Development of Checkpoint Inhibitors for Sarcomas

Oncology & Hematology Review, 2017;13(1):25–9 DOI: https://doi.org/10.17925/OHR.2017.13.01.25

Abstract:

Sarcomas comprise a rare and heterogeneous group of malignancies of bone and soft tissue origin. Despite optimal approach, a significant proportion of patients will develop recurrent/metastatic disease. Although advances have been achieved, therapeutic options for these patients are limited and prognosis remains poor. Over the past century, the characterization of mechanisms involved in the interaction between tumor cells and the immune system has paved the way for the development of different forms of cancer immunotherapy, including cytokines, vaccines, cell therapies, and, more recently and successfully, monoclonal antibodies against molecules involved in the modulation of immune response, or immune checkpoint inhibitors. While the clinical applicability of this approach has been limited in sarcomas, the immunogenic potential of this group of malignancies was demonstrated more than 100 years ago. In this article, we review aspects associated with the immunogenicity of sarcomas and how the use of checkpoint inhibitors is being explored for this group of patients.
Keywords: Soft tissue sarcomas, immunotherapy, anti-PD-1, immune checkpoint blockade
Disclosure: Rodrigo R Munhoz, William D Tap, and Sandra P D’Angelo have nothing to disclose in relation to this article. No funding was received for the publication of this article. This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors.

Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.

Received: March 01, 2017 Accepted April 12, 2017
Correspondence: Sandra P D’Angleo, Sarcoma Medical Oncology Service, 300 East 66th Street, New York, NY 10065, US. E: dangelos@mskcc.org
Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit.

Sarcomas consist of a highly diverse group of malignancies of mesenchymal origin, encompassing more than 80 distinct subtypes and diagnosed in approximately 15,000 patients every year in the US.1

Surgery still represents the mainstay of therapy for patients with localized disease. Although the use of multimodal treatment with curative intent remains debatable in soft tissue sarcomas (STS), radiation therapy and chemotherapy are often used in the neo- or adjuvant settings in select situations; for bone sarcomas, combination regimens in association with surgical resection remain the standard treatment.2 For patients with advanced (unresectable or metastatic) disease, however, the prognosis remains poor, and median survival rarely exceeds 12–15 months.2 Alternatives for patients with sarcomas not amenable to treatment with curative intent still rely on cytotoxic agents; standard chemotherapy such as doxorubicin, ifosfamide, and dacarbazine result in objective responses in 10–30% of the patients, usually of short duration, and the efficacy of these agents is largely influenced by the histologic subtype and tumor grade.3,4 During the past years, new options became available for clinical use, including pazopanib, trabectedin, eribulin, and olaratumab. Of note, olaratumab, a monoclonal antibody against the subunit alpha of the plateletderived growth factor receptor (PDGFR), resulted in an 11.8 month-overall survival improvement (hazard ratio [HR] 0.46; 95% confidence interval [CI] 0.30–0.71; p=0.0003) when used in combination with doxorubicin, versus doxorubicin alone, in a randomized, phase II trial.5 Although survival gains have indeed been achieved,5,6 improvements have been modest and short lived in most scenarios and the therapeutic development has been slower in comparison to other solid tumors, highlighting the need for new, effective treatment options for this group of patients.

Manipulation of the immune system has emerged as a new hallmark of cancer therapeutics during the past decade, although observations of tumor regressions mediated by what is now characterized as an anticancer immune response date back to the nineteenth century.7,8 Different approaches to harness the immune system have been investigated: while cytokines, vaccines, and adoptive cell therapy with artificially engineered antigen receptors (or chimeric antigen receptor [CAR] T cells) or modified T cell receptors (TCRs) resulted in variable degrees of antitumor effect, the most practicechanging and clinically applicable development in the management of solid tumors resulted from the use of monoclonal antibodies targeting molecules involved in the modulation of immune activation and response, or checkpoints.9,10

In physiologic conditions, antigens or peptides derived from potential pathogens (bacteria, viruses, tumor cells, etc.) are processed and expressed by antigen-presenting cells (dendritic cells, macrophages, and B cells) through the major histocompatibility complex that engages T cells through the TCR, eliciting a complex sequence of events that culminate with the activation of both innate and adaptive immunity.10,11 Key players of cell-mediated adaptive responses are T cells with either helper cells (CD4+ T cells) or cytotoxic capabilities (CD8+ T cells), as well as memory cells involved in sustained immunity.12 Across different steps of this cycle, the magnitude, duration, and, ultimately, efficacy, of the immune response are influenced by modulatory mechanisms, which can result in either amplification or abrogation of this cycle. While essential in avoiding uncontrolled immune responses and autoimmunity in physiologic situations, these negative regulatory pathways can be exploited by tumor cells as immune evasion mechanisms.13,14 As examples of cell surface molecules involved in immunosuppressive singling pathways, cytotoxic T-lymphocyte associated protein-4 (CTLA-4, or CD152) and programmed cell death receptor-1 (PD-1, or CD274) or its ligand (PD-L1) have been successfully targeted by inhibitory monoclonal antibodies, or immune checkpoint inhibitors (ICIs), resulting in a paradigm shift in the management of a growing number of malignancies.15,16 The ICI ipilimumab, a human monoclonal antibody that binds to CTLA-4; pembrolizumab and nivolumab, molecules that target PD-1; and atezoluzimab, an anti-PD-L1 agent, have all been approved for clinical use. In addition to response rates varying from 10% to more than 50%, ICIs have been shown to allow for sustained disease control and long-lasting immune-mediated responses,15–21 and striking activity resulted from combined CTLA-4 and PD-1 blockade.22,23

Interestingly enough, preliminary observations of tumor regressions following wound infections and erysipelas by Busch and Coley alluded to patients with sarcomas.7,8 Antitumor activity has been further demonstrated in sarcomas with the use of various forms of immunotherapy.24 As examples, cytokine therapy with interleukin-2 (Il-2) and interferons lead to occasional responses in patients with heavily pretreated Ewing sarcoma (ES) and osteosarcoma.25–29 Similarly, liposomal muramyl tripeptide phosphatidylethanolamine (L-MTP-PE), a muramyl dipeptide analogue associated with enhanced NK-κβ signaling and monocyte/macrophage activation, is approved for clinical use in Europe (although not by the US Food and Drug Administration) based on survival improvements in a randomized trial investigating the addition of this agent to conventional chemotherapy in patients with osteosarcoma receiving adjuvant treatment.30 Trabectedin, a compound with a complex mechanism of action currently approved for the treatment of sarcomas, was shown to affect macrophage viability, differentiation, and the production of CCL2 and IL-6, suggesting an immune-mediated effect that could potentially be involved in antitumor activity.31 Additional proofs of the concept that mobilization of the immune system can result in antitumor effect in sarcoma patients are plentiful in the literature, deriving from different forms of vaccines, tumor antigens/peptides, lysates, and, more recently, TCR-transduced T cells specific to NY-ESO-1 in synovial sarcomas.32–34

Evidence addressing the efficacy of monoclonal antibodies against immune checkpoints begins to emerge, as recent studies have yielded both promising and disappointing results across different histologies. In this review, we revisit the mechanisms underlying the immunogenic potential of sarcomas, the currently available clinical data regarding the efficacy of ICIs in sarcomas, as well as future directions.

References:
1. Siegel RL, Miller KD, Jemal A, Cancer statistics, 2015, CA Cancer J Clin, 2016;66:7–30.
2. The ESMO/European Sarcoma Network Working Group, soft tissue and visceral sarcomas: ESMO clinical practice guidelines for diagnosis, treatment and follow up, Ann Oncol, 2014;25:102–12.
3. Van Glabbeke M, Van Oosterom AT, Oosterhuis JW, et al., Prognostic factors for the outcome of chemotherapy in advanced soft tissue sarcoma: an analysis of 2185 patients treated with anthracycline-containing first-line regimens – A European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group study, J Clin Oncol, 1999;17:150–7.
4. Brennan MF, Antonescu CR, Maki RG, Management of Soft Tissue Sarcoma, New York: Springer, 2012.
5. 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;388:488–97.
6. Schöffski P, Chawla S, Maki RG, et al., Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, phase 3 trial, Lancet, 2016;387:1629–37.
7. Coley WB, II. Contribution to the knowledge of sarcoma, Ann Surg, 1891;14:199–220.
8. Curiel TJ, Historical Perspectives and Current Trends in Cancer Immunotherapy. In T.J. Curiel (ed), Cancer Immunotherapy. Paradigms, Practice and Promise, New York: Springer, 2012.
9. Rosenberg AS, Yang JC, Restifo NP, Cancer immunotherapy: moving beyond current vaccines, Nat Med, 2004;10:909–15.
10. Chen DS, Mellman I, Oncology meets immunology: the cancer-immunity cycle, Immunity, 2013;39:1–10.
11. Banchereau J, Steinman RM, Dendritic cells and the control of immunity, Nature, 1998;392:245–52.
12. Grakoui A, Bromley S, Sumen C, et al., The immunological synapse: a molecular machine controlling T cell activation, Science, 1999;285:221–7.
13. Chen L, Flies DB, Molecular mechanisms of T cell co-stimulation and co-inhibition, Nat Rev Immunol, 2013;13:227–42.
14. Peggs KS, Quezada SA, Korman AJ, Allison JP, Principles and use of anti-CTLA4 antibody in human cancer immunotherapy, Curr Opin Immunol, 2006;18:206–13.
15. Hodi FS, O’Day SJ, McDermott DF, et al., Improved survival with ipilimumab in patients with metastatic melanoma, N Engl J Med, 2010;363:711–23.
16. Topalian SL, Hodi FS, Brahmer JR, et al., Safety, activity and immune correlates of anti-PD1 antibody in cancer, N Engl J Med, 2012;366:2443–54.
17. Hodi FS, Kluger H, Sznol M, et al., Durable, long-term survival in previously treated patients with advanced melanoma (MEL) who received nivolumab (NIVO) monotherapy in a phase I trial, Presented at: AACR Annual Meeting, La Nouvelle Orleans Ballroom, Morial Convention Center, 17, April, 2016. Abstr no: CT001.
18. Ribas A, Hamid O, Daud A, et al., Association of pembrolizumab with tumor response and survival among patients with advanced melanoma, JAMA, 2016;315:1600–9.
19. Le ST, Uram JN, Wang H, et al., PD-1 blockade in tumors with mismatch repair deficiency, N Engl J Med, 2015;372:2509–20.
20. Reck M, Rodriguez/Abreu D, Robinson AG, et al., Pembrolizumab versus chemotherapy for PD-L1-positive non-small cell lung cancer, N Engl J Med, 2016;375:1823–33.
21. Rosenberg JE, Hoffman-Censits J, Powles T, et al., Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial, Lancet, 2016;387:1909–20.
22. Wolchok JD, Kluger H, Callahan MK, et al., Nivolumab plus ipilimumab in advanced melanoma, N Engl J Med, 2013;369:122–33.
23. Postow MA, Chesney J, Pavlick AC, et al., Nivolumab and Ipilimumab versus Ipilimumab in untreated melanoma, N Engl J Med, 2015;372:2006–17.
24. D’Angelo SP, Tap WD, Schwartz GK, et al., Sarcoma immunotherapy: past approaches and future directions, Sarcoma, 2014;2914:391967.
25. Lee S, Margolin K, Cytokines in cancer immunotherapy, Cancers, 2011;3:3856–93.
26. Schwinger W, Klass V, Benesch M, et al., Feasibility of high-dose interleukin-2 in heavily pretreated pediatric cancer patients, Ann Oncol, 2005;16:1199–206.
27. Ito H, Murakami K, Yanagawa T, et al., Effect of human leukocyte interferon on the metastatic lung tumor of osteosarcoma: case reports, Cancer, 1980;46:1562–5.
28. Muller CR, Smeland S, Bauer HC, et al., Interferon-α as the only adjuvant treatment in high-grade osteosarcoma: long term results of the Karolinska hospital series, Acta Oncologica, 2005;44:475–80.
29. Bielack SS, Smeland S, Whelan JS, et al., Methotrexate, doxorubicin, and cisplatin (MAP) plus maintenance pegylated interferon alfa-2b 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 randomized controlled trial, J Clin Oncol, 2015;33:2279–87.
30. Meyers PA, Schwartz CL, Krailo MD, et al., Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival – a report from the children’s oncology group, J Clin Oncol, 2008;26:633–8.
31. Allavena P, Signorelli M, Chieppa M, et al., Anti-inflammatory properties of the novel antitumor agent yondelis (trabectedin): inhibition of macrophage differentiation and cytokine production, Cancer Res, 2005;65:2964–71.
32. Suminoe A, Matsuzako A, Hattori H, et al., Immunotherapy with autologous dendritic cells and tumor antigens for children with refractory malignant solid tumors, Pediatr Transplant, 2009;13:746–53.
33. Dillman R, Barth N, Selvan S, et al., A phase I/II trial of autologous tumor cell line-derived vaccines for recurrent or metastatic sarcomas, Cancer Biother Radiopharm, 2004;19:581–8.
34. 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;29:917–24.
35. Gatti RA, Good RA, Occurrence of malignancy in immunodeficiency diseases. A Literature Review, Cancer, 1971;28:89–98.
36. Rubinstein PG, Aboulafia DM, Zloza A, Malignancies in HIV/AIDS: from epidemiology to therapeutic challenges, AIDS, 2014;28:453–65.
37. Penn J, Sarcomas in organ allograft recipients, Transplantation, 1995;60:1485–91.
38. Sorbye SW, Kilvaer T, Valkov A, et al., Prognostic impact of lymphocytes in soft tissue sarcomas, PLoS One, 2011;6:e14611.
39. Berghuis D, Santos SJ, Baelde HJ, et al., Pro-inflammatory chemokine-chemokine receptor interactions within the Ewing sarcoma microenvironment determine CD8(+) T-lymphocyte infiltration and affect tumour progression, J Pathol, 2011;223:347–57.
40. Tseng WW, Malu S, Zhang M, et al., Analysis of the intratumoral adaptive immune response in well differentiated and dedifferentiated retroperitoneal liposarcoma, Sarcoma, 2015;2015:547460.
41. 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;46:357–65.
42. Feng Y, Shen J, Gao Y, et al., Expression of programmed death ligand 1 (PD-L1) and prevalence of tumor-infiltrating lymphocytes (TILs) in chordoma, Oncotarget, 2015;6:11139–49.
43. Fuji H, Arakawa A, Utsumi D, et al., Cd8+ tumor-infiltrating lymphocytes at primary sites as a possible prognostic factor of cutaneous angiosarcoma, Int J Cancer, 2014;134:2393–402.
44. Zitvogel L, Rusakiewicz S, Routy B, et al., Immunological off-target effects of imatinib, Nat Rev Clin Oncol, 2016;13:431–46.
45. Balachandran VP, Cavnar MJ, Zeng S, et al., Imatinib potentiates anti-tumor T cell response in gastrointestinal stromal tumor through the inhibition of IDO, Nat Med, 2011;17:1094–100.
46. Van der Bruggen P, Traversari C, Chomez P, et al., A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma, Science, 1991;254:1643–7.
47. Vigneron N, Human tumor antigens and cancer immunotherapy, Biomed Res Int, 2015;2015:948501.
48. Jacobs JFM, Brasseur F, Hulsbergen-van de Kaa CA, et al., Cancer-germline gene expression in pediatric solid tumors using quantitative real-time PCR, Int J Cancer, 2007;120:67–75.
49. Skubitz KM, Pambuccian S, Carlos JC, et al., Identification of heterogeneity among soft tissue sarcomas by gene expression profiles from different tumors, J Translat Med, 2008;6:23.
50. Maki RG, Soft tissue sarcoma as model disease to examine cancer immunotherapy, Curr Opin Oncol, 2001;13:270–4.
51. Snyder A, Makarov V, Merghoub T, et al., Genetic basis for clinical response to CTLA-4 blockade in melanoma, N Engl J Med, 2014;371:2189–99.
52. Brown SD, Warren RL, Gibb EA, et al., Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival, Genome Res, 2014;24:743–50.
53. Rizvi NA, Hellmann MD, Snyder A, et al., Cancer immunology. Mutational landscape determines sensitivity do PD-1 blockade in non-small cell lung cancer, Science, 2015;348:124–8.
54. McGranahan N, Furness AJS, Rosenthal R, et al., Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade, Science, 2016;351:1463–9.
55. Taylor BS, Barretina J, Maki RG, et al., Advances in sarcoma genomics and new therapeutic targets, Nat Rev Cancer, 2011;11:541–57.
56. Jain S, Xu R, Prieto VG, Lee P, Molecular classification of soft tissue sarcomas and its clinical applications, Int J Clin Exp Pathol, 2010;3:416–28.
57. Ohali A, Avigad S, Cohen IH, High frequency of genomic instability in Ewing family of tumors, Cancer Genet Cytogenet, 2004;150:50–6.
58. Davoli T, Uno H, Wooten EC, Elledge SJ, Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy, Science, 2017;355: pii: eaaf8389.
59. Swann JB, Vesely MD, Silva A, et al., Demonstration of inflammation-induced cancer and cancer immunoediting during primary tumorigenesis, Proc Natl Acad Sci U S A, 2008;105:652–6.
60. Gooden MJM, de Bock GH, Leffers N, et al., The prognostic influence of tumor-infiltrating lymphocytes in cancer: a systematic review with meta-analysis, Br J Cancer, 2011;105:93–103.
61. Tumeh PC, Harview CL, Yearley JH, et al., PD-1 blockade induces responses by inhibiting adaptive immune resistance, Nature, 2014;515:568–71.
62. Fridman WH, Pages F, Sautes-Fridman C, et al., The immune contexture in human tumors: Impact on clinical outcome, Nat Rev Cancer, 2012;12:298–306.
63. Daud AI, Wolchok JD, Robert C, et al., Programmed deathligand 1 expression and response to the anti-programmed death 1 antibody pembrolizumab in melanoma, J Clin Oncol, 2016;34:4102–9.
64. Kim JR, Moon YJ, Kwon KS, et al., Tumor infiltrating PD-1 positive lymphocytes and the expression of PD-L1 predict poor prognosis of soft tissue sarcomas, PLoS One, 2013;8:e82870.
65. Movva S, Wen W, Chen W, et al., Multi-platform profiling of over 2000 sarcomas: identification of biomarkers and novel therapeutic targets, Oncotarget, 2015;6:12234–47.
66. Paydas S, Bagir EK, Deveci MA, et al., Clinical and prognostic significance of PD-1 and PD-L1 expression in sarcomas. Med Oncol, 2016;33:93.
67. Toulmonde M, Adam J, Bessede A, et al., Integrative assessment of expression and prognostic value of PDL1, IDO and kynurenine in 371 primary soft tissue sarcomas with genomic complexity, J Clin Oncol, 2016;34 (suppl; abstr 11008).
68. Dasanu CA, Sustained clinico-radiologic response to anti-cytotoxic T lymphocyte antigen 4 antibody therapy in metastatic myxoid liposarcoma, J Oncol Pharm Practice, 2016;1–2.
69. McCaughan GJB, Fulham MJ, Mahar A, et al., Programmed cell death-1 blockade in recurrent disseminated Ewing sarcoma, J Hematol Oncol, 2016;9:48–53.
70. Miao D, Addegbe D, Rodig SJ, et al., Response and oligoclonal resistance to pembrolizumab in uterine leiomyosarcoma: genomic, neoantigen, and immunohistochemical evaluation, J Clin Oncol, 34,2016 (suppl; abstr 11043).
71. 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.
72. Merchant MS, Wright M, Baird K, et al., Phase I clinical trial of Ipilimumab in pediatric patients with advanced solid tumors, Clin Cancer Res, 2016;22:1364–70.
73. D’Angelo SP, Shoushtari NA, Keohan ML, et al., Combined KIT and CTLA-4 blockade in patients with refractory GIST and other advanced sarcomas: a phase Ib study of dasatinib plus ipilimumab, Clin Cancer Res, 2016; doi: 10.1158/1078-0432: Epub ahead of print.
74. Paoluzzi L, Cacavio A, Ghesani M, et al., Response to anti-PD1 therapy with nivolumab in metastatic sarcomas, Clin Sarcoma Res, 2016;6:24.
75. Tawbi HA, Burgess MA, Corwley J, et al., Safety and efficacy of PD-1 blockade using pembrolizumab in patients with advanced soft tissue (STS) and bone sarcomas (BS): results of SARC028—A multicenter phase II study, J Clin Oncol, 34, 2016 (suppl; abstr 11006)
76. Patnaik A, Kang SP, Rasco D, et al., A phase I study of pembrolizumab (MK-3475); anti-PD-1 monoclonal antibody) in patients with advanced solid tumors, Clin Cancer Res, 2015;21:4286–93.
77. George S, Barysauskas CM, Solomon S, et al., Phase 2 study of nivolumab in metastatic leiomyosarcoma of the uterus, J Clin Oncol 34, 2016 (suppl; abstr 11007)
78. Mellman I, Coukos G, Dranoff G, Cancer immunotherapy comes of age, Nature, 2011;480:480–9.
79. Blankenstein T, Coulie PG, Gilboa E, Jaffee EM, The determinants of tumor immunogenicity, Nat Rev Cancer, 2012;12:307–13.
80. Robbins PF, Morgan RA, Feldman AS, 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;29:917–24.
81. Davila ML, Brentjens R, Wang R, et al., How do CARs work? Early insights from recent clinical studies targeting CD19, Oncoimmunology, 2012;1:1577–83.
82. Lettieri CK, Hingorani P, Kolb EA, Progress of oncolytic viruses in sarcomas. Expert Rev, Anticancer Ther, 2012;12:229–42.
83. Nemunaitis J, Tong AW, Nemunaitis M, et al., A phase I study of telomerase-specific replication competent oncolytic adenovirus (telomelysin) for various solid tumors,Mol Ther, 2010;18:429–34.
84. Currier MA, Adams LC, Mahller YY, Cripe TP, Widespread intratumoral virus distribution with fractionated injection enables local control of large human rhabdomyosarcoma xenografts by oncolytic herpes simplex viruses, Cancer Gene Ther, 2005;12:407–16.
85. Puzanov I, Milhem MM, Minor D, et al., Talimogene laherparepvec in combination with Ipilimumab in previously untreated, unresectable stage IIIB-IV melanoma, J clin Oncol, 2016;34:2619–26.
86. Long GV, Dummer R, Ribas A, et al., Efficacy analysis of MASTERKEY-265 phase 1b study of talimogene laherparepvec (T-VEC) and pembrolizumab (pembro) for unresectable stage IIIB-IV melanoma, J Clin Oncol, 2016;34 (suppl; abstr 9568).
87. Krishnadas DK, Bao L, Bai F, et al., Decitabine facilitates imune recognition of sarcoma cells by upregulating CT antigens, MHC moleculaes, and ICAM-1, Tumour Biol, 2014;35:5353–62.
88. Krishnadas DK, Shusterman S, Bai F, et al., A phase I trial combining decitabine/dendritic cell vaccine targeting MAGE-A1, MAGE-A3 and NY-ESO-1 for children with relapsed or therapy-refractory neuroblastoma and sarcoma, Cancer Immunol Immunother, 2015;64:1251–60.
Keywords: Soft tissue sarcomas, immunotherapy, anti-PD-1, immune checkpoint blockade