Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Post-Transplant Events

Early recovery of aggressive cytotoxic cells and improved immune resurgence with post-transplant immunotherapy for multiple myeloma

Bone Marrow Transplantation volume 39, pages 695–703 (2007)Cite this article

Abstract

A phase I/II trial evaluated early administration and dose escalation of interleukin (IL)-2 with granulocyte macrophage colony stimulating factor (GM-CSF) post-transplant. Following melphalan (200 mg/m2) and an autologous transplant, IL-2 was initiated (day 0) and continued for 4 weeks. GM-CSF (250 mcg/m2/day) began on day 5. Fifteen of 19 patients completed therapy. No treatment-related deaths occurred. IL-2 (1 × 106 IU/m2/day) was not tolerated in two of six patients due to ⩾grade 3 fatigue/diarrhea (n=1) or supraventricular tachycardia (n=1). The maximum tolerated dose of IL-2 was 6 × 105 IU/m2/day; this dose was well tolerated by 11 of 13 patients. Neutrophil and platelet engraftment occurred on day 13 (median; range 10–17 days) and day 13 (median; range 0–74 days), respectively. When compared to control patients, there was a marked increase in the number of CD3+ T cells (P=0.005), CD4+ T cells (P=0.01), CD8+ T cells (P=0.001) and CD4+CD25+Treg cells (P=0.015) post-transplant. Cytotoxicity directed against myeloma cells was markedly increased when compared to control patients (P=0.017). This unique trial design using early administration of IL-2 with GM-CSF during the period of lymphodepletion, demonstrated a marked increase in the number and function of early cytotoxic effector T cells, without suppression of engraftment.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med 1996; 335: 91–97.

    Article  CAS  Google Scholar 

  2. Child J, Morgan G, Davies F, Owen R, Bell S, Phil D et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. New Eng J Med 2003; 348: 1875–1883.

    Article  CAS  Google Scholar 

  3. Dudley ME, Wunderlich JR, Robbins PF, Yang JC, Hwu P, Schwartzentruber DJ et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 2002; 298: 850–854.

    Article  CAS  Google Scholar 

  4. Dudley ME, Wunderlich J, Nishimura MI, Yu D, Yang JC, Topalian SL et al. Adoptive transfer of cloned melanoma-reactive T lymphocytes for the treatment of patients with metastatic melanoma. J Immunother 2001; 24: 363–373.

    Article  CAS  Google Scholar 

  5. Klebanoff CA, Khong HT, Antony PA, Palmer DC, Restifo NP . Sinks, suppressors and antigen presenters: how lymphodepletion enhances T cell-mediated tumor immunotherapy. Trends Immunol 2005; 26: 111–117.

    Article  CAS  Google Scholar 

  6. Porrata LF, Gertz MA, Inwards DJ, Litzow MR, Lacy MQ, Tefferi A et al. Early lymphocyte recovery predicts superior survival after autologous hematopoietic stem cell transplantation in multiple myeloma or non-Hodgkin lymphoma. Blood 2001; 98: 579–585.

    Article  CAS  Google Scholar 

  7. Powles R, Singhal S, Treleaven J, Kulkarni S, Horton C, Mehta J . Identification of patients who may benefit from prophylactic immunotherapy after bone marrow transplantation for acute myeloid leukemia on the basis of lymphocyte recovery early after transplantation. Blood 1998; 91: 3481–3486.

    CAS  PubMed  Google Scholar 

  8. Pavletic ZS, Joshi SS, Pirruccello SJ, Tarantolo SR, Kollath J, Reed EC et al. Lymphocyte reconstitution after allogeneic blood stem cell transplantation for hematologic malignancies. Bone Marrow Transplant 1998; 21: 33–41.

    Article  CAS  Google Scholar 

  9. Maurizio M, Chiriva-Internati, Du J, Cannon M, Barlogie B, Yi Q et al. Myeloma-reactive allospecific cytotoxic T lymphocytes lyse target cells via the granule exocytosis pathway. Br J Haemat 2001; 112: 410–420.

    Article  Google Scholar 

  10. Wen Y, Barlogie B, Yi Q . Idiotype-specific cytotoxic T lymphocytes in multiple myeloma: evidence for their capacity to lyse autologous primary tumor cells. Blood 2001; 97: 1750–1755.

    Article  CAS  Google Scholar 

  11. Hayashi T, Hideshima T, Akiyama M, Raje N, Richardson P, Chauhan D et al. Ex vivo expansion of multiple myeloma-specific cytotoxic T lymphocytes. Blood 2003; 102: 1435–1442.

    Article  CAS  Google Scholar 

  12. Alvarnas JC, Linn Y, Hope EG, Negrin RS . Expansion of cytotoxic CD3+CD56+ cells from peripheral blood progenitor cells of patients undergoing autologous hematopoietic cell transplantation. Biol Blood Marrow Transplant 2001; 7: 216–222.

    Article  CAS  Google Scholar 

  13. Verneris MR, Ito M, Baker J, Arshi A, Negrin RS, Shizuru JA . Engineering hematopoietic grafts: purified allogeneic hematopoietic stem cells plus expanded CD8+ NKT cells in the treatment of lymphoma. Biol Blood Marrow Transplant 2001; 7: 532–542.

    Article  CAS  Google Scholar 

  14. Meehan KR, Verma UN, Rajogopal C, Cahill R, Frankel S, Mazumder A . Stem cell transplantation with chemoradiotherapy myeloablation and interleukin-2. J Infus Chemother 1996; 6: 28–32.

    CAS  PubMed  Google Scholar 

  15. 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: 643–651.

    Article  CAS  Google Scholar 

  16. Meehan KR, Badros A, Frankel SR, Cahill R, Areman E, Jenson M et al. A pilot study evaluating IL-2 activated hematopoietic stem cell transplantation for hematologic malignancies. J. Hematotherapy 1997; 6: 457–464.

    Article  CAS  Google Scholar 

  17. Verma UN, Meehan KR, Mazumder A . Post-bone marrow transplant use of immunotherapy. Cancer Treat Res 1997; 77: 27–55.

    Article  CAS  Google Scholar 

  18. Meehan KR, Arun B, Gehan EA, Berberian B, Sulica V, Areman EM et al. Immunotherapy with interleukin-2 and alpha-interferon following IL-2 activated hematopoietic stem cell transplantation for breast cancer. Bone Marrow Transplant 1999; 23: 667–673.

    Article  CAS  Google Scholar 

  19. Porrata LF, Gertz MA, Geyer SM, Litzow MR, Gastineau DA, Moore SB et al. The dose of infused lymphocytes in the autograft directly correlates with clinical outcome after autologous peripheral blood heamtopoietic stem cell transplantation in multiple myeloma. Leukemia 2004; 18: 1085–1092.

    Article  CAS  Google Scholar 

  20. Kay NE, Leong TL, Bone N, Vesole DH, Greipp PR, Ness BV et al. Blood levels of immune cells predict survival in myeloma patients: Results of an Eastern Cooperative Oncology Group phase III trial for newly diagnosed multiple myeloma patients. Blood 2001; 98: 23–28.

    Article  CAS  Google Scholar 

  21. Ito M, Shizuru J . Graft-vs-Lymphoma effect in an allogeneic hematopoietic stem cell transplantation model. Biol Blood Marrow Transplant 1999; 5: 357–368.

    Article  CAS  Google Scholar 

  22. Rosinski SL, McNiece IK, Shpall EJ, Clough N, Russell P, Blunk B et al. Prognostic analysis of pre-transplant peripheral T-cell levels in patients receiving an autologous hematopoietic progenitor-cell transplant. Bone Marrow Transplant 2005; 36: 425–430.

    Article  CAS  Google Scholar 

  23. Hess AD, Bright EC, Thoburn C, Vogelsang GB, Jones RJ, Kennedy MJ . Specificity of effector T lymphocytes in autologous graft-versus-host disease: Role of the major histocompatibility complex class II invariant chain peptide. Blood 1997; 89: 2203–2209.

    CAS  PubMed  Google Scholar 

  24. Porrata LF, Gertz MA, Litzow MR, Lacy MQ, Dispenzieri A, Inwards DJ et al. Early lymphocyte recovery predicts superior survival after autologous hematopoietic stem cell transplantation for patients with primary systemic amyloidosis. Clin Cancer Res 2005; 11: 1210–1218.

    CAS  PubMed  Google Scholar 

  25. Zhang H, Chua KS, Guimond M, Kapoor V, Brown MV, Fleisher TA et al. Lymphopenia and interleukin-2 therapy alter hemostasis of CD4+ CD25+ regulatory T cells. Nat Med 2005; 11: 1238–1243.

    Article  CAS  Google Scholar 

  26. Wang L, Shu S, Plautz G . Host lymphodepletion augments T cell adoptive immunotherapy through enhanced intratumoral proliferation of effector cells. Cancer Res 2005; 65: 9547–9554.

    Article  CAS  Google Scholar 

  27. Zorn E, Nelson EA, Mohseni M, Porcheray F, Kim H, Litsa D et al. IL-2 regulates FOXP3 expression in human CD4+ CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo. Blood 2006; 108: 1571–1579.

    Article  CAS  Google Scholar 

  28. Figlin RA, Thompson JA, Bukowski RM, Vogelzang NJ, Novick AC, Lange P et al. Multicenter, randomized, phase III trial of CD8(+) tumor-infiltrating lymphocytes in combination with recombinant interleukin-2 in metastatic renal cell carcinoma. J Clin Oncol 1999; 17: 2521–2529.

    Article  CAS  Google Scholar 

  29. Hellstrom KE, Hellstrom I, Kant JA, Tamerius JD . Regression and inhibition of sarcoma growth by interference with a radiosensitive T-cell population. J Exp Med 1978; 148: 799.

    Article  CAS  Google Scholar 

  30. Kirkwood JM . Systemic therapy of melanoma. Curr Opin Oncol 1994; 6: 204–211.

    Article  CAS  Google Scholar 

  31. Massumoto C, Benyunes MC, Sale G, Beauchamp M, York A, Thompson JA et al. Close simulation of acute graft-versus-host disease by interleukin-2 administered after autologous bone marrow transplantation for hematologic malignancy. Bone Marrow Transplant 1996; 17: 351–356.

    CAS  PubMed  Google Scholar 

  32. Robinson N, Benyunes MC, Thompson JA, York A, Petersdorf S, Press O et al. Interleukin-2 after autologous stem cell transplantation for hematologic malignancies: a phase I/lI study. Bone Marrow Transplant 1997; 19: 435–442.

    Article  CAS  Google Scholar 

  33. Fefer A, Robinson N, Benyunes MC, Bensinger WI, Press O, Thompson JA et al. Interleukin-2 therapy after bone marrow or stem cell transplantation for hematologic malignancies. Cancer J Sci Am 1997; 3 (Suppl 1): S48–S53.

    PubMed  Google Scholar 

  34. deMagalhaes-Silverman M, Donnenberg A, Lembersky B, Elder E, Lister J, Rybka W et al. Post transplant adoptive immunotherapy with activated natural killer cells in patients with metastatic breast cancer. J Immunother 2000; 23: 154–160.

    Article  CAS  Google Scholar 

  35. Vivancos P, Granena Jr A, Sarra J, Granena A . Treatment with interleukin-2 (IL-2) and interferon (IFN-alpha 2b) after autologous bone marrow or peripheral blood stem cell transplantation in onco-hematological malignancies with a high risk of relapse. Bone Marrow Transplant 1999; 23: 169–172.

    Article  CAS  Google Scholar 

  36. Maraninchi D, Vey N, Viens P, Stoppa AM, Archimbaud E, Attal M et al. A Phase II study of IL-2 in 49 pts with relapsed or refractory leukemia. Leuk Lymphoma 1998; 31: 343–349.

    Article  CAS  Google Scholar 

  37. Ragnhammar P, Frodin JE, Trotta PP, Mellstedt H . Cytotoxicity of white cells activated by granulocyte-colony stimulating factor, GM-CSF and macrophage-CSF against tumor cells in the presence of various monoclonal antibodies. Cancer Immunol Immunother 1994; 39: 254–262.

    Article  CAS  Google Scholar 

  38. Spitler LE, Grossbard ML, Ernstoff MS, Silver G, Jacobs M, Hayes FA et al. Adjuvant therapy of stage III and IV malignant melanoma using granulocyte-macrophage colony-stimulating factor. J Clin Oncol 2000; 18: 1614–1621.

    Article  CAS  Google Scholar 

  39. Wing EJ, Magee DM, Whiteside TL, Kaplan SS, Shadduck RK . Recombinant human granulocyte-macrophage colony-stimulating factor enhances monocyte cytotoxicity and secretion of tumor necrosis factor alpha and interferon in cancer patients. Blood 1989; 73: 643–646.

    CAS  PubMed  Google Scholar 

  40. Gazitt Y . Immunologic profiles of effector cells and peripheral blood stem cells mobilized with different hematopoietic growth factors. Stem Cells 2001; 18: 390–398.

    Article  Google Scholar 

Download references

Acknowledgements

This study was sponsored in part by a grant from the Hitchcock Foundation, Dartmouth Medical School and the Dartmouth-Hitchcock Medical Center (KRM), Leukemia and Lymphoma Society Translational Research Grant 6061-06 (KRM), R21 CA112761 (KRM, MSE) and R01CA095648 (MSE).

Author information

Authors and Affiliations

  1. Bone Marrow Transplant Program, Dartmouth Hitchcock Medical Center, Dartmouth Medical School and the Norris Cotton Cancer Center, Lebanon, NH, USA

    K R Meehan, J Wu, E Bengtson, J Hill, P Ely & M Kendall

  2. The Cellular Therapy Center and Blood Bank/Transfusion Medicine Service, Dartmouth Hitchcock Medical Center, Dartmouth Medical School and the Norris Cotton Cancer Center, Lebanon, NH, USA

    Z Szczepiorkowski

  3. Section of Hematology and Oncology, Dartmouth Hitchcock Medical Center, Dartmouth Medical School and the Norris Cotton Cancer Center, Lebanon, NH, USA

    M S Ernstoff

Authors
  1. K R Meehan
    View author publications

    Search author on:PubMed Google Scholar

  2. J Wu
    View author publications

    Search author on:PubMed Google Scholar

  3. E Bengtson
    View author publications

    Search author on:PubMed Google Scholar

  4. J Hill
    View author publications

    Search author on:PubMed Google Scholar

  5. P Ely
    View author publications

    Search author on:PubMed Google Scholar

  6. Z Szczepiorkowski
    View author publications

    Search author on:PubMed Google Scholar

  7. M Kendall
    View author publications

    Search author on:PubMed Google Scholar

  8. M S Ernstoff
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to K R Meehan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Meehan, K., Wu, J., Bengtson, E. et al. Early recovery of aggressive cytotoxic cells and improved immune resurgence with post-transplant immunotherapy for multiple myeloma. Bone Marrow Transplant 39, 695–703 (2007). https://doi.org/10.1038/sj.bmt.1705665

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/sj.bmt.1705665

Keywords

This article is cited by

Search

Advanced search

Quick links