Skip to main content

Advertisement

SpringerLink
Log in

Active Immunotherapy: Current State of the Art in Vaccine Approaches for NHL

  • Lymphomas (PA Hamlin, Section Editor)
  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

Immune therapy of cancer is a rapidly evolving field, with long-deserved successes now finally achieved. As new pathways triggered by the immune synapsis are elucidated, and new molecules responsible for immune checkpoints are being discovered, it is becoming clear that vaccination against a single antigen aided by non-specific immune stimulation is not sufficient for an efficient, long term, immune response. Though lymphoma is a highly curable malignancy, there is still a subset of patients that is at very high risk of disease relapse even after successfully completing chemotherapy or a stem cell transplant. Patients with minimal residual disease are particularly suitable for vaccination. Over the past 3 decades, the classic model of lymphoma-specific idiotype vaccine has evolved and recent data on vaccination with nonspecific oligodeoxynucleotides has provided very encouraging results. Furthermore, the introduction of checkpoint blockade via agonist or antagonist monoclonal antibodies holds the promise of significant improvement in the efficacy of future vaccines. What follows is a brief summary of the historical highlights in lymphoma immunotherapy as well as an update on the most recently published clinical trials and a look at future developments.

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

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Grube M, Rezvani K, Wiestner A, et al. Autoreactive, cytotoxic T lymphocytes specific for peptides derived from normal B-cell differentiation antigens in healthy individuals and patients with B-cell malignancies. Clin Cancer Res. 2004;10:1047–56.

    Article  PubMed  CAS  Google Scholar 

  2. Guevara-Patino JA, Engelhorn ME, Turk MJ, et al. Optimization of a self antigen for presentation of multiple epitopes in cancer immunity. J Clin Invest. 2006;116:1382–90.

    Article  PubMed  CAS  Google Scholar 

  3. Houghton AN. Cancer antigens: immune recognition of self and altered self. J Exp Med. 1994;180:1–4.

    Article  PubMed  CAS  Google Scholar 

  4. Eisen HN, Sakato N, Hall SJ. Myeloma proteins as tumor-specific antigens. Transplant Proc. 1975;7:209–14.

    PubMed  CAS  Google Scholar 

  5. Janeway Jr CA, Sakato N, Eisen HN. Recognition of immunoglobulin idiotypes by thymus-derived lymphocytes. Proc Natl Acad Sci U S A. 1975;72:2357–60.

    Article  PubMed  Google Scholar 

  6. Davis TA, Maloney DG, Czerwinski DK, Liles TM, Levy R. Anti-idiotype antibodies can induce long-term complete remissions in non-Hodgkin's lymphoma without eradicating the malignant clone. Blood. 1998;92:1184–90.

    PubMed  CAS  Google Scholar 

  7. Meeker T, Lowder J, Cleary ML, et al. Emergence of idiotype variants during treatment of B-cell lymphoma with anti-idiotype antibodies. N Engl J Med. 1985;312:1658–65.

    Article  PubMed  CAS  Google Scholar 

  8. Kwak LW, Campbell MJ, Czerwinski DK, Hart S, Miller RA, Levy R. Induction of immune responses in patients with B-cell lymphoma against the surface-immunoglobulin idiotype expressed by their tumors. N Engl J Med. 1992;327:1209–15.

    Article  PubMed  CAS  Google Scholar 

  9. Timmerman JM, Singh G, Hermanson G, et al. Immunogenicity of a plasmid DNA vaccine encoding chimeric idiotype in patients with B-cell lymphoma. Cancer Res. 2002;62:5845–52.

    PubMed  CAS  Google Scholar 

  10. King CA, Spellerberg MB, Zhu D, et al. DNA vaccines with single-chain Fv fused to fragment C of tetanus toxin induce protective immunity against lymphoma and myeloma. Nat Med. 1998;4:1281–6.

    Article  PubMed  CAS  Google Scholar 

  11. Bertinetti C, Simon F, Zirlik K, et al. Cloning of idiotype immunoglobulin genes in B cell lymphomas by anchored PCR and production of individual recombinant idiotype vaccines in Escherichia coli. Eur J Haematol. 2006;77:395–402.

    Article  PubMed  CAS  Google Scholar 

  12. Navarrete MA, Heining-Mikesch K, Schüler F, et al. Upfront immunization with autologous recombinant idiotype Fab fragment without prior cytoreduction in indolent B-cell lymphoma. Blood. 2011;117:1483–91.

    Article  PubMed  CAS  Google Scholar 

  13. Patel KG, Ng PP, Levy S, Levy R, Swartz JR. Escherichia coli-based production of a tumor idiotype antibody fragment – tetanus toxin fragment C fusion protein vaccine for B cell lymphoma. Protein Expr Purif. 2011;75:15–20.

    Article  PubMed  CAS  Google Scholar 

  14. Iurescia S, Fioretti D, Fazio VM, Rinaldi M. Epitope-driven DNA vaccine design employing immunoinformatics against B-cell lymphoma: a biotech's challenge. Biotechnol Adv. 2012;30:372–83.

    Article  PubMed  CAS  Google Scholar 

  15. Malmberg KJ. Effective immunotherapy against cancer: a question of overcoming immune suppression and immune escape? Cancer Immunol Immunother. 2004;53:879–92.

    Article  PubMed  CAS  Google Scholar 

  16. • Freedman AS, Nichols CR, Robertson M, Djulbegovic B, Winter JN, Gold D, et al. A placebo-controlled phase III trial of patient-specific immunotherapy with Multiprotimut-T (ID-KLH) and GM-CSF following Rituximab in patients with CD20+ follicular lymphoma. Blood. 2008;112:94. This is the Favrille study, one of 3 randomized anti‐Id clinical trials, and it describes the outcome of weekly Rituximab followed by anti‐Id versus weekly Rituximab followed by placebo.

    Google Scholar 

  17. • Levy R, Robertson M, Ganjoo K, Leonard J, Vose J, Denney D. Results of a Phase 3 trial evaluating safety and efficacy of specific immunotherapy, recombinant idiotype (Id) conjugated to KLH (Id-KLH) with GM-CSF, compared to non-specific immunotherapy, KLH with GM-CSF, in patients with follicular non-Hodgkin's Lymphoma (fNHL). AACR Meeting Abstracts. 2008. 2008;(1 Annual Meeting):LB-204. This is the only phase III study of idiotype vaccination that resulted in a significant difference between groups.

  18. • Schuster SJ, Neelapu SS, Gause BL, et al. Vaccination with patient-specific tumor-derived antigen in first remission improves disease-free survival in follicular lymphoma. J Clin Oncol. 2011;29:2787–94. In this randomized study, the Genitope study, patients received CVP followed by idiotype vaccine.

    Article  PubMed  CAS  Google Scholar 

  19. Neelapu SS, Kwak LW, Kobrin CB, et al. Vaccine-induced tumor-specific immunity despite severe B-cell depletion in mantle cell lymphoma. Nat Med. 2005;11:986–91.

    PubMed  CAS  Google Scholar 

  20. Liggins AP, Guinn BA, Hatton CS, Pulford K, Banham AH. Serologic detection of diffuse large B-cell lymphoma-associated antigens. Int J Cancer. 2004;110:563–9.

    Article  PubMed  CAS  Google Scholar 

  21. Zwick C, Preuss KD, Kubuschok B, et al. Analysis of the antibody repertoire of patients with mantle cell lymphoma directed against mantle cell lymphoma-associated antigens. Ann Hematol. 2009;88:999–1003.

    Article  PubMed  Google Scholar 

  22. Nishikawa H, Maeda Y, Ishida T, et al. Cancer/testis antigens are novel targets of immunotherapy for adult T-cell leukemia/lymphoma. Blood. 2012;119:3097–104.

    Article  PubMed  CAS  Google Scholar 

  23. Inaoka R, Jungbluth A, Baiocchi O, et al. An overview of cancer/testis antigens expression in classical Hodgkin's Lymphoma (cHL) identifies MAGE-A family and MAGE-C1 as the most frequently expressed antigens in a set of Brazilian cHL patients. BMC Cancer. 2011;11:416.

    Article  PubMed  CAS  Google Scholar 

  24. Winkler C, Steingrube D, Altermann W, et al. Hodgkin’s Lymphoma RNA-transfected dendritic cells induce cancer/testis antigen-specific immune responses. Cancer Immunol Immunother.:1-11. doi:10.1007/s00262-012-1239-z.

  25. Palomba ML, Roberts WK, Dao T, et al. CD8+ T-cell-dependent immunity following xenogeneic DNA immunization against CD20 in a tumor challenge model of B-cell lymphoma. Clin Cancer Res. 2005;11:370–9.

    PubMed  CAS  Google Scholar 

  26. Franki SN, Steward KK, Betting DJ, Kafi K, Yamada RE, Timmerman JM. Dendritic cells loaded with apoptotic antibody-coated tumor cells provide protective immunity against B-cell lymphoma in vivo. Blood. 2008;111:1504–11

    Article  PubMed  CAS  Google Scholar 

  27. Timmerman JM, Czerwinski DK, Davis TA, et al. Idiotype-pulsed dendritic cell vaccination for B-cell lymphoma: clinical and immune responses in 35 patients. Blood. 2002;99:1517–26.

    Article  PubMed  CAS  Google Scholar 

  28. Di Nicola M, Zappasodi R, Carlo-Stella C, et al. Vaccination with autologous tumor-loaded dendritic cells induces clinical and immunologic responses in indolent B-cell lymphoma patients with relapsed and measurable disease: a pilot study. Blood. 2009;113:18–27.

    Article  PubMed  Google Scholar 

  29. Wang J, Saffold S, Cao X, Krauss J, Chen W. Eliciting T cell immunity against poorly immunogenic tumors by immunization with dendritic cell-tumor fusion vaccines. J Immunol. 1998;161:5516–24.

    PubMed  CAS  Google Scholar 

  30. Ni X, Richmond HM, Liao XM, et al. Induction of T-cell responses against cutaneous T-cell lymphomas ex vivo by autologous dendritic cells transfected with amplified tumor mRNA. J Invest Dermatol. 2008;128:2631–9.

    Article  PubMed  CAS  Google Scholar 

  31. Van Meirvenne S, Straetman L, Heirman C, et al. Efficient genetic modification of murine dendritic cells by electroporation with mRNA. Cancer Gene Ther. 2002;9:787–97.

    Article  PubMed  Google Scholar 

  32. Li J, Song W, Czerwinski DK, et al. Lymphoma immunotherapy with CpG oligodeoxynucleotides requires TLR9 either in the host or in the tumor itself. J Immunol. 2007;179:2493–500.

    PubMed  CAS  Google Scholar 

  33. •• Brody JD, Ai WZ, Czerwinski DK, et al. In situ vaccination with a TLR9 agonist induces systemic lymphoma regression: a phase I/II study. J Clin Oncol. 2010;28:4324–32. This is the first study showing that customized vaccines are not required to induce a systemic anti lymphoma response. In a preclinical lymphoma model, injection of a Toll‐like receptor 9 agonist induced effective systemic antitumor immunity.

    Article  PubMed  Google Scholar 

  34. Thirdborough SM, Radcliffe JN, Friedmann PS, Stevenson FK. Vaccination with DNA encoding a single-chain TCR fusion protein induces anticlonotypic immunity and protects against T-cell lymphoma. Cancer Res. 2002;62:1757–60.

    PubMed  CAS  Google Scholar 

  35. Okada C, Wong C, Denney D, Levy R. TCR vaccines for active immunotherapy of T cell malignancies. J Immunol. 1997;159:5516–27.

    PubMed  CAS  Google Scholar 

  36. Brody JD, Goldstein MJ, Czerwinski DK, Levy R. Immunotransplantation preferentially expands T-effector cells over T-regulatory cells and cures large lymphoma tumors. Blood. 2009;113:85–94.

    Article  PubMed  CAS  Google Scholar 

  37. Brody JD, Advani R, Weng W, et al. Immunotransplant for mantle cell lymphoma: phase I/II study preliminary results. J Clin Oncol. 2011;29(Suppl):abstract 2509.

    Google Scholar 

  38. French RR, Taraban VY, Crowther GR, et al. Eradication of lymphoma by CD8 T cells following anti-CD40 monoclonal antibody therapy is critically dependent on CD27 costimulation. Blood. 2007;109:4810–5.

    Article  PubMed  CAS  Google Scholar 

  39. Carlring J, Szabo MJ, Dickinson R, De Leenheer E, Heath AW. Conjugation of lymphoma idiotype to CD40 antibody enhances lymphoma vaccine immunogenicity and antitumor effects in mice. Blood. 2012;119:2056–65.

    Article  PubMed  CAS  Google Scholar 

  40. Houot R, Levy R. T-cell modulation combined with intratumoral CpG cures lymphoma in a mouse model without the need for chemotherapy. Blood. 2009;113:3546–52.

    Article  PubMed  CAS  Google Scholar 

  41. Met O, Wang M, Pedersen AE, Nissen MH, Buus S, Claesson MH. The effect of a therapeutic dendritic cell-based cancer vaccination depends on the blockage of CTLA-4 signaling. Cancer Lett. 2006;231:247–56.

    Article  PubMed  CAS  Google Scholar 

  42. Curran MA, Kim M, Montalvo W, Al-Shamkhani A, Allison JP. Combination CTLA-4 blockade and 4-1BB activation enhances tumor rejection by increasing T-cell infiltration, proliferation, and cytokine production. PLoS One. 2011;6:e19499.

    Article  PubMed  CAS  Google Scholar 

  43. Hirschhorn-Cymerman D, Rizzuto GA, Merghoub T, et al. OX40 engagement and chemotherapy combination provides potent antitumor immunity with concomitant regulatory T cell apoptosis. J Exp Med. 2009;206:1103–16.

    Article  PubMed  CAS  Google Scholar 

  44. 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.

    Article  PubMed  CAS  Google Scholar 

  45. Zhou J, Bashey A, Zhong R, et al. CTLA-4 blockade following relapse of malignancy after allogeneic stem cell transplantation is associated with T cell activation but not with increased levels of T regulatory cells. Biol Blood Marrow Transplant. 2011;17:682–92.

    Article  PubMed  Google Scholar 

  46. Ansell SM, Hurvitz SA, Koenig PA, et al. Phase I study of ipilimumab, an anti–CTLA-4 monoclonal antibody, in patients with relapsed and refractory B-cell non–Hodgkin Lymphoma. Clin Cancer Res. 2009;15:6446–53.

    Article  PubMed  CAS  Google Scholar 

  47. Yamamoto R, Nishikori M, Kitawaki T, et al. PD-1-PD-1 ligand interaction contributes to immunosuppressive microenvironment of Hodgkin Lymphoma. Blood. 2008;111:3220–4.

    Article  PubMed  CAS  Google Scholar 

  48. Andorsky DJ, Yamada RE, Said J, Pinkus GS, Betting DJ, Timmerman JM. Programmed death ligand 1 is expressed by non–Hodgkin Lymphomas and inhibits the activity of tumor-associated T cells. Clin Cancer Res. 2011;17:4232–44.

    Article  PubMed  CAS  Google Scholar 

  49. Berger R, Rotem-Yehudar R, Slama G, et al. Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin Cancer Res. 2008;14:3044–51.

    Article  PubMed  CAS  Google Scholar 

  50. Westin FC Jr, Foglietta M, Rotem-Yehudar R, Neelapu SS. CureTech, Yavne, Israel phase II safety and efficacy study of CT-011, a humanized anti-PD-1 monoclonal antibody, in combination with rituximab in patients with relapsed follicular lymphoma. J Clin Oncol 2010;28(15S).

  51. Brahmer ST Jr, Wollner I, Powderly JD, Picus J, Drake C, Covino J, et al. Safety and activity of MDX-1106 (ONO-4538), an anti-PD-1 monoclonal antibody, in patients with selected refractory or relapsed malignancies. J Clin Oncol 2008;28 (Suppl): abstract 3006.

    Google Scholar 

  52. Hsu FJ, Caspar CB, Czerwinski D, et al. Tumor-specific idiotype vaccines in the treatment of patients with B-cell lymphoma–long-term results of a clinical trial. Blood. 1997;89:3129–35.

    PubMed  CAS  Google Scholar 

  53. Bendandi M, Gocke CD, Kobrin CB, et al. Complete molecular remissions induced by patient-specific vaccination plus granulocyte-monocyte colony-stimulating factor against lymphoma. Nat Med. 1999;5:1171–7.

    Article  PubMed  CAS  Google Scholar 

  54. Hsu FJ, Benike C, Fagnoni F, et al. Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed dendritic cells. Nat Med. 1996;2:52–8.

    Article  PubMed  CAS  Google Scholar 

  55. Barrios Y, Cabrera R, Yanez R, et al. Anti-idiotypic vaccination in the treatment of low-grade B-cell lymphoma. Haematologica. 2002;87:400–7.

    PubMed  Google Scholar 

  56. Neelapu SS, Baskar S, Gause BL, et al. Human autologous tumor-specific T-cell responses induced by liposomal delivery of a lymphoma antigen. Clin Cancer Res. 2004;10:8309–17.

    Article  PubMed  CAS  Google Scholar 

  57. Inoges S, Rodriguez-Calvillo M, Zabalegui N, et al. Clinical benefit associated with idiotypic vaccination in patients with follicular lymphoma. J Natl Cancer Inst. 2006;98:1292–301.

    Article  PubMed  Google Scholar 

  58. Bertinetti C, Zirlik K, Heining-Mikesch K, et al. Phase I trial of a novel intradermal idiotype vaccine in patients with advanced B-cell lymphoma: specific immune responses despite profound immunosuppression. Cancer Res. 2006;66:4496–502.

    Article  PubMed  CAS  Google Scholar 

  59. Redfern CH, Guthrie TH, Bessudo A, et al. Phase II trial of idiotype vaccination in previously treated patients with indolent non-Hodgkin's Lymphoma resulting in durable clinical responses. J Clin Oncol. 2006;24:3107–12.

    Article  PubMed  CAS  Google Scholar 

Download references

Disclosure

No potential conflicts of interest relevant to this article were reported.

Author information

Authors and Affiliations

  1. Lymphoma Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    M. Lia Palomba

Authors
  1. M. Lia Palomba
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. Lia Palomba.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Palomba, M.L. Active Immunotherapy: Current State of the Art in Vaccine Approaches for NHL. Curr Oncol Rep 14, 433–440 (2012). https://doi.org/10.1007/s11912-012-0255-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11912-012-0255-7

Keywords

Search

Navigation