Cancer Immunology, Immunotherapy

, Volume 57, Issue 11, pp 1705–1710 | Cite as

Development of a dendritic cell-based vaccine for chronic lymphocytic leukemia

  • M. Palma
  • L. Adamson
  • L. Hansson
  • P. Kokhaei
  • R. Rezvany
  • H. Mellstedt
  • A. Österborg
  • A. Choudhury
Symposium Paper

Abstract

Evidence for the existence of CLL-specific antigens recognized by the immune system can be gathered from the observation that many patients display monoclonal or oligoclonal expansions and skewed repertoire of T cells. In vitro functional studies have shown that tumor-specific T-cells are able to lyse the leukemic cells. Antileukemic cellular immunity may be boosted in vivo using dendritic cell-based immunotherapy. Our preclinical studies provide evidence that DC that had endocytosed apoptotic CLL cells (Apo-DC) were superior to fusion hybrids, tumor lysate or RNA in eliciting antileukemic T-cell responses in vitro. We have validated a method for enriching the small number of monocyte precursors present in the peripheral blood of CLL patients and utilize them for generating individualized, Apo-DC cellular vaccines. In most cases, a minimum of 50 × 106 Apo-DC could be generated, beginning with immunomagnetically enriched monocytes from a single leukapheresis product containing at least 1% CD14+ cells. Cryopreservation and thawing did not affect the phenotype or the T cell stimulatory function of Apo-DC. A phase I/II, open label clinical trial examining the feasibility, safety and immunogenicity of Apo-DC vaccination has been initiated. CLL patients receive 107 Apo-DC for at least five immunizations and monitored clinically and immunologically for 52 weeks. Three cohorts are accrued stepwise. Cohort I receives Apo-DC alone; Cohort II: Apo-DC+ repeated doses of low-dose GM-CSF; Cohort III: low-dose cyclophosphamide followed by Apo-DC + GM-CSF.

Keywords

CLL Dendritic cell T cell Immunotherapy Clinical trial 

References

  1. 1.
    Adamson L, Palmborg A, Svensson A et al (2004) Development of a technology platform for large-scale clinical grade production of DC. Cytotherapy 6:363–371PubMedCrossRefGoogle Scholar
  2. 2.
    Beyer M, Kochanek M, Darabi K et al (2005) Reduced frequencies and suppressive function of CD4+ CD25hi regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine. Blood 106:2018–2025PubMedCrossRefGoogle Scholar
  3. 3.
    Biagi E, Rousseau R, Yvon E et al (2005) Responses to human CD40 ligand/human interleukin-2 autologous cell vaccine in patients with B-cell chronic lymphocytic leukemia. Clin Cancer Res 11:6916–6923PubMedCrossRefGoogle Scholar
  4. 4.
    Buhmann R, Nolte A, Westhaus D et al (1999) CD40-activated B-cell chronic lymphocytic leukemia cells for tumor immunotherapy: stimulation of allogeneic versus autologous T cells generates different types of effector cells. Blood 93:1992–2002PubMedGoogle Scholar
  5. 5.
    Butts C, Murray N, Maksymiuk A et al (2005) Randomized phase IIB trial of BLP25 liposome vaccine in stage IIIB and IV non-small-cell lung cancer. J Clin Oncol 23:6674–6681PubMedCrossRefGoogle Scholar
  6. 6.
    Byrd JC, Rai K, Peterson BL et al (2005) Addition of rituximab to fludarabine may prolong progression-free survival and overall survival in patients with previously untreated chronic lymphocytic leukemia: an updated retrospective comparative analysis of CALGB 9712 and CALGB 9011. Blood 105:49–53PubMedCrossRefGoogle Scholar
  7. 7.
    Counter CM, Gupta J, Harley CB et al (1995) Telomerase activity in normal leukocytes and in hematologic malignancies. Blood 85:2315–2320PubMedGoogle Scholar
  8. 8.
    Cranmer LD, Trevor KT, Hersh EM (2004) Clinical applications of dendritic cell vaccination in the treatment of cancer. Cancer Immunol Immunother 53:275–306PubMedCrossRefGoogle Scholar
  9. 9.
    Dannull J, Su Z, Rizzieri D et al (2005) Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells. J Clin Invest 115:3623–3633PubMedCrossRefGoogle Scholar
  10. 10.
    Dillman RO, Selvan SR, Schiltz PM (2006) Patient-specific dendritic-cell vaccines for metastatic melanoma. N Engl J Med 355:1179–1181PubMedCrossRefGoogle Scholar
  11. 11.
    Dranoff G (2002) GM-CSF-based cancer vaccines. Immunol Rev 188:147–154PubMedCrossRefGoogle Scholar
  12. 12.
    Dreger P, Brand R, Milligan D et al (2005) Reduced-intensity conditioning lowers treatment-related mortality of allogeneic stem cell transplantation for chronic lymphocytic leukemia: a population-matched analysis. Leukemia 19:1029–1033PubMedCrossRefGoogle Scholar
  13. 13.
    Eichhorst BF, Busch R, Hopfinger G et al (2006) Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia. Blood 107:885–891PubMedCrossRefGoogle Scholar
  14. 14.
    Giannopoulos K, Hus I, Li L et al (2005) The receptor for hyaluronic acid mediated motility (RHAMM/CD168) is a potential target for immunotherapy of patients with B-cell chronic lymphocytic leukemia. Blood 106(11):53Google Scholar
  15. 15.
    Gribben JG, Zahrieh D, Stephans K et al (2005) Autologous and allogeneic stem cell transplantations for poor-risk chronic lymphocytic leukemia. Blood 106:4389–4396PubMedCrossRefGoogle Scholar
  16. 16.
    Hallek M, Cheson BD, Catovsky D et al (2008) Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) updating the National Cancer Institute-Working Group (NCI-WG) 1996 guidelines. Blood 111(12):5446–5456PubMedCrossRefGoogle Scholar
  17. 17.
    Hamblin TJ, Davis Z, Gardiner A et al (1999) Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 94:1848–1854PubMedGoogle Scholar
  18. 18.
    Harig S, Witzens M, Krackhardt AM et al (2001) Induction of cytotoxic T-cell responses against immunoglobulin V region-derived peptides modified at human leukocyte antigen-A2 binding residues. Blood 98:2999–3005PubMedCrossRefGoogle Scholar
  19. 19.
    Hoon DS, Foshag LJ, Nizze AS et al (1990) Suppressor cell activity in a randomized trial of patients receiving active specific immunotherapy with melanoma cell vaccine and low dosages of cyclophosphamide. Cancer Res 50:5358–5364PubMedGoogle Scholar
  20. 20.
    Hus I, Rolinski J, Tabarkiewicz J et al (2005) Allogeneic dendritic cells pulsed with tumor lysates or apoptotic bodies as immunotherapy for patients with early-stage B-cell chronic lymphocytic leukemia. Leukemia 19:1621–1627PubMedCrossRefGoogle Scholar
  21. 21.
    Hus I, Schmitt M, Tabarkiewicz J et al (2008) Vaccination of B-CLL patients with autologous dendritic cells can change the frequency of leukemia antigen-specific CD8+ T cells as well as CD4+ CD25+ FoxP3+ regulatory T cells toward an antileukemia response. Leukemia 22:1007–1017PubMedCrossRefGoogle Scholar
  22. 22.
    Kokhaei P, Adamson L, Palma M et al (2006) Generation of DC-based vaccine for therapy of B-CLL patients Comparison of two methods for enriching monocytic precursors. Cytotherapy 8:318–326PubMedCrossRefGoogle Scholar
  23. 23.
    Kokhaei P, Choudhury A, Mahdian R et al (2004) Apoptotic tumor cells are superior to tumor cell lysate, and tumor cell RNA in induction of autologous T cell response in B-CLL. Leukemia 18:1810–1815PubMedCrossRefGoogle Scholar
  24. 24.
    Kokhaei P, Palma M, Hansson L et al (2007) Telomerase (hTERT 611–626) serves as a tumor antigen in B-cell chronic lymphocytic leukemia and generates spontaneously antileukemic, cytotoxic T cells. Exp Hematol 35:297–304PubMedCrossRefGoogle Scholar
  25. 25.
    Kokhaei P, Rezvany MR, Virving L et al (2003) Dendritic cells loaded with apoptotic tumour cells induce a stronger T-cell response than dendritic cell-tumour hybrids in B-CLL. Leukemia 17:894–899PubMedCrossRefGoogle Scholar
  26. 26.
    Kollgaard T, Petersen SL, Hadrup SR et al (2005) Evidence for involvement of clonally expanded CD8+ T cells in anticancer immune responses in CLL patients following nonmyeloablative conditioning and hematopoietic cell transplantation. Leukemia 19:2273–2280PubMedCrossRefGoogle Scholar
  27. 27.
    MacLean GD, Miles DW, Rubens RD et al (1996) Enhancing the effect of THERATOPE STn-KLH cancer vaccine in patients with metastatic breast cancer by pretreatment with low-dose intravenous cyclophosphamide. J Immunother Emphasis Tumor Immunol 19:309–316PubMedGoogle Scholar
  28. 28.
    Marks DI, Lush R, Cavenagh J et al (2002) The toxicity and efficacy of donor lymphocyte infusions given after reduced-intensity conditioning allogeneic stem cell transplantation. Blood 100:3108–3114PubMedCrossRefGoogle Scholar
  29. 29.
    Mayr C, Bund D, Schlee M et al (2006) MDM2 is recognized as a tumor-associated antigen in chronic lymphocytic leukemia by CD8+ autologous T lymphocytes. Exp Hematol 34:44–53PubMedCrossRefGoogle Scholar
  30. 30.
    Mayr C, Bund D, Schlee M et al (2005) Fibromodulin as a novel tumor-associated antigen (TAA) in chronic lymphocytic leukemia (CLL), which allows expansion of specific CD8+ autologous T lymphocytes. Blood 105:1566–1573PubMedCrossRefGoogle Scholar
  31. 31.
    Mikaelsson E, Danesh-Manesh AH, Luppert A et al (2005) Fibromodulin, an extracellular matrix protein: characterization of its unique gene and protein expression in B-cell chronic lymphocytic leukemia and mantle cell lymphoma. Blood 105:4828–4835PubMedCrossRefGoogle Scholar
  32. 32.
    Rezvany MR, Jeddi-Tehrani M, Rabbani H et al (2000) Autologous T lymphocytes recognize the tumour-derived immunoglobulin VH-CDR3 region in patients with B-cell chronic lymphocytic leukaemia. Br J Haematol 111:230–238PubMedCrossRefGoogle Scholar
  33. 33.
    Rezvany MR, Jeddi-Tehrani M, Wigzell H et al (2003) Leukemia-associated monoclonal and oligoclonal TCR-BV use in patients with B-cell chronic lymphocytic leukemia. Blood 101:1063–1070PubMedCrossRefGoogle Scholar
  34. 34.
    Ribera JM, Vinolas N, Urbano-Ispizua A et al (1987) “Spontaneous” complete remissions in chronic lymphocytic leukemia: report of three cases and review of the literature. Blood Cells 12:471–483PubMedGoogle Scholar
  35. 35.
    Ridgway D (2003) The first 1000 dendritic cell vaccinees. Cancer Invest 21:873–886PubMedCrossRefGoogle Scholar
  36. 36.
    Schuler M, Tretter T, Schneller F et al (1999) Autocrine transforming growth factor-beta from chronic lymphocytic leukemia-B cells interferes with proliferative T cell signals. Immunobiology 200:128–139PubMedGoogle Scholar
  37. 37.
    Siegel S, Wagner A, Kabelitz D et al (2003) Induction of cytotoxic T-cell responses against the oncofetal antigen-immature laminin receptor for the treatment of hematologic malignancies. Blood 102:4416–4423PubMedCrossRefGoogle Scholar
  38. 38.
    Slingluff CL Jr, Petroni GR, Yamshchikov GV et al (2003) Clinical and immunologic results of a randomized phase II trial of vaccination using four melanoma peptides either administered in granulocyte-macrophage colony-stimulating factor in adjuvant or pulsed on dendritic cells. J Clin Oncol 21:4016–4026PubMedCrossRefGoogle Scholar
  39. 39.
    Trojan A, Schultze JL, Witzens M et al (2000) Immunoglobulin framework-derived peptides function as cytotoxic T-cell epitopes commonly expressed in B-cell malignancies. Nat Med 6:667–672PubMedCrossRefGoogle Scholar
  40. 40.
    Wierda WG, Cantwell MJ, Woods SJ et al (2000) CD40-ligand (CD154) gene therapy for chronic lymphocytic leukemia. Blood 96:2917–2924PubMedGoogle Scholar
  41. 41.
    Vonderheide RH, Domchek SM, Schultze JL et al (2004) Vaccination of cancer patients against telomerase induces functional antitumor CD8+ T lymphocytes. Clin Cancer Res 10:828–839PubMedCrossRefGoogle Scholar
  42. 42.
    Vuylsteke RJ, Molenkamp BG, Gietema HA et al (2004) Local administration of granulocyte/macrophage colony-stimulating factor increases the number and activation state of dendritic cells in the sentinel lymph node of early-stage melanoma. Cancer Res 64:8456–8460PubMedCrossRefGoogle Scholar
  43. 43.
    Yamanaka R, Abe T, Yajima N et al (2003) Vaccination of recurrent glioma patients with tumour lysate-pulsed dendritic cells elicits immune responses: results of a clinical phase I/II trial. Br J Cancer 89:1172–1179PubMedCrossRefGoogle Scholar
  44. 44.
    Ziegler-Heitbrock HW, Schlag R, Flieger D, Thiel E (1989) Favorable response of early stage B CLL patients to treatment with IFN-alpha 2. Blood 73:1426–1430PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • M. Palma
    • 1
  • L. Adamson
    • 1
  • L. Hansson
    • 1
  • P. Kokhaei
    • 1
  • R. Rezvany
    • 1
  • H. Mellstedt
    • 2
  • A. Österborg
    • 1
  • A. Choudhury
    • 1
  1. 1.Departments of Oncology and HematologyKarolinska University HospitalStockholmSweden
  2. 2.Department of Oncology (Radiumhemmet)Karolinska University Hospital SolnaStockholmSweden

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