Targeting the Molecular and Immunologic Features of Leiomyosarcoma
Abstract
:Simple Summary
Abstract
1. Introduction
2. Current Standard of Care Treatment for LMS
2.1. uLMS-Specific Considerations
2.2. ST-LMS-Specific Considerations
3. Emerging Role of Immunotherapy in the Treatment of LMS
4. Molecular Landscape of LMS
4.1. Complex Karyotype
4.2. Molecular Subtypes of LMS
4.3. TP53
4.4. RB1
4.5. PTEN Deletion and PI3k/AKt/mOR Pathway
4.6. DNA Damage Response
4.7. Whole-Genome Doubling
4.8. Alternative Lengthening of Telomeres
5. Immune Landscape of LMS
5.1. Tertiary Lymphoid Structures
5.2. PD-L1
5.3. Tumor-Infiltrating Lymphocytes
5.4. Macrophages
5.5. Association of Molecular Subtypes with Immune Microenvironment
6. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Type of LMS | Molecule Tested | Target | Design | ORR | DCR (ORR + SD) | PFS and OS Duration, Median (Range) | Reference |
---|---|---|---|---|---|---|---|
uLMS | Nivolumab | Anti-PD1 | Phase II | 0% | 8.3% | PFS: 1.8 months (0.8-unknown) OS: not met; 4 of 12 died during the 100-day study follow-up period because of progression | [48] |
Pembrolizumab | Anti-PD1 | Retrospective case study | 100% | 100% | NA | [61] | |
Pembrolizumab | Anti-PD1 | Retrospective case study | 100% | 100% | NA | [62] | |
ST-LMS | Pembrolizumab | Anti-PD1 | Phase II | 0% | 60% | * PFS: 15 weeks (8–21) * OS: 49 weeks (24–73) | [49] |
Ipilimumab plus nivolumab | Anti-PD1 and anti-CTLA-4 | Retrospective | 13% | NR | PFS: 4.1 months (3.2–4.5) OS: 12.2 months (6.1–13.7) | [52] | |
Nivolumab | Anti-PD1 | Retrospective case study | 100% | 100% | NA | [63] | |
Both | Iplimumab plus nivolumab | Anti-PD1 and anti-CTLA-4 | Phase II | 14.3% | NR | PFS: 4.1 months (2.6–4.7) OS: 14.3 months (9.6-nr) | [51] |
Pembro plus axitinib | Anti-PD1 and VEGF inhibitor | Phase II | * 25% | 53.1% | * PFS: 4.7 months (3–9.4) * OS: 18.7 months (12-nr) | [59] | |
Pembrolizumab plus doxorubicin | Anti-PD1 | Phase II | 40% | 100% | * PFS: 5.7 months (4.1–8.9) * OS: 17.0 months (9.9-nr) | [57] | |
Pembrolizumab plus doxorubicin | Anti-PD1 | Phase I/II | 20% | 50% | * PFS: 8.1 months (7.6–10.8) * OS: 27.6 months (18.7-nr) | [56] | |
Durvalumab plus tremelimumab | Anti-PDL1 and anti-CTLA-4 | Phase II | [50] | ||||
Avelumab plus trabectedin | Anti-PDL1 | Phase I/II | * 13% | * 43% | * PFS: 8.3 months Study was halted as it did not meet the primary objective response rate endpoint | [64] | |
PD-1 inhibitors (pembrolizumab/toripalimab/sintilimab) plus standard chemotherapy | Anti-PD1 | Retrospective cohort study | 17.1% | 73.2% | PFS: 8.8 months (4.57–13.0) OS: not reached; no difference in OS was observed for chemotherapy alone and chemotherapy plus PD-1 | [55] | |
PD-1/PDL1 inhibitors plus TKI | Anti-PD1/PDL1 and VEGF inhibitor | Retrospective cohort study | 0% | 50% | * PFS: 11.74 months | [60] |
LMS Subtype | Prognosis | Mutational Burden | Cellular Lineage | Molecular Characteristics | Gene Expression | Immune Microenvironment |
---|---|---|---|---|---|---|
Well-differentiated ST-LMS | Better | Low | Vascular and digestive smooth muscle | MYOCD amplification and upregulated muscle-associated transcripts TP53 mutations | Enriched: PDGFRA, LRRC15, IGF1R | Inflammatory NK cell signature |
Dedifferentiated ST-LMS | Poor | Vascular smooth muscle | DMD deletion Reduced markers of muscle differentiation PTEN loss, overexpression of Akt pathway RB1 and TP53 mutations | Enriched: ACTA1, SYNM, LMO1 | Higher immune infiltration overall, dominated by M2-Macrophages Higher leukocyte count overexpression | |
uLMS | Poor | Gynecologic (uterine, vaginal, fallopian tube) smooth muscle | DMD expression inhibition PTEN loss, overexpression of Akt pathway TP53 mutations RB1 fusion and loss of function | Enriched: ESR1, PGR, EMX2 | M2 macrophage-dominant |
Primary Intervention | Secondary Intervention | NCT | Tumor Type | Phase | Status | |
---|---|---|---|---|---|---|
Immunotherapy | ||||||
Durvalumab | Tremelimumab | NCT02815995 | Advanced/metastatic STS | II | Active, not recruiting | |
Nivolumab | Ipilimumab | NCT02428192 | uLMS | II | Active, not recruiting | |
Itacitinib | NCT03670069 | Advanced/metastatic STS | I | Recruiting | ||
LMP1/2 CTLs | NCT01956084 | ST-LMS | I | Active, not recruiting | ||
Nivolumab | NCT03241745 | Uterine sarcoma | II | Active, not recruiting | ||
Tabelecleucel | NCT04554914 | ST-LMS | II | Recruiting | ||
Talimogene laherparepvec | NCT02923778 | ST-LMS | II | Recruiting | ||
Immunotherapy + anti-angiogenics | ||||||
Durvalumab | Olaparib, cediranib | NCT03851614 | ST-LMS | II | Active, not recruiting | |
Nivolumab | Sunitinib, epirubicin | NCT03277924 | Advanced/metastatic STS | I/II | Recruiting | |
PD-1 inhibition | BA3011 | NCT03425279 | ST-LMS | I/II | Recruiting | |
Pembrolizumab | Eribulin | NCT03899805 | ST-LMS | II | Active, not recruiting | |
Immunotherapy + chemotherapy | ||||||
APX005M | Doxorubicin | NCT03719430 | Advanced/metastatic STS | II | Recruiting | |
Cabozantinib | Temozolomide | NCT04200443 | ST-LMS, uLMS | II | Recruiting | |
Nivolumab | Rucaparib | NCT04624178 | ST-LMS | II | Active, not recruiting | |
Nivolumab | BO-112 | NCT04420975 | ST-LMS | I | Active, not recruiting | |
OR2805 | Cemiplimab, docetaxel | NCT05094804 | Advanced/metastatic STS | I/II | Recruiting | |
Pembrolizumab | Gemcitabine | NCT03123276 | ST-LMS | I/II | Active, not recruiting | |
Pembrolizumab | Cyclophosphamide | NCT02406781 | ST-LMS | II | Active, not recruiting | |
Ribociclib | Doxorubicin | NCT03009201 | Advanced/metastatic STS | I | Active, not recruiting | |
TTI-621 | Doxorubicin | NCT04996004 | ST-LMS | II | Recruiting |
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Share and Cite
Cope, B.M.; Traweek, R.S.; Lazcano, R.; Keung, E.Z.; Lazar, A.J.; Roland, C.L.; Nassif, E.F. Targeting the Molecular and Immunologic Features of Leiomyosarcoma. Cancers 2023, 15, 2099. https://doi.org/10.3390/cancers15072099
Cope BM, Traweek RS, Lazcano R, Keung EZ, Lazar AJ, Roland CL, Nassif EF. Targeting the Molecular and Immunologic Features of Leiomyosarcoma. Cancers. 2023; 15(7):2099. https://doi.org/10.3390/cancers15072099
Chicago/Turabian StyleCope, Brandon M., Raymond S. Traweek, Rossana Lazcano, Emily Z. Keung, Alexander J. Lazar, Christina L. Roland, and Elise F. Nassif. 2023. "Targeting the Molecular and Immunologic Features of Leiomyosarcoma" Cancers 15, no. 7: 2099. https://doi.org/10.3390/cancers15072099