CONCLUSION

Sarcomas are uncommon tumors. Currently, no effective systemic therapeutic modality for patients with advanced sarcomas exists, and the prognosis remains very poor. The advent of PD-1-blocking agents changed the treatment modality for many types of solid tumors, in which they show satisfactory efficacy. However, data corresponding to sarcomas, especially from randomized clinical studies of PD-1 blockade, are rare, and no results of randomized Phase 3 studies of PD-1 blockade in sarcomas are available. Sarcomas represent a large group of heterogeneous diseases including more than 50 subtypes, and the tumor microenvironment is highly complicated. PD-1 blockade monotherapy cannot achieve satisfactory efficacy according to the available data. As research on the sarcomas microenvironment proceeds, it may be possible to identify patients who are sensitive to PD-1 blockade by examination of PD-L1 expression, TMB, and MSI. For unselected sarcoma patients, PD-1 blockade combined with other types of treatment, such as localized radiation, tumor injection with cytokines or oncolytic viruses, and treatment with other types of immunomodulatory agents, may provide better results.

Abbreviations


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PD-1, programmed death protein 1; Ig, immunoglobulin; MoAb, onoclonal antibody; STS, soft tissue sarcoma; UPS, undifferentiated pleomorphic sarcoma; PFS, progression-free survival; SAE, severe adverse events; PD-L1, programmed death protein ligand 1; TAM, tumor-associated macrophage; SBRT, stereotactic body radiotherapy; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; MDSCs, myeloid-derived suppressor cells; Tregs, regulatory T cells; CTL, cytotoxic T lymphocyte; PDGFR, platelet-derived growth factor receptor; TMB tumor mutation burden; TIL, tumor-infiltrating lymphocyte; MSI, microsatellite instability; MMR, mismatch repair.

Acknowledgment

We would like to give our thanks to www.editage.cn for the language editing. This study was funded by Industry-University-Research Collaboration of Health Commission of Henan Province (No. 182107000027).

Disclosure

The authors report no conflicts of interest in this work.


Wenli Zuo, Lingdi Zhao

Hematology Department, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou City 450008, People’s Republic of China

Correspondence: Lingdi Zhao
Hematology Department, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, No. 127 Dongming Road, Jinshui District, Zhengzhou City 450008, People’s Republic of China
E-mail: [email protected]


References

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7–30. doi:10.3322/caac.21442

2. Brennan MF, Antonescu CR, Moraco N, Singer S. Lessons learned from the study of 10,000 patients with soft tissue sarcoma. Ann Surg. 2014;260(3):416–421. doi:10.1097/SLA.0000000000000869

3. Gelderblom H, Blay JY, Seddon BM, et al. Brostallicin versus doxorubicin as first-line chemotherapy in patients with advanced or metastatic soft tissue sarcoma: an European organisation for research and treatment of cancer soft tissue and bone sarcoma group randomised phase II and pharmacogenetic study. Eur J Cancer. 2014;50(2):388–396. doi:10.1016/j.ejca.2013.10.002

4. Ben-Ami E, Barysauskas CM, Solomon S, et al. Immunotherapy with single agent nivolumab for advanced leiomyosarcoma of the uterus: results of a phase 2 study. Cancer. 2017;123(17):3285–3290. doi:10.1002/cncr.30738

5. Hellmann MD, Rizvi NA, Goldman JW, et al. Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. Lancet Oncol. 2017;18(1):31–41. doi:10.1016/S1470-2045(16)30624-6

6. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277–1290. doi:10.1056/NEJMoa1712126

7. Paoluzzi L, Cacavio A, Ghesani M, et al. Response to anti-PD1 therapy with nivolumab in metastatic sarcomas. Clin Sarcoma Res. 2016;6:24. doi:10.1186/s13569-016-0064-0

8. Sindhu S, Gimber LH, Cranmer L, et al. Angiosarcoma treated successfully with anti-PD-1 therapy – a case report. J Immunother Cancer. 2017;5(1):58. doi:10.1186/s40425-017-0263-0

9. Marcrom S, De Los Santos JF, Conry RM. Complete response of mediastinal clear cell sarcoma to pembrolizumab with radiotherapy. Clin Sarcoma Res. 2017;7:14. doi:10.1186/s13569-017-0079-1

10. Song HN, Kang MG, Park JR, et al. Pembrolizumab for refractory metastatic myxofibrosarcoma: a case report. Cancer Res Treat. 2018;50(4):1458–1461. doi:10.4143/crt.2017.529

11. Delyon J, Bizot A, Battistella M, Madelaine I, Vercellino L, Lebbé C. PD-1 blockade with nivolumab in endemic kaposi sarcoma. Ann Oncol. 2018;29(4):1067–1069. doi:10.1093/annonc/mdy006

12. D’Angelo SP, Mahoney MR, Van Tine BA, et al. Nivolumab with or without ipilimumab treatment for metastatic sarcoma (Alliance A091401): two open-label, non-comparative, randomised, phase 2 trials. Lancet Oncol. 2018;19(3):416–426. doi:10.1016/S1470-2045(18)30006-8

13. Tawbi HA, Burgess M, Bolejack V, et al. Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial. Lancet Oncol. 2017;18(11):1493–1501. doi:10.1016/S1470-2045(17)30624-1

14. Langer CJ, Gadgeet SM, Borghaei H, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016;17(11):1497–1508. doi:10.1016/S1470-2045(16)30498-3

15. Atkins MB, Plimack ER, Puzanov I, et al. Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-expansion phase 1b trial. Lancet Oncol. 2018;19(3):405–415. doi:10.1016/S1470-2045(18)30081-0

16. Deng L, Liang H, Burnette B, et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest. 2014;124(2):687–695. doi:10.1172/JCI67313

17. Song X, Shao Y, Jiang T, et al. Radiotherapy upregulates programmed death ligand-1 through the pathways downstream of epidermal growth factor receptor in glioma. EBioMedicine. 2018;28:105–113. doi:10.1016/j.ebiom.2018.01.027

18. Patel KR, Martinez A, Stahl JM, et al. Increase in PD-L1 expression after pre-operative radiotherapy for soft tissue sarcoma. Oncoimmunology. 2018;7(7):e1442168. doi:10.1080/2162402X.2018.1490854

19. D’Angelo SP, Shoushtari AN, Agaram NP, et al. Prevalence of tumor-infiltrating lymphocytes and PD-L1 expression in the soft tissue sarcoma microenvironment. Hum Pathol. 2015;46(3):357–365. doi:10.1016/j.humpath.2014.11.001

20. Kim C, Kim EK, Jung H, et al. Prognostic implications of PD-L1 expression in patients with soft tissue sarcoma. BMC Cancer. 2016;16:434. doi:10.1186/s12885-016-2451-6

21. Boxberg M, Steiger K, Lenze U, et al. PD-L1 and PD-1 and characterization of tumor-infiltrating lymph.ocytes in high grade sarcomas of soft tissue – prognostic implications and rationale for immunotherapy. Oncoimmunology. 2018;7(3):e1389366. doi:10.1080/2162402X.2018.1490854

22. D’Ignazio L, Batie M, Rocha S. Hypoxia and inflammation in cancer, focus on HIF and NF-kappaB. Biomedicines. 2017;5(2). pii: E21. doi:10.3390/biomedicines5020021.

23. Kim JR, Moon YJ, Kwon KS, et al. Tumor infiltrating PD1-positive lymphocytes and the expression of PD-L1 predict poor prognosis of soft tissue sarcomas. PLoS One. 2013;8(12):e82870. doi:10.1371/journal.pone.0082870

24. Noguchi T, Ward JP, Gubin MM, et al. Temporally distinct PD-L1 expression by tumor and host cells contributes to immune escape. Cancer Immunol Res. 2017;5(2):106–117. doi:10.1158/2326-6066.CIR-16-0391

25. Dewan MZ, Galloway AE, Kawashima N, et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res. 2009;15(17):5379–5388. doi:10.1158/1078-0432.CCR-09-0265

26. Dovedi SJ, Cheadle EJ, Popple AL, et al. Fractionated radiation therapy stimulates antitumor immunity mediated by both resident and infiltrating polyclonal T-cell populations when combined with PD-1 blockade. Clin Cancer Res. 2017;23(18):5514–5526. doi:10.1158/1078-0432.CCR-16-1673

27. Keung EZ, Tsai JW, Ali AM, et al. Analysis of the immune infiltrate in undifferentiated pleomorphic sarcoma of the extremity and trunk in response to radiotherapy: rationale for combination neoadjuvant immune checkpoint inhibition and radiotherapy. Oncoimmunology. 2018;7(2):e1385689. doi:10.1080/2162402X.2018.1490854

28. Xi C, Wencheng Z, Dong Q, et al. Tumor regression after combination of radiation and PD-1 antibody nivolumab treatment in a patient with metastatic mediastinal leiomyosarcoma: a case report. Cancer Biol Ther. 2019;20(4):408–412. doi:10.1080/15384047. 2018.1537577.

29. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39(1):1–10. doi:10.1016/j.immuni.2013.07.012

30. Apetoh L, Ladoire S, Coukos G, Ghiringhelli F. Combining immunotherapy and anticancer agents: the right path to achieve cancer cure? Ann Oncol. 2015;26(9):1813–1823. doi:10.1093/annonc/mdv209

31. Qiao M, Jiang T, Ren S, Zhou C. Combination strategies on the basis of immune checkpoint inhibitors in non-small-cell lung cancer: where do we stand?. Clin Lung Cancer. 2018;19(1):1–11. doi:10.1016/j.cllc.2017.06.005

32. Fang W, Yang Y, Ma Y, et al. Camrelizumab (SHR-1210) alone or in combination with gemcitabine plus cisplatin for nasopharyngeal carcinoma: results from two single-arm, phase 1 trials. Lancet Oncol. 2018;19(10):1338–1350. doi:10.1016/S1470-2045(18)30495-9

33. Mkrtichyan M, Najjar YG, Raulfs EC, et al. Anti-PD-1 synergizes with cyclophosphamide to induce potent anti-tumor vaccine effects through novel mechanisms. Eur J Immunol. 2011;41(10):2977–2986. doi:10.1002/eji.201141639

34. Toulmonde M, Penel N, Adam J, et al. Use of PD-1 targeting, macrophage infiltration, and IDO pathway activation in sarcomas: a phase 2 clinical trial. JAMA Oncol. 2018;4(1):93–97. doi:10.1001/jamaoncol.2017.1617

35. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9(6):669–676. doi:10.1038/nm0603-669

36. Li Y, Zhao H, Ren XB. Relationship of VEGF/VEGFR with immune and cancer cells: staggering or forward? Cancer Biol Med. 2016;13(2):206–214. doi:10.20892/j.issn.2095-3941.2015.0070

37. Socinski MA, Jotte RM, Cappuzzo F, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018;378(24):2288–2301. doi:10.1056/NEJMoa1716948

38. Pishvaian MJ, Lee MS, Ryoo BY, et al. Updated safety and clinical activity results from a phase 1b study of atezolizumab+bevacizumab in hepatocellular carcinoma (HCC). Ann Oncol. 2018;29(suppl_8):LBA26. doi:10.1093/annonc/mdx807

39. Xue JM, Astere M, Zhong MX, Lin H, Shen J, Zhu Y-X. Efficacy and safety of apatinib treatment for gastric cancer, hepatocellular carcinoma and non-small cell lung cancer: a meta-analysis. Onco Targets Ther. 2018;11:6119–6128. doi:10.2147/OTT.S172717

40. Zhao D, Hou H, Zhang X. Progress in the treatment of solid tumors with apatinib: a systematic review. Onco Targets Ther. 2018;11:4137–4147. doi:10.2147/OTT.S172305

41. Xie L, Guo W, Wang Y, et al. Apatinib for advanced sarcoma: results from multiple institutions’ off-label use in China. BMC Cancer. 2018;18(1):396. doi:10.1186/s12885-018-4242-8

42. Xu JM, Zhang Y, Jia R, et al. Anti-PD-1 Antibody SHR-1210 combined with apatinib for advanced hepatocellular carcinoma, gastric or esophagogastric junction cancer: an open-label, dose escalation and expansion study. Clin Cancer Res. 2019;25(2):515–523. doi:10.1158/1078-0432.CCR-18-2484

43. Hutson TE, Lesovoy V, AI-Shukri S, et al. Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomised open-label phase 3 trial. Lancet Oncol. 2013;14(13):1287–1294. doi:10.1016/S1470-2045(13)70465-0

44. Wilky BA, Trucco MM, Kolonias D, et al. A phase II trial of axitinib plus pembrolizumab for patients with advanced alveolar soft part sarcoma (ASPS) and other soft tissue sarcomas (STS). J Clin Oncol. 2018;36(15_suppl):11547. doi:10.1200/JCO.2018.36.15_suppl.11547

45. Lewin J, Davidson S, Anderson ND, et al. Response to immune checkpoint inhibition in two patients with alveolar soft-part sarcoma. Cancer Immunol Res. 2018;6(9):1001–1007. doi:10.1158/2326-6066.CIR-18-0037

46. Mejean A, Ravaud A, Thezenas S, et al. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. N Engl J Med. 2018;379(5):417–427. doi:10.1056/NEJMoa1803675

47. Faivre S, Zappa M, Vilgrain V, et al. Changes in tumor density in patients with advanced hepatocellular carcinoma treated with sunitinib. Clin Cancer Res. 2011;17(13):4504–4512. doi:10.1158/1078-0432.CCR-10-1708

48. Reichardt P, Kang YK, Rutkowski P, et al. Clinical outcomes of patients with advanced gastrointestinal stromal tumors: safety and efficacy in a worldwide treatment-use trial of sunitinib. Cancer. 2015;121(9):1405–1413. doi:10.1002/cncr.29220

49. Tap WD, Jones RL, Van Tine BA, et al. Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial. Lancet. 2016;388(10043):488–497. doi:10.1016/S0140-6736(16)30587-6

50. Parry RV, Chemnitz JM, Frauwirth KA, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol. 2005;25(21):9543–9553. doi:10.1128/MCB.25.21.9543-9553.2005

51. Hodi FS, Chiarion-Sileni V, Gonzalez R, et al. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018;19(11):1480–1492. doi:10.1016/S1470-2045(18)30700-9

52. Patel SP, Kurzrock R. PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther. 2015;14(4):847–856. doi:10.1158/1535-7163.MCT-14-0983

53. Kim TK, Herbst RS, Chen L. Defining and understanding adaptive resistance in cancer immunotherapy. Trends Immunol. 2018;39(8):624–631. doi:10.1016/j.it.2018.05.001

54. Movva S, Wen W, Chen W, et al. Multi-platform profiling of over 2000 sarcomas: identification of biomarkers and novel therapeutic targets. Oncotarget. 2015;6(14):12234–12247. doi:10.18632/oncotarget.3498

55. Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348(6230):124–128. doi:10.1126/science.aaa1348

56. Palmieri G, Colombino M, Cossu A, et al. Genetic instability and increased mutational load: which diagnostic tool best direct patients with cancer to immunotherapy? J Transl Med. 2017;15(1):17. doi:10.1186/s12967-017-1119-6

57. Saller J, Walko CM, Millis SZ, et al. Response to checkpoint inhibitor therapy in advanced classic kaposi sarcoma: a case report and immunogenomic study. J Natl Compr Canc Netw. 2018;16(7):797–800. doi:10.6004/jnccn.2018.7018

58. Dudley JC, Lin MT, Le DT, et al. Microsatellite instability as a biomarker for PD-1 blockade. Clin Cancer Res. 2016;22(4):813–820. doi:10.1158/1078-0432.CCR-15-1678

59. Tlemsani C, Leroy K, Gimenez-Roqueplo AP, et al. Chemoresistant pleomorphic rhabdomyosarcoma: whole exome sequencing reveals underlying cancer predisposition and therapeutic options. J Med Genet. 2018. pii: jmedgenet-2018-105594. doi:10.1136/jmedgenet-2018-105594.

Source: OncoTargets and Therapy.
Originally published August 23, 2019.

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