Skip to main content

Immunotherapeutic Approaches to Sarcoma

Opinion statement

Current therapies in advanced sarcomas are primarily based on cytotoxic chemotherapy and have modest efficacy coupled with significant toxicity. Little progress has been made in the field since imatinib was approved for the treatment of gastrointestinal stromal tumor (GIST) in 2002 despite the recent FDA approval of the multi-tyrosine kinase inhibitor pazopanib. Novel therapies are clearly needed. Immunotherapy utilizing checkpoint inhibitors has yielded significant clinical benefit in multiple solid tumors manifesting as durable responses in melanoma, kidney, lung, and bladder cancers, as well as hematologic malignancies. Given the success in several “non-immunogenic” tumors and recent preclinical data, there is sufficient evidence to support the use of immunotherapy in sarcoma. Cytokine-based therapies have shown no benefit in the advanced setting. Two large randomized trials of muramyl tripeptide or of interferon maintenance in resected osteosarcoma patients did not provide unequivocal statistically significant benefit. More promising results have been reported in small studies evaluating vaccines and adoptive T cell therapy in specific subtypes of sarcoma such as synovial sarcoma, which widely expresses the immunogenic cancer testis antigen NY-ESO-1. Emerging approaches with chimeric antigen receptor (CAR)-engineered T cells are hypothesis-generating and thought-provoking. However, the unprecedented clinical activity and excellent safety profile of checkpoint inhibitors targeting programmed death-1 receptor and its ligand (PD-1/PD-L1) have galvanized the field and generated much enthusiasm to harness the power of immunotherapy in pursuit of cures in patients with advanced sarcomas. An ongoing phase II study (SARC028) will hopefully usher an era of investigation of this exciting approach in sarcoma. However, it is unlikely that one agent will carry a universal cure and future approaches need to focus on patient selection as well as on identifying the optimal combination of checkpoint inhibitors with targeted therapy, chemotherapy, or radiation therapy.

This is a preview of subscription content, access via your institution.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. American Cancer Society. Cancer Facts & Figures 2015. Atlanta: American Cancer Society; 2015.

    Google Scholar 

  2. Judson I, Verweij J, Gelderblom H, et al. Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial. Lancet Oncol. 2014;15(4):415–23.

    CAS  PubMed  Article  Google Scholar 

  3. Maki RG. Gemcitabine and docetaxel in metastatic sarcoma: past, present, and future. Oncologist. 2007;12(8):999–1006.

    CAS  PubMed  Article  Google Scholar 

  4. Hensley ML, Wathen JK, Maki RG, et al. Adjuvant therapy for high-grade, uterus-limited leiomyosarcoma: results of a phase 2 trial (SARC 005). Cancer. 2013;119(8):1555–61.

    CAS  PubMed  Article  Google Scholar 

  5. Leu KM, Ostruszka LJ, Shewach D, et al. Laboratory and clinical evidence of synergistic cytotoxicity of sequential treatment with gemcitabine followed by docetaxel in the treatment of sarcoma. J Clin Oncol. 2004;22(9):1706–12.

    CAS  PubMed  Article  Google Scholar 

  6. Italiano A, Mathoulin-Pelissier S, Cesne AL, et al. Trends in survival for patients with metastatic soft-tissue sarcoma. Cancer. 2011;117(5):1049–54.

    PubMed  Article  Google Scholar 

  7. Coley II WB. Contribution to the knowledge of sarcoma. Ann Surg. 1891;14(3):199–220.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  8. Johnston BJ, Novales ET. Clinical effect of Coley’s toxin. II. A seven-year study. Cancer Chemother Rep Part 1. 1962;21:43–68.

    CAS  Google Scholar 

  9. Nauts HC, McLaren JR. Coley toxins—the first century. Adv Exp Med Biol. 1990;267:483–500.

    CAS  PubMed  Article  Google Scholar 

  10. Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol. 2004;22:329–60.

    CAS  PubMed  Article  Google Scholar 

  11. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol. 2002;3(11):991–8.

    CAS  PubMed  Article  Google Scholar 

  12. Tsukahara T, Kawaguchi S, Torigoe T, et al. Prognostic significance of HLA class I expression in osteosarcoma defined by anti-pan HLA class I monoclonal antibody, EMR8-5. Cancer Sci. 2006;97(12):1374–80.

    CAS  PubMed  Article  Google Scholar 

  13. Atkins MB, Lotze MT, Dutcher JP, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999;17(7):2105–16.

    CAS  PubMed  Google Scholar 

  14. Atkins MB, Regan M, McDermott D. Update on the role of interleukin 2 and other cytokines in the treatment of patients with stage IV renal carcinoma. Clin Cancer Res. 2004;10(18 Pt 2):6342. s-6s.

  15. Atkins MB, Kunkel L, Sznol M, Rosenberg SA. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am. 2000;6 Suppl 1:S11–4.

    PubMed  Google Scholar 

  16. Fisher RI, Rosenberg SA, Fyfe G. Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell carcinoma. Cancer J Sci Am. 2000;6 Suppl 1:S55–7.

    PubMed  Google Scholar 

  17. Rosenberg SA, Yang JC, White DE, Steinberg SM. Durability of complete responses in patients with metastatic cancer treated with high-dose interleukin-2: identification of the antigens mediating response. Ann Surg. 1998;228(3):307–19.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  18. Rosenberg SA, Lotze MT, Yang JC, et al. Experience with the use of high-dose interleukin-2 in the treatment of 652 cancer patients. Ann Surg. 1989;210(4):474–84. discussion 84-5.

  19. Schwinger W, Klass V, Benesch M, et al. Feasibility of high-dose interleukin-2 in heavily pretreated pediatric cancer patients. Ann Oncol. 2005;16(7):1199–206.

    CAS  PubMed  Article  Google Scholar 

  20. Muller CR, Smeland S, Bauer HC, Saeter G, Strander H. Interferon-alpha as the only adjuvant treatment in high-grade osteosarcoma: long term results of the Karolinska Hospital series. Acta Oncol. 2005;44(5):475–80.

    PubMed  Article  Google Scholar 

  21. Strander H, Bauer HC, Brosjo O, et al. Long-term adjuvant interferon treatment of human osteosarcoma. A pilot study. Acta Oncol. 1995;34(6):877–80.

    CAS  PubMed  Article  Google Scholar 

  22. Bielack S, Whelan J, Marina N, et al. MAP plus maintenance pegylated interferon alpha-2b (MAPIfn) versus MAP alone in patients with resectable high-grade osteosarcoma and good histologic response to preoperative MAP: first results of the EURAMOS-1 "good response" randomization. J Clin Oncol 2013; 31(supplement, abstract LBA10504).

  23. MacEwen EG, Kurzman ID, Rosenthal RC, et al. Therapy for osteosarcoma in dogs with intravenous injection of liposome-encapsulated muramyl tripeptide. J Natl Cancer Inst. 1989;81(12):935–8.

    CAS  PubMed  Article  Google Scholar 

  24. Kleinerman ES, Jia SF, Griffin J, Seibel NL, Benjamin RS, Jaffe N. Phase II study of liposomal muramyl tripeptide in osteosarcoma: the cytokine cascade and monocyte activation following administration. J Clin Oncol. 1992;10(8):1310–6.

    CAS  PubMed  Google Scholar 

  25. Chou AJ, Kleinerman ES, Krailo MD, et al. Addition of muramyl tripeptide to chemotherapy for patients with newly diagnosed metastatic osteosarcoma: a report from the Children’s Oncology Group. Cancer. 2009;115(22):5339–48.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  26. Lai JP, Robbins PF, Raffeld M, et al. NY-ESO-1 expression in synovial sarcoma and other mesenchymal tumors: significance for NY-ESO-1-based targeted therapy and differential diagnosis. Mod Pathol. 2012;25(6):854–8.

    PubMed  Article  Google Scholar 

  27. Pollack SM, Jungbluth AA, Hoch BL, et al. NY-ESO-1 is a ubiquitous immunotherapeutic target antigen for patients with myxoid/round cell liposarcoma. Cancer. 2012;118(18):4564–70.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  28. Kawaguchi S, Wada T, Ida K, et al. Phase I vaccination trial of SYT-SSX junction peptide in patients with disseminated synovial sarcoma. J Transl Med. 2005;3(1):1.

    PubMed Central  PubMed  Article  Google Scholar 

  29. Kawaguchi S, Tsukahara T, Ida K, et al. SYT-SSX breakpoint peptide vaccines in patients with synovial sarcoma: a study from the Japanese Musculoskeletal Oncology Group. Cancer Sci. 2012;103(9):1625–30.

    CAS  PubMed  Article  Google Scholar 

  30. Chang HR, Cordon-Cardo C, Houghton AN, Cheung NK, Brennan MF. Expression of disialogangliosides GD2 and GD3 on human soft tissue sarcomas. Cancer. 1992;70(3):633–8.

    CAS  PubMed  Article  Google Scholar 

  31. Ziebarth AJ, Felder MA, Harter J, Connor JP. Uterine leiomyosarcoma diffusely express disialoganglioside GD2 and bind the therapeutic immunocytokine 14.18-IL2: implications for immunotherapy. Cancer Immunol Immunother. 2012;61(7):1149–53.

    CAS  PubMed  Article  Google Scholar 

  32. Carvajal R, Agulnik M, Ryan CW, et al. Trivalent ganglioside vaccine and immunologic adjuvant versus adjuvant alone in metastatic sarcoma patients rendered disease-free by surgery: a randomized phase 2 trial. J Clin Oncol. 2014;32:5. s(supplement; abstract 10520).

  33. Brahmer JR, Drake CG, Wollner I, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28(19):3167–75.

    CAS  PubMed  Article  Google Scholar 

  34. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–54. This phase I trial evaluated the anti-PD-1 antibody, nivolumab, in patients with advanced solid tumors including melanoma and non-small cell lung cancer. Response rates seen were between 18-28 %, and these results helped nivolumab gain FDA approval in December 2014.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  35. Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol. 2012;24(2):207–12.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  36. Ribas A. Tumor immunotherapy directed at PD-1. N Engl J Med. 2012;366(26):2517–9.

    CAS  PubMed  Article  Google Scholar 

  37. Maki RG, Jungbluth AA, Gnjatic S, et al. A pilot study of anti-CTLA4 antibody ipilimumab in patients with synovial sarcoma. Sarcoma. 2013;2013:168145.

    PubMed Central  PubMed  Article  Google Scholar 

  38. Lai JP, Rosenberg AZ, Miettinen MM, Lee CC. NY-ESO-1 expression in sarcomas: a diagnostic marker and immunotherapy target. Oncoimmunology. 2012;1(8):1409–10.

    PubMed Central  PubMed  Article  Google Scholar 

  39. Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  40. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369(2):134–44. This trial studied the anti-PD1 antibody, lambrolizumab, later named pembrolizumab, in advanced melanoma. Response rates averaged 38 % and were typically durable, and these results helped pembrolizumab gain FDA approval in September 2014.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  41. 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. This article highlights both frequency of PD-1 positive tumor infiltrating lymphocytes (TILs) and PD-L1 tumor expression in a cohort of mixed sarcoma subtypes. PD-1 positive TILs and PD-L1 tumor expression correlated with poorer overall and event free survival, as well as, more aggressive tumor features.

    PubMed Central  PubMed  Article  Google Scholar 

  42. 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. 2014;100:199–204. This study is one of the studies examining the presence of tumor-infiltrating lymphocytes as well as PD-L1 expression in sarcoma tumors.

    Google Scholar 

  43. Topalian SL, Sznol M, Brahmer JR. Nivolumab (anti-PD-1; BMS-936558; ONO-4538) in patients with advanced solid tumors: survival and long-term safety in a phase I trial. J Clin Oncol. 2013;31:2404–12.

    Article  Google Scholar 

  44. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369(2):122–33. This phase I trial examined the combination of the anti-CTLA-4 antibody, ipilimumab, and the anti-PD-1 antibody, nivolumab in patients with advanced melanoma. With a manageable side effect profile, the combination produced durable responses with over half of the patients having objective responses (53 %).

    CAS  PubMed  Article  Google Scholar 

  45. Wei S, Shreiner AB, Takeshita N, Chen L, Zou W, Chang AE. Tumor-induced immune suppression of in vivo effector T-cell priming is mediated by the B7-H1/PD-1 axis and transforming growth factor beta. Cancer Res. 2008;68(13):5432–8.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  46. Woo SR, Turnis ME, Goldberg MV, et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 2012;72(4):917–27.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  47. Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515(7528):568–71.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  48. Robbins PF, Morgan RA, Feldman SA, et al. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol. 2011;29(7):917–24.

    PubMed Central  PubMed  Article  Google Scholar 

  49. Ahmed N, Salsman VS, Yvon E, et al. Immunotherapy for osteosarcoma: genetic modification of T cells overcomes low levels of tumor antigen expression. Mol Ther. 2009;17(10):1779–87.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  50. Lehner M, Gotz G, Proff J, et al. Redirecting T cells to Ewing’s sarcoma family of tumors by a chimeric NKG2D receptor expressed by lentiviral transduction or mRNA transfection. PLoS One. 2012;7(2), e31210.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  51. Gattenlohner S, Marx A, Markfort B, et al. Rhabdomyosarcoma lysis by T cells expressing a human autoantibody-based chimeric receptor targeting the fetal acetylcholine receptor. Cancer Res. 2006;66(1):24–8.

    PubMed  Article  Google Scholar 

  52. Rainusso N, Brawley VS, Ghazi A, et al. Immunotherapy targeting HER2 with genetically modified T cells eliminates tumor-initiating cells in osteosarcoma. Cancer Gene Ther. 2012;19(3):212–7.

    CAS  PubMed  Article  Google Scholar 

  53. Lawrence MS, Stojanov P, Mermel CH, et al. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature. 2014;505(7484):495–501.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  54. Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014;371(23):2189–99. This important translational study highlights the differences between frequency of mutations and neoepitope signatures in melanoma patients that responded to ipilimumab versus those patients who did not respond. This study revolutionizes how we will write future immune checkpoint inhibitor trials with better patient selection.

    PubMed Central  PubMed  Article  Google Scholar 

  55. Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med. 2012;366(10):925–31.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  56. Sharma A, Bode B, Studer G, et al. Radiotherapy of human sarcoma promotes an intratumoral immune effector signature. Clin Cancer Res. 2013;19(17):4843–53.

    CAS  PubMed  Article  Google Scholar 

  57. Himoudi N, Wallace R, Parsley KL, et al. Lack of T-cell responses following autologous tumour lysate pulsed dendritic cell vaccination, in patients with relapsed osteosarcoma. Clin Transl Oncol. 2012;14(4):271–9.

    CAS  PubMed  Article  Google Scholar 

  58. Shen JK, Cote GM, Choy E, et al. Programmed cell death ligand 1 expression in osteosarcoma. Cancer Immunol Res. 2014;2(7):690–8.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  59. Endo M, de Graaff MA, Ingram DR, et al. NY-ESO-1 (CTAG1B) expression in mesenchymal tumors. Mod Pathol 2014.

  60. Hemminger JA, Toland AE. Expression of cancer-testis antigens MAGEA1, MAGEA3, ACRBP, PRAME, SSX2, and CTAG2 in myxoid and round cell liposarcoma. Mod Pathol. 2014;27(9):1238–45.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

Download references

Compliance with Ethics Guidelines

Conflict of Interest

Melissa Burgess and Hussein Tawbi declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hussein Tawbi M.D., Ph.D..

Additional information

This article is part of the Topical Collection on Sarcoma

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Burgess, M., Tawbi, H. Immunotherapeutic Approaches to Sarcoma. Curr. Treat. Options in Oncol. 16, 26 (2015). https://doi.org/10.1007/s11864-015-0345-5

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11864-015-0345-5

Keywords

  • Sarcoma
  • Immunotherapy
  • Programmed death-1 (PD-1)
  • Chimeric antigen receptor
  • Neoantigen