Cancer Immunology, Immunotherapy

, Volume 61, Issue 7, pp 1149–1153 | Cite as

Uterine leiomyosarcoma diffusely express disialoganglioside GD2 and bind the therapeutic immunocytokine 14.18-IL2: implications for immunotherapy

  • Angela J. Ziebarth
  • Mildred A. Felder
  • Josephine Harter
  • Joseph P. Connor
Short Communication

Abstract

Uterine leiomyosarcoma comprises <1 % of uterine malignancies and is known for its clinically aggressive course. Extrapelvic recurrences are common and often lethal. No adjuvant therapies have been shown to significantly improve overall survival, highlighting the need for new and novel therapies. Our objective was to determine whether GD2-specific immunocytokine therapy may be explored for the treatment for uterine leiomyosarcoma. To do so, frozen tissue sections were obtained from the Gynecologic Oncology Group tumor bank and evaluated by immunohistochemistry (IHC) for GD2 expression using both the parent mouse monoclonal antibody 14G2A and immunocytokine 14.18-IL2 generated from the 14G2A sequence. Immunoreactivity was detected by avidin–biotin complex with DAB substrate. Specimens were reviewed by a pathologist with light microscopy and classified as negative, 1+, 2+ or 3+, compared to human melanoma cells as positive control and tissue incubated in the absence of primary antibody as negative control. GD2 was diffusely present in all evaluable samples. 10 tumors (67 %) demonstrated 3+ IHC intensity for GD2, two tumors (13 %) demonstrated 2+ intensity, and 3 (20 %) tumors demonstrated 1+ intensity. Eleven cases had sufficient tissue to assess 14.18-IL2 binding. All 11 cases bound 14.18-IL2 in a pattern identical to the parent antibody. Uterine leiomyosarcoma diffusely express GD2 and bind the therapeutic immunocytokine 14.18-IL2. This warrants further exploration to determine whether immunocytokine therapy may have a clinical role in the management of these aggressive tumors.

Keywords

14.18 Uterine leiomyosarcoma Immunotherapy GD2 Sarcoma 

Notes

Conflict of interest

The authors declare no conflict of interest.

References

  1. 1.
    Reed NS, Mangioni C, Malmstrom H et al (2008) Phase III randomised study to evaluate the role of adjuvant pelvic radiotherapy in the treatment of uterine sarcomas stages I and II: an European Organisation for Research and Treatment of Cancer Gynaecological Cancer Group Study (protocol 55874). Eur J Cancer 44(6):808–818PubMedCrossRefGoogle Scholar
  2. 2.
    Sleijfer S, Seynaeve C, Verweij J (2007) Gynaecological sarcomas. Curr Opin Oncol 19(5):492–496PubMedCrossRefGoogle Scholar
  3. 3.
    Cheung NK, Saarinen UM, Neely JE, Landmeier B, Donovan D, Coccia PF (1985) Monoclonal antibodies to a glycolipid antigen on human neuroblastoma cells. Cancer Res 45(6):2642–2649PubMedGoogle Scholar
  4. 4.
    Chang HR, Cordon-Cardo C, Houghton AN, Cheung NK, Brennan MF (1992) Expression of disialogangliosides GD2 and GD3 on human soft tissue sarcomas. Cancer 70(3):633–638PubMedCrossRefGoogle Scholar
  5. 5.
    Heiner JP, Miraldi F, Kallick S et al (1987) Localization of GD2-specific monoclonal antibody 3F8 in human osteosarcoma. Cancer Res 47(20):5377–5381PubMedGoogle Scholar
  6. 6.
    Batova A, Kamps A, Gillies SD, Reisfeld RA, Yu AL (1999) The Ch14.18-GM-CSF fusion protein is effective at mediating antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity in vitro. Clin Cancer Res 5(12):4259–4263PubMedGoogle Scholar
  7. 7.
    Hank JA, Surfus JE, Gan J et al (1996) Activation of human effector cells by a tumor reactive recombinant anti-ganglioside GD2 interleukin-2 fusion protein (ch14.18-IL2). Clin Cancer Res 2(12):1951–1959PubMedGoogle Scholar
  8. 8.
    Frost JD, Hank JA, Reaman GH et al (1997) A phase I/IB trial of murine monoclonal anti-GD2 antibody 14.G2a plus interleukin-2 in children with refractory neuroblastoma: a report of the Children’s Cancer Group. Cancer 80(2):317–333PubMedCrossRefGoogle Scholar
  9. 9.
    King DM, Albertini MR, Schalch H et al (2004) Phase I clinical trial of the immunocytokine EMD 273063 in melanoma patients. J Clin Oncol 22(22):4463–4473PubMedCrossRefGoogle Scholar
  10. 10.
    Saleh MN, Khazaeli MB, Wheeler RH et al (1992) Phase I trial of the chimeric anti-GD2 monoclonal antibody ch14.18 in patients with malignant melanoma. Hum Antibodies Hybridomas 3(1):19–24PubMedGoogle Scholar
  11. 11.
    Hank JA, Surfus JE, Gan J, Ostendorf A, Gillies SD, Sondel PM (2003) Determination of peak serum levels and immune response to the humanized anti-ganglioside antibody-interleukin-2 immunocytokine. Methods Mol Med 85:123–131PubMedGoogle Scholar
  12. 12.
    Kendra K, Gan J, Ricci M et al (1999) Pharmacokinetics and stability of the ch14.18-interleukin-2 fusion protein in mice. Cancer Immunol Immunother 48(5):219–229PubMedCrossRefGoogle Scholar
  13. 13.
    Osenga KL, Hank JA, Albertini MR et al (2006) A phase I clinical trial of the hu14.18-IL2 (EMD 273063) as a treatment for children with refractory or recurrent neuroblastoma and melanoma: a study of the Children’s Oncology Group. Clin Cancer Res 12(6):1750–1759PubMedCrossRefGoogle Scholar
  14. 14.
    Yu AL, Gilman AL, Ozkaynak MF et al (2010) Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med 363(14):1324–1334PubMedCrossRefGoogle Scholar
  15. 15.
    Gadducci A, Cosio S, Romanini A, Genazzani AR (2008) The management of patients with uterine sarcoma: a debated clinical challenge. Crit Rev Oncol Hematol 65(2):129–142PubMedCrossRefGoogle Scholar
  16. 16.
    Koivisto-Korander R, Leminen A, Heikinheimo O (2007) Mifepristone as treatment of recurrent progesterone receptor-positive uterine leiomyosarcoma. Obstet Gynecol 109(2 Pt2):512–514PubMedCrossRefGoogle Scholar
  17. 17.
    Verleye L, Ottevanger PB, van der Graaf W, Reed NS, Vergote I (2009) EORTC-GCG process quality indicators for ovarian cancer surgery. Eur J Cancer 45(4):517–526PubMedCrossRefGoogle Scholar
  18. 18.
    Muss HB, Bundy B, DiSaia PJ et al (1985) Treatment of recurrent or advanced uterine sarcoma. A randomized trial of doxorubicin versus doxorubicin and cyclophosphamide (a phase III trial of the Gynecologic Oncology Group). Cancer 55(8):1648–1653PubMedCrossRefGoogle Scholar
  19. 19.
    Omura GA, Major FJ, Blessing JA et al (1983) A randomized study of adriamycin with and without dimethyl triazenoimidazole carboxamide in advanced uterine sarcomas. Cancer 52(4):626–632PubMedCrossRefGoogle Scholar
  20. 20.
    Sutton G, Blessing J, Hanjani P, Kramer P (2005) Phase II evaluation of liposomal doxorubicin (Doxil) in recurrent or advanced leiomyosarcoma of the uterus: a Gynecologic Oncology Group study. Gynecol Oncol 96(3):749–752PubMedCrossRefGoogle Scholar
  21. 21.
    Thigpen T, Blessing JA, Yordan E, Valea F, Vaccarello L (1996) Phase II trial of etoposide in leiomyosarcoma of the uterus: a Gynecologic Oncology Group study. Gynecol Oncol 63(1):120–122PubMedCrossRefGoogle Scholar
  22. 22.
    Leyvraz S, Zweifel M, Jundt G et al (2006) Long-term results of a multicenter SAKK trial on high-dose ifosfamide and doxorubicin in advanced or metastatic gynecologic sarcomas. Ann Oncol 17(4):646–651PubMedCrossRefGoogle Scholar
  23. 23.
    Hensley ML, Ishill N, Soslow R et al (2009) Adjuvant gemcitabine plus docetaxel for completely resected stages I-IV high grade uterine leiomyosarcoma: results of a prospective study. Gynecol Oncol 112(3):563–567PubMedCrossRefGoogle Scholar
  24. 24.
    Hensley ML, Blessing JA, Mannel R, Rose PG (2008) Fixed-dose rate gemcitabine plus docetaxel as first-line therapy for metastatic uterine leiomyosarcoma: a Gynecologic Oncology Group phase II trial. Gynecol Oncol 109(3):329–334PubMedCrossRefGoogle Scholar
  25. 25.
    Brignole C, Marimpietri D, Gambini C, Allen TM, Ponzoni M, Pastorino F (2003) Development of Fab’ fragments of anti-GD(2) immunoliposomes entrapping doxorubicin for experimental therapy of human neuroblastoma. Cancer Lett 197(1–2):199–204PubMedCrossRefGoogle Scholar
  26. 26.
    Ragupathi G, Livingston PO, Hood C et al (2003) Consistent antibody response against ganglioside GD2 induced in patients with melanoma by a GD2 lactone-keyhole limpet hemocyanin conjugate vaccine plus immunological adjuvant QS-21. Clin Cancer Res 9(14):5214–5220PubMedGoogle Scholar
  27. 27.
    Shusterman S, London WB, Gillies SD et al (2010) Antitumor activity of hu14.18-IL2 in patients with relapsed/refractory neuroblastoma: a Children’s Oncology Group (COG) phase II study. J Clin Oncol 28(33):4969–4975PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Angela J. Ziebarth
    • 1
  • Mildred A. Felder
    • 2
  • Josephine Harter
    • 3
  • Joseph P. Connor
    • 1
    • 2
  1. 1.Division of Gynecologic Oncology, Department of Obstetrics and GynecologyUniversity of Alabama at BirminghamBirminghamUSA
  2. 2.Division of Gynecologic Oncology, Department of Obstetrics and GynecologyUniversity of Wisconsin MadisonMadisonUSA
  3. 3.Department of PathologyUniversity of Wisconsin MadisonMadisonUSA

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