.
- Versleijen-Jonkers Y.M.H.
- Hillebrandt-Roeffen M.H.S.
- van Houdt L.
- Gorris M.A.J.
- van Dam L.S.
- et al.
- van Erp A.E.M.
- Versleijen-Jonkers Y.M.H.
- Hillebrandt-Roeffen M.H.S.
- van Houdt L.
- Gorris M.A.J.
- van Dam L.S.
- et al.
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- van Erp A.E.M.
- Versleijen-Jonkers Y.M.H.
- Hillebrandt-Roeffen M.H.S.
- van Houdt L.
- Gorris M.A.J.
- van Dam L.S.
- et al.
B cell infiltration: CD20
Macrophage infiltration: CD163, CD68, CD204
Immune checkpoints
PD-1
- van Erp A.E.M.
- Versleijen-Jonkers Y.M.H.
- Hillebrandt-Roeffen M.H.S.
- van Houdt L.
- Gorris M.A.J.
- van Dam L.S.
- et al.
- van Erp A.E.M.
- Versleijen-Jonkers Y.M.H.
- Hillebrandt-Roeffen M.H.S.
- van Houdt L.
- Gorris M.A.J.
- van Dam L.S.
- et al.
- van Erp A.E.M.
- Versleijen-Jonkers Y.M.H.
- Hillebrandt-Roeffen M.H.S.
- van Houdt L.
- Gorris M.A.J.
- van Dam L.S.
- et al.
- van Erp A.E.M.
- Versleijen-Jonkers Y.M.H.
- Hillebrandt-Roeffen M.H.S.
- van Houdt L.
- Gorris M.A.J.
- van Dam L.S.
- et al.
PD-L1
- van Erp A.E.M.
- Versleijen-Jonkers Y.M.H.
- Hillebrandt-Roeffen M.H.S.
- van Houdt L.
- Gorris M.A.J.
- van Dam L.S.
- et al.
- van Erp A.E.M.
- Versleijen-Jonkers Y.M.H.
- Hillebrandt-Roeffen M.H.S.
- van Houdt L.
- Gorris M.A.J.
- van Dam L.S.
- et al.
- van Erp A.E.M.
- Versleijen-Jonkers Y.M.H.
- Hillebrandt-Roeffen M.H.S.
- van Houdt L.
- Gorris M.A.J.
- van Dam L.S.
- et al.
- van Erp A.E.M.
- Versleijen-Jonkers Y.M.H.
- Hillebrandt-Roeffen M.H.S.
- van Houdt L.
- Gorris M.A.J.
- van Dam L.S.
- et al.
Others: IDO, LAG3, TIM3
Tumor mutation burden and microsatellite instability
New technologies
Immune checkpoint inhibitor clinical trials
Mono and dual immune checkpoint inhibitor therapy
Immune checkpoint inhibitor | NCT trial number | Phase | Status | Participants | Sarcoma subtype(s) | Includes pediatric patients |
---|---|---|---|---|---|---|
Ipilimumab (anti-CTLA4) | NCT01445379 | I | Completed | 33 | Sarcoma, Wilm's tumor, lymphoma, neuroblastoma | Yes: 3–21 years |
ZKAB001 (anti-PD-L1) | NCT03676985 | I/II | Recruiting | 15 | High-grade osteosarcoma | No |
Atezolizumab (anti-PD-L1) | NCT03141684 | II | Recruiting | 46 | Metastatic alveolar soft part sarcoma | Yes: 2 years and older |
NCT03474094 | II | Active, not recruiting | 22 | Liposarcoma, undifferentiated pleomorphic sarcoma, leiomyosarcoma, myxofibrosarcoma, angiosarcoma, all translocation sarcoma except Ewing, rhabdomyosarcoma and myxoid liposarcoma | No | |
Avelumab (anti-PD-L1) | NCT03006848 | II | Active, not recruiting | 15 | Recurrent or refractory osteosarcoma | Yes: 12–49 years |
MDX-010 (anti-CTLA4) | NCT00140855 | II | Terminated (study discontinued due to poor accrual) | 17 | Synovial sarcoma | Yes: 13 years and older |
Nivolumab | NCT02428192 | II | Completed | 12 | Advanced uterine leiomyosarcoma | No |
Pembrolizumab(anti-PD-1) | NCT02301039 (SARC028) | II | Active, not recruiting | 146 | Bone and soft-tissue sarcoma | Yes: 12 years and older |
NCT03013127 | II | Active, not recruiting | 12 | Osteosarcoma | No | |
NCT03316573 | II | Recruiting | 30 | Histiocytic Sarcoma, follicular dendritic cell sarcoma, interdigitating dendritic cell sarcoma, lymphoma | No | |
TSR-042 (anti-PD-1) | NCT04274023 | II | Not yet recruiting | 16 | Clear cell sarcoma | No |
Immune checkpoint inhibitor | Other agents | NCT trial number | Phase | Status | Participants | Sarcoma subtype(s) | Includes pediatric patients |
---|---|---|---|---|---|---|---|
Immune checkpoint inhibitor in combination with another immunotherapy agent | |||||||
Atezolizumab (anti-PD-L1) | CMB305 (dendritic cell-targeting viral vector expressing the NY-ESO-1 gene and G305 [NY-ESO-1 recombinant protein plus GLA-SE]) | NCT02609984 | II | Completed | 88 | Metastatic/ recurrent/ locally advanced soft tissue sarcoma | No |
Avelumab (anti-PD-L-1) | DCC-3014 (CSF1R inhibitor) | NCT04242238 | I | Recruiting | 48 | Advanced or metastatic sarcoma | No |
Nivolumab (anti-CTLA-4) | NKTR-214 (CD122 agonist) | NCT03282344 | II | Active, not recruiting | 85 | Metastatic and/or locally advanced sarcoma | Yes: 12 years and older |
Pembrolizumab(anti-PD-1) | GSK3377794 (genetically engineered NY-ESO-1 Specific [c259] T Cells) | NCT03697824 | II | Withdrawn | 0 | Synovial sarcoma | Yes: 10 years and older |
INFγ-1b | NCT03063632 | II | Active, not recruiting | 46 | Advanced synovial sarcoma, previously treated mycosis fungoides and Sezary syndrome | Yes: 12 years and older | |
Metronomic chemotherapy +/− intratumoral G100 (toll-like receptor 4 agonist) | NCT02406781 | II | Recruiting | 227 | Leiomyosarcoma, undifferentiated pleomorphic sarcoma, other sarcoma, gastrointestinal stromal tumor, osteosarcoma, advanced or metastatic soft-tissue sarcoma with presence of tertiary lymphoid structures | No | |
Talimogene Laherparepvec (T-VEC) | NCT03069378 | II | Recruiting | 60 | Metastatic and/or locally advanced sarcoma | No | |
PD-1 antibody | MASCT-I (multi-antigen autoimmune cell injection) and Apatinib (tyrosine kinase inhibitor) | NCT04074564 | I | Not yet recruiting | 20 | Sarcoma, excluding bone or brain metastases | Yes: 14–70 years |
Immune checkpoint inhibitor in combination with chemotherapy or radiation therapy | |||||||
Atezolizumab | Stereotactic body radiation therapy | NCT03548428 | II | Not yet recruiting | 103 | Soft tissue sarcoma | No |
Avelumab | Trabectedin | NCT03074318 | I/II | Active, not recruiting | 35 | Metastatic or unresectable leiomyosarcoma and liposarcoma | No |
Durvalumab (anti-PD-L1) | Trabectedin | NCT03085225 | I | Active, not recruiting | 50 | Soft tissue sarcomas and ovarian carcinomas | No |
Nivolumab | Trabectedin | NCT03590210 | II | Recruiting | 92 | Advanced or metastatic soft tissue sarcoma | No |
Pembrolizumab | Doxorubicin | NCT02888665 | I/II | Active, not recruiting | 37 | Advanced soft tissue sarcoma | No |
Gemcitabine | NCT03123276 | I/II | Recruiting | 24 | Undifferentiated pleomorphic sarcoma or leiomyosarcoma | No | |
Radiation therapy | NCT03338959 | I/II | Suspended (Administrative) | 26 | Intermediate or high-grade soft tissue sarcoma | No | |
Radiation therapy | NCT03092323 | II | Recruiting | 102 | High-risk soft-tissue sarcoma | Yes: 12 years and older | |
Immune checkpoint inhibitor in combination with other agents | |||||||
Camrelizumab (anti-PD-1) | Famitinib (tyrosine kinase inhibitor) | NCT04044378 | I/II | Recruiting | 80 | Advanced osteosarcoma | Yes: 12 years and older |
Ipilimumab (anti-CTLA-4) | Dasatinib (tyosine kinase inhibitor) | NCT01643278 | I | Completed | 29 | Gastrointestinal stromal tumor, stage III and IV soft tissue sarcoma | No |
Nivolumab or ipilimumab | Cryoablation | NCT04118166 | II | Recruiting | 30 | Soft tissue sarcoma | N |
Pembrolizumab | Axitinib (tyrosine kinase inhibitor) | NCT02636725 | II | Active, not recruiting | 33 | Advanced alveolar soft part sarcoma and other soft tissue sarcomas | Yes: 16 years and older |
Eribulin (tyrosine kinase inhibitor) | NCT03899805 | II | Recruiting | 57 | Sarcoma, liposarcoma, leiomyosarcoma, undifferentiated pleomorphic sarcoma | No | |
Ziv-aflibercept (VEGF inhibitor) | NCT02298959 | I | Recruiting | 78 | Unresectable stage III or stage IV melanoma, renal cell cancer, ovarian cancer, colorectal cancer, or sarcoma | No | |
Toripalimab (anti-PD-1) | Anlotinib (tyrosine kinase inhibitor) | NCT03946943 | II | Not yet recruiting | 25 | Undifferentiated pleomorphic sarcoma | Yes: 16 years and older |
Dual immune checkpoint inhibitor therapy | |||||||
Durvalumab (anti-PD-L1) | Tremelimumab (anti-CTLA-4) | NCT02815995 | II | Active, not recruiting | 62 | Adipocytic tumors (well-diff/ de-differentiated, pleomorphic and myxoid liposarcoma), vascular tumors (leiomyosarcomas, angiosarcomas, epithelioid hemangioendotheliomas, and hemangiopericytomas), undifferentiated pleomorphic sarcoma, synovial sarcoma, osteosarcoma, other sarcomas | No |
Tremelimumab | NCT02879162 | II | Active, not recruiting | 140 | Advanced rare tumors | Yes: 16 years and older | |
Nivolumab | Ipilimumab | NCT02500797 | II | Active, not recruiting | 164 | Unresectable metastatic sarcoma | No |
NCT02982486 | II | Not yet recruiting | 60 | Bone and soft-tissue sarcoma, chondrosarcoma, gastrointestinal stromal sarcoma, Ewing's tumor, osteosarcoma, desmoplastic small round cell tumor | No | ||
Relatlimab (anti-LAG-3) | NCT04095208 | II | Not yet recruiting | 67 | Advanced or metastatic soft tissue sarcoma | No | |
Pembrolizumab | Epacadostat (IDO1 inhibitor) | NCT03414229 | II | Active, not recruiting | 48 | Metastatic and/or locally advanced sarcoma | No |
Dual immune checkpoint inhibitor therapy in combination with chemotherapy or radiation therapy | |||||||
AGEN1884 (anti-CTLA-4)+AGEN2034 (anti-PD-1) | Doxorubicin | NCT04028063 | II | Recruiting | 28 | Soft tissue sarcoma | No |
Durvalumab + Tremelimumab | Radiation therapy +/− surgical resection | NCT03116529 | I/II | Recruiting | 35 | Predominantly low-grade soft tissue sarcoma | No |
Nivolumab+ipilimumab | Radiation therapy+surgical resection | NCT03463408 | I | Recruiting | 24 | Soft-tissue sarcoma | No |
Radiation therapy | NCT03307616 | II | Recruiting | 40 | Undifferentiated pleomorphic sarcoma or dedifferentiated liposarcoma | No | |
Trabectedin | NCT03138161 | I/II | Recruiting | 45 | Advanced and metastatic soft tissue sarcoma | No |
Immune checkpoint inhibitors in combination with other agents
- van Erp A.E.M.
- Versleijen-Jonkers Y.M.H.
- Hillebrandt-Roeffen M.H.S.
- van Houdt L.
- Gorris M.A.J.
- van Dam L.S.
- et al.
- Schoffski P.
- Wozniak A.
- Kasper B.
- Aamdal S.
- Leahy M.G.
- Rutkowski P.
- et al.
- Schoffski P.
- Wozniak A.
- Kasper B.
- Aamdal S.
- Leahy M.G.
- Rutkowski P.
- et al.
Limitations of published studies
Conclusion
Declaration of Competing Interest
Acknowledgements
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