Active Immunotherapy: Current State of the Art in Vaccine Approaches for NHL Authors
Lymphomas (PA Hamlin, Section Editor)
First Online: 28 July 2012 DOI:
Cite this article as: Palomba, M.L. Curr Oncol Rep (2012) 14: 433. doi:10.1007/s11912-012-0255-7 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.
Keywords Lymphoma Immunotherapy Vaccination Idiotype Adjuvants Checkpoint blockade References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
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.
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.
Houghton AN. Cancer antigens: immune recognition of self and altered self. J Exp Med. 1994;180:1–4.
Eisen HN, Sakato N, Hall SJ. Myeloma proteins as tumor-specific antigens. Transplant Proc. 1975;7:209–14.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Malmberg KJ. Effective immunotherapy against cancer: a question of overcoming immune suppression and immune escape? Cancer Immunol Immunother. 2004;53:879–92.
• 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.
• 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.
• 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
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.
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.
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.
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.
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.
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:
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.
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
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.
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.
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.
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.
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.
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.
•• 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
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.
Okada C, Wong C, Denney D, Levy R. TCR vaccines for active immunotherapy of T cell malignancies. J Immunol. 1997;159:5516–27.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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