Skip to main content

Advertisement

SpringerLink
Log in

Interleukin-2 and granulocyte–macrophage–colony-stimulating factor immunomodulation with high-dose chemotherapy and autologous hematopoietic stem cell transplantation for patients with metastatic breast cancer

  • Original Article
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

Immunomodulation with cytokines was used to improve the result of high-dose chemotherapy (HDC)/autologous hematopoietic stem cell transplantation (AHST). We examined the use of IL-2 and growth factors for mobilization, ex vivo activation of peripheral blood stem cell (PBSC) and maintenance therapy after HDC/AHST in metastatic breast cancer. Eligible patients with metastatic breast cancer for HDC/AHST were assigned to 1 of 3 protocols for PBSC mobilization: G-CSF (group 1); IL-2 + G-CSF (group 2); or IL-2 + G-CSF + GM–CSF (group 3). HDC with cyclophosphamide, carmustine and thiotepa was given from day −7 to −5. PBSCs were treated ex vivo with IL-2 for 24 h and reinfused on day 0. Maintenance therapy included low-dose IL-2, followed by 2 courses of intermediate-dose IL-2. GM–CSF was given from day 1 until neutrophil recovery. Thirty-four patients (10 in group 1, 14 in group 2, and 10 in group 3) were included. Comparable numbers of CD34+ cells were collected from all 3 groups; incremental increases of CD3+ cells were collected from groups 1 to 2 and to 3 (p = 0.03). Major adverse effects from IL-2 were fever, hypotension and fatigue; no treatment-related mortality was seen. At a median follow-up of 790.5 days (range 150–2,722 days), median progression-free survival was 434 days and median overall survival was 1,432 days. Estimated 3-year progression-free and overall survival rates were 31 and 57%. Our study suggested that the use of IL-2 and growth factors immunomodulation with HDC/AHST was feasible with comparable survival rates.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Greenberg PA, Hortobagyi GN, Smith TL, Ziegler LD, Frye DK, Buzdar AU. Long-term follow-up of patients with complete remission following combination chemotherapy for metastatic breast cancer. J Clin Oncol. 1996;14:2197–205.

    Article  CAS  PubMed  Google Scholar 

  2. Eder JP, Antman K, Peters W, Henner WD, Elias A, Shea T, et al. High-dose combination alkylating agent chemotherapy with autologous bone marrow support for metastatic breast cancer. J Clin Oncol. 1986;4:1592–7.

    Article  CAS  PubMed  Google Scholar 

  3. Peters WP, Shpall EJ, Jones RB, Olsen GA, Bast RC, Gockerman JP, et al. High-dose combination alkylating agents with bone marrow support as initial treatment for metastatic breast cancer. J Clin Oncol. 1988;6:1368–76.

    Article  CAS  PubMed  Google Scholar 

  4. Williams SF, Mick R, Desser R, Golick J, Beschorner J, Bitran JD. High-dose consolidation therapy with autologous stem cell rescue in stage IV breast cancer. J Clin Oncol. 1989;7:1824–30.

    Article  CAS  PubMed  Google Scholar 

  5. Kennedy MJ, Beveridge RA, Rowley SD, Gordon GB, Abeloff MD, Davidson NE. High-dose chemotherapy with reinfusion of purged autologous bone marrow following dose-intense induction as initial therapy for metastatic breast cancer. J Natl Cancer Inst. 1991;83:920–6.

    Article  CAS  PubMed  Google Scholar 

  6. Williams SF, Gilewski T, Mick R, Bitran JD. High-dose consolidation therapy with autologous stem cell rescue in stage IV breast cancer: follow-up report. J Clin Oncol. 1992;10:1743–7.

    Article  CAS  PubMed  Google Scholar 

  7. Antman K, Ayash L, Elias A, Wheeler C, Hunt M, Eder JP, et al. A phase II study of high-dose cyclophosphamide, thiotepa, and carboplatin with autologous marrow support in women with measurable advanced breast cancer responding to standard-dose therapy. J Clin Oncol. 1992;10:102–10.

    Article  CAS  PubMed  Google Scholar 

  8. Antman KH, Rowlings PA, Vaughan WP, Pelz CJ, Fay JW, Fields KK, et al. High-dose chemotherapy with autologous hematopoietic stem cell support for breast cancer in North America. J Clin Oncol. 1997;15:1870–9.

    Article  CAS  PubMed  Google Scholar 

  9. Weaver CH, West WH, Schwartzberg LS, Alberico T, Leff R, Greco FA, et al. Induction, mobilization of peripheral blood stem cells (PBSC), high-dose chemotherapy and PBSC infusion in patients with untreated stage IV breast cancer: outcomes by intent to treat analyses. Bone Marrow Transplant. 1997;19:661–70.

    Article  CAS  PubMed  Google Scholar 

  10. Bensinger WI, Schiffman KS, Holmberg L, Appelbaum FR, Maziarz R, Montgomery P, et al. High-dose busulfan, melphalan, thiotepa and peripheral blood stem cell infusion for the treatment of metastatic breast cancer. Bone Marrow Transplant. 1997;19:1183–9.

    Article  CAS  PubMed  Google Scholar 

  11. Ljungman P, Bjorkstrand B, Fornander T, Hoglund M, Juliusson G, Lindman H, et al. High-dose chemotherapy with autologous stem cell support in patients with responding stage IV breast cancer. Bone Marrow Transplant. 1998;22:445–8.

    Article  CAS  PubMed  Google Scholar 

  12. Crump M, Gluck S, Tu D, Stewart D, Levine M, Kirkbride P, et al. Randomized trial of high-dose chemotherapy with autologous peripheral-blood stem cell support compared with standard-dose chemotherapy in women with metastatic breast cancer. NCIC MA.16. J Clin Oncol. 2008;26:37–43.

    Article  CAS  PubMed  Google Scholar 

  13. Roche H, Viens P, Biron P, Lotz JP, Asselain B. High-dose chemotherapy for breast cancer: the French PEGASE experience. Cancer Control. 2003;10:42–7.

    Article  PubMed  Google Scholar 

  14. Biron P, Durand M, Roche H, Delozier T, Battista C, Fargeot P, et al. Pegase 3: a prospective randomized phase III trial of FEC with or without high-dose thiotepa, cyclophosphamide and autologous stem cell transplantation in first-line treatment of metastatic breast cancer. Bone Marrow Transplant. 2008;41:555–62.

    Article  CAS  PubMed  Google Scholar 

  15. Lotz JP, Cure H, Janvier M, Asselain B, Morvan F, Legros M, et al. High-dose chemotherapy with haematopoietic stem cell transplantation for metastatic breast cancer patients: final results of the French multicentric randomised CMA/PEGASE 04 protocol. Eur J Cancer. 2005;41:71–80.

    Article  CAS  PubMed  Google Scholar 

  16. Vredenburgh JJ, Coniglio D, Broadwater G, Jones RB, Ross M, Shpall EJ, et al. Consolidation with high-dose combination alkylating agents with bone marrow transplantation significantly improves disease-free survival in hormone-insensitive metastatic breast cancer in complete remission compared with intensive standard-dose chemotherapy alone. Biol Blood Marrow Transplant. 2006;12:195–203.

    Article  CAS  PubMed  Google Scholar 

  17. Vredenburgh JJ, Madan B, Coniglio D, Ross M, Broadwater G, Niedzwiecki D, et al. A randomized phase III comparative trial of immediate consolidation with high-dose chemotherapy and autologous peripheral blood progenitor cell support compared to observation with delayed consolidation in women with metastatic breast cancer and only bone metastases following intensive induction chemotherapy. Bone Marrow Transplant. 2006;37:1009–15.

    Article  CAS  PubMed  Google Scholar 

  18. Stadtmauer EA, O’Neill A, Goldstein LJ, Crilley PA, Mangan KF, Ingle JN, et al. Conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem cell transplantation for metastatic breast cancer. Philadelphia Bone Marrow Transplant Group. N Engl J Med. 2000;342:1069–76.

    Article  CAS  PubMed  Google Scholar 

  19. Ueno NT, Rondon G, Mirza NQ, Geisler DK, Anderlini P, Giralt SA, et al. Allogeneic peripheral-blood progenitor-cell transplantation for poor-risk patients with metastatic breast cancer. J Clin Oncol. 1998;16:986–93.

    Article  CAS  PubMed  Google Scholar 

  20. Ueno NT, Cheng YC, Rondon G, Tannir NM, Gajewski JL, Couriel DR, et al. Rapid induction of complete donor chimerism by the use of a reduced-intensity conditioning regimen composed of fludarabine and melphalan in allogeneic stem cell transplantation for metastatic solid tumors. Blood. 2003;102:3829–36.

    Article  CAS  PubMed  Google Scholar 

  21. Bishop MR, Fowler DH, Marchigiani D, Castro K, Kasten-Sportes C, Steinberg SM, et al. Allogeneic lymphocytes induce tumor regression of advanced metastatic breast cancer. J Clin Oncol. 2004;22:3886–92.

    Article  PubMed  Google Scholar 

  22. Lister J, Rybka WB, Donnenberg AD, deMagalhaes-Silverman M, Pincus SM, Bloom EJ, et al. Autologous peripheral blood stem cell transplantation and adoptive immunotherapy with activated natural killer cells in the immediate posttransplant period. Clin Cancer Res. 1995;1:607–14.

    CAS  PubMed  Google Scholar 

  23. Meehan KR, Badros A, Frankel SR, Cahill R, Areman E, Jenson M, et al. A pilot study evaluating interleukin-2-activated hematopoietic stem cell transplantation for hematologic malignancies. J Hematother. 1997;6:457–64.

    CAS  PubMed  Google Scholar 

  24. Robinson N, Benyunes MC, Thompson JA, York A, Petersdorf S, Press O, et al. Interleukin-2 after autologous stem cell transplantation for hematologic malignancy: a phase I/II study. Bone Marrow Transplant. 1997;19:435–42.

    Article  CAS  PubMed  Google Scholar 

  25. Margolin K, Forman SJ. Immunotherapy with interleukin-2 after hematopoietic cell transplantation for hematologic malignancy. Cancer J Sci Am. 2000;6(Suppl 1):S33–8.

    PubMed  Google Scholar 

  26. Areman EM, Mazumder A, Kotula PL, Verma UN, Rajagopal C, Hancock S, et al. Hematopoietic potential of IL-2-cultured peripheral blood stem cells from breast cancer patients. Bone Marrow Transplant. 1996;18:521–5.

    CAS  PubMed  Google Scholar 

  27. Gravis G, Viens P, Vey N, Blaise D, Stoppa AM, Olive D, et al. Pilot study of immunotherapy with interleukin-2 after autologous stem cell transplantation in advanced breast cancers. Anticancer Res. 2000;20:3987–91.

    CAS  PubMed  Google Scholar 

  28. Meehan KR, Verma UN, Cahill R, Frankel S, Areman EM, Sacher RA, et al. Interleukin-2-activated hematopoietic stem cell transplantation for breast cancer: investigation of dose level with clinical correlates. Bone Marrow Transplant. 1997;20:643–51.

    Article  CAS  PubMed  Google Scholar 

  29. Meehan KR, Arun B, Gehan EA, Berberian B, Sulica V, Areman EM, et al. Immunotherapy with interleukin-2 and alpha-interferon after IL-2-activated hematopoietic stem cell transplantation for breast cancer. Bone Marrow Transplant. 1999;23:667–73.

    Article  CAS  PubMed  Google Scholar 

  30. Toh HC, McAfee SL, Sackstein R, Multani P, Cox BF, Garcia-Carbonero R, et al. High-dose cyclophosphamide + carboplatin and interleukin-2 (IL-2) activated autologous stem cell transplantation followed by maintenance IL-2 therapy in metastatic breast carcinoma: a phase II study. Bone Marrow Transplant. 2000;25:19–24.

    Article  CAS  PubMed  Google Scholar 

  31. Burns LJ, Weisdorf DJ, DeFor TE, Repka TL, Ogle KM, Hummer C, et al. Enhancement of the anti-tumor activity of a peripheral blood progenitor cell graft by mobilization with interleukin 2 plus granulocyte colony-stimulating factor in patients with advanced breast cancer. Exp Hematol. 2000;28:96–103.

    Article  CAS  PubMed  Google Scholar 

  32. Sosman JA, Stiff P, Moss SM, Sorokin P, Martone B, Bayer R, et al. Pilot trial of interleukin-2 with granulocyte colony-stimulating factor for the mobilization of progenitor cells in advanced breast cancer patients undergoing high-dose chemotherapy: expansion of immune effectors within the stem cell graft and post-stem cell infusion. J Clin Oncol. 2001;19:634–44.

    Article  CAS  PubMed  Google Scholar 

  33. Burns LJ, Weisdorf DJ, DeFor TE, Vesole DH, Repka TL, Blazar BR, et al. IL-2-based immunotherapy after autologous transplantation for lymphoma and breast cancer induces immune activation and cytokine release: a phase I/II trial. Bone Marrow Transplant. 2003;32:177–86.

    Article  CAS  PubMed  Google Scholar 

  34. Savary CA, Grazziutti ML, Melichar B, Przepiorka D, Freedman RS, Cowart RE, et al. Multidimensional flow-cytometric analysis of dendritic cells in peripheral blood of normal donors and cancer patients. Cancer Immunol Immunother. 1998;45:234–40.

    Article  CAS  PubMed  Google Scholar 

  35. Hakim AA. Peripheral blood lymphocytes from patients with cancer lack interleukin-2 receptors. Cancer. 1988;61:689–701.

    Article  CAS  PubMed  Google Scholar 

  36. Cordon-Cardo C, Fuks Z, Drobnjak M, Moreno C, Eisenbach L, Feldman M. Expression of HLA-A, B, C antigens on primary and metastatic tumor cell populations of human carcinomas. Cancer Res. 1991;51:6372–80.

    CAS  PubMed  Google Scholar 

  37. Yamasaki S, Kan N, Mise K, Harada T, Ichinose Y, Moriguchi Y, et al. Cellular interaction against autologous tumor cells between IL-2-cultured lymphocytes and fresh peripheral blood lymphocytes in patients with breast cancer given immuno-chemotherapy. Biotherapy. 1993;6:63–71.

    Article  CAS  PubMed  Google Scholar 

  38. Konjevic G, Spuzic I. Stage dependence of NK cell activity and its modulation by interleukin 2 in patients with breast cancer. Neoplasma. 1993;40:81–5.

    CAS  PubMed  Google Scholar 

  39. Arduino S, Tessarolo M, Bellino R, Colombatto S, Leo L, Wierdis T, et al. Reduced IL-2 level concentration in patients with breast cancer as a possible risk factor for relapse. Eur J Gynaecol Oncol. 1996;17:535–7.

    CAS  PubMed  Google Scholar 

  40. Chen-Woan M, Delaney CP, Fournier V, Wakizaka Y, Murase N, Fung J, et al. A new protocol for the propagation of dendritic cells from rat bone marrow using recombinant GM–CSF, and their quantification using the mAb OX-62. J Immunol Methods. 1995;178:157–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Szabolcs P, Feller ED, Moore MA, Young JW. Progenitor recruitment and in vitro expansion of immunostimulatory dendritic cells from human CD34+ bone marrow cells by c-kit-ligand, GM–CSF, and TNF alpha. Adv Exp Med Biol. 1995;378:17–20.

    Article  CAS  PubMed  Google Scholar 

  42. Caux C, Vanbervliet B, Massacrier C, Dezutter-Dambuyant C, de Saint-Vis B, Jacquet C, et al. CD34+ hematopoietic progenitors from human cord blood differentiate along two independent dendritic cell pathways in response to GM–CSF + TNF alpha. J Exp Med. 1996;184:695–706.

    Article  CAS  PubMed  Google Scholar 

  43. Montemurro F, Rondon G, Munsell M, Smith TL, Donato ML, Gajewski JL, et al. Predicting outcome based on Swenerton score in patients with metastatic breast cancer undergoing high-dose chemotherapy and autologous hematopoietic stem cell transplantation: implications for patient selection. Biol Blood Marrow Transplant. 2003;9:330–40.

    Article  PubMed  Google Scholar 

  44. Nitz UA, Mohrmann S, Fischer J, Lindemann W, Berdel WE, Jackisch C, et al. Comparison of rapidly cycled tandem high-dose chemotherapy plus peripheral-blood stem cell support versus dose-dense conventional chemotherapy for adjuvant treatment of high-risk breast cancer: results of a multicentre phase III trial. Lancet. 2005;366:1935–44.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Christine F. Wogan, MS, for her excellent help in developing this manuscript. This research work was supported in part by Berlex Inc. (to N.T.U).

Author information

Authors and Affiliations

  1. Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

    Yee Chung Cheng, Gabriela Rondón, Leah F. Sanchez, John D. McMannis, Daniel R. Couriel, Marcos J. de Lima, Chitra Hosing, Issa F. Khouri, Sergio A. Giralt, Richard E. Champlin & Naoto T. Ueno

  2. Department of Breast Medical Oncology, Unit 1354, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA

    Naoto T. Ueno

  3. Division of Neoplastic Diseases and Related Disorders, Medical College of Wisconsin, Milwaukee, WI, USA

    Yee Chung Cheng

Authors
  1. Yee Chung Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gabriela Rondón
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Leah F. Sanchez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. John D. McMannis
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Daniel R. Couriel
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Marcos J. de Lima
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chitra Hosing
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Issa F. Khouri
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sergio A. Giralt
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Richard E. Champlin
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Naoto T. Ueno
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Naoto T. Ueno.

About this article

Cite this article

Cheng, Y.C., Rondón, G., Sanchez, L.F. et al. Interleukin-2 and granulocyte–macrophage–colony-stimulating factor immunomodulation with high-dose chemotherapy and autologous hematopoietic stem cell transplantation for patients with metastatic breast cancer. Int J Hematol 90, 627–634 (2009). https://doi.org/10.1007/s12185-009-0439-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-009-0439-6

Keywords

Search

Navigation