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Review

Challenges in vaccine therapy in hematological malignancies and strategies to overcome them

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Pages 1093-1104 | Received 28 Mar 2016, Accepted 13 May 2016, Published online: 13 Jun 2016

References

  • Copelan EA. Hematopoietic stem-cell transplantation. N Engl J Med. 2006;354(17):1813–1826.
  • Coley WB. The treatment of malignant tumors by repeated inoculations of erysipelas. With a report of ten original cases. 1893. Clin Orthop Relat Res. 1893;1991:3–11.
  • Dhodapkar MV, Dhodapkar KM. Immune modulation in hematologic malignancies. Semin Oncol. 2015;42:617–625.
  • Joyce JA, Fearon DT. T cell exclusion, immune privilege, and the tumor microenvironment. Science (New York, NY). 2015;348:74–80.
  • Xia Y, Medeiros LJ, Young KH. Immune checkpoint blockade: releasing the brake towards hematological malignancies. Blood Rev. 2015. doi:10.1016/j.blre.2015.11.003.
  • Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Reviews Immunol. 2009;9:162–174.
  • Mougiakakos D, Choudhury A, Lladser A, et al. Regulatory T cells in cancer. Adv Cancer Res. 2010;107:57–117.
  • Li L, Boussiotis VA. Physiologic regulation of central and peripheral T cell tolerance: lessons for therapeutic applications. J Mol Med (Berl). 2006;84:887–899.
  • Pardoll D. Cancer and the immune system: basic concepts and targets for intervention. Semin Oncol. 2015;42:523–538.
  • Pistillo MP, Tazzari PL, Palmisano GL, et al. CTLA-4 is not restricted to the lymphoid cell lineage and can function as a target molecule for apoptosis induction of leukemic cells. Blood. 2003;101:202–209.
  • Pérez-García A, Brunet S, Berlanga JJ, et al. CTLA-4 genotype and relapse incidence in patients with acute myeloid leukemia in first complete remission after induction chemotherapy. Leukemia. 2009;23:486–491.
  • Green MR, Monti S, Rodig SJ, et al. Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood. 2010;116:3268–3277.
  • Myklebust JH, Irish JM, Brody J, et al. High PD-1 expression and suppressed cytokine signaling distinguish T cells infiltrating follicular lymphoma tumors from peripheral T cells. Blood. 2013;121:1367–1376.
  • Ramsdell F, Ziegler SF. FOXP3 and scurfy: how it all began. Nat Reviews Immunol. 2014;14:343–349.
  • Tzankov A, Meier C, Hirschmann P, et al. Correlation of high numbers of intratumoral FOXP3+ regulatory T cells with improved survival in germinal center-like diffuse large B-cell lymphoma, follicular lymphoma and classical Hodgkin’s lymphoma. Haematologica. 2008;93:193–200.
  • Liu W, Putnam AL, Xu-Yu Z, et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med. 2006;203:1701–1711.
  • Sakaguchi S, Sakaguchi N, Asano M, et al. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol (Baltimore, Md: 1950). 1995;155:1151–1164.
  • Nizar S, Copier J, Meyer B, et al. T-regulatory cell modulation: the future of cancer immunotherapy? Br J Cancer. 2009;100:1697–1703.
  • Chen M-L, Pittet MJ, Gorelik L, et al. Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-beta signals in vivo. Proc Natl Acad Sci U S A. 2005;102:419–424.
  • Beyer M, Kochanek M, Darabi K, et al. Reduced frequencies and suppressive function of CD4+CD25hi regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine. Blood. 2005;106:2018–2025.
  • Motta M, Rassenti L, Shelvin BJ, et al. Increased expression of CD152 (CTLA-4) by normal T lymphocytes in untreated patients with B-cell chronic lymphocytic leukemia. Leukemia. 2005;19:1788–1793.
  • Movahedi K, Guilliams M, Van den Bossche J, et al. Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity. Blood. 2008;111:4233–4244.
  • Tadmor T, Attias D, Polliack A. Myeloid-derived suppressor cells – their role in haemato-oncological malignancies and other cancers and possible implications for therapy. Br J Haematol. 2011;153:557–567.
  • Serafini P, Mgebroff S, Noonan K, et al. Myeloid-derived suppressor cells promote cross-tolerance in B-cell lymphoma by expanding regulatory T cells. Cancer Res. 2008;68:5439–5449.
  • Ostrand-Rosenberg S. Myeloid-derived suppressor cells: more mechanisms for inhibiting antitumor immunity. Cancer Immunol Immunother. 2010;59:1593–1600.
  • De Veirman K, Van Valckenborgh E, Lahmar Q, et al. Myeloid-derived suppressor cells as therapeutic target in hematological malignancies. Front Oncol. 2014;4:349.
  • Marigo I, Dolcetti L, Serafini P, et al. Tumor-induced tolerance and immune suppression by myeloid derived suppressor cells. Immunol Rev. 2008;222:162–179.
  • Ugel S, Facciponte JG, De Sanctis F, et al. Targeting tumor vasculature: expanding the potential of DNA cancer vaccines. Cancer Immunol Immunother. 2015;64:1339–1348.
  • Peske JD, Woods AB, Engelhard VH. Control of CD8 T-cell infiltration into tumors by vasculature and microenvironment. Adv Cancer Res. 2015;128:263–307.
  • Cammarota F, Laukkanen MO. Mesenchymal stem/stromal cells in stromal evolution and cancer progression. Stem Cells Int. 2016;2016:4824573.
  • Kozłowska A, Mackiewicz J, Mackiewicz A. Therapeutic gene modified cell based cancer vaccines. Gene. 2013;525:200–207.
  • Platten M, Wick W, Van den Eynde BJ. Tryptophan catabolism in cancer: beyond IDO and tryptophan depletion. Cancer Res. 2012;72:5435–5440.
  • Prendergast GC, Smith C, Thomas S, et al. Indoleamine 2,3-dioxygenase pathways of pathogenic inflammation and immune escape in cancer. Cancer Immunol Immunother. 2014;63:721–735.
  • Gabrilovich D. Mechanisms and functional significance of tumour-induced dendritic-cell defects. Nat Reviews Immunol. 2004;4:941–952.
  • Chamuleau MED, van de Loosdrecht AA, Hess CJ, et al. High INDO (indoleamine 2,3-dioxygenase) mRNA level in blasts of acute myeloid leukemic patients predicts poor clinical outcome. Haematologica. 2008;93:1894–1898.
  • Martner A, Thorén FB, Aurelius J, et al. Immunotherapeutic strategies for relapse control in acute myeloid leukemia. Blood Rev. 2013;27:209–216.
  • Motz GT, Santoro SP, Wang L-P, et al. Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nat Med. 2014;20:607–615.
  • Moehler TM, Ho AD, Goldschmidt H, et al. Angiogenesis in hematologic malignancies. Crit Rev Oncol Hematol. 2003;45:227–244.
  • Dong X, Han ZC, Yang R. Angiogenesis and antiangiogenic therapy in hematologic malignancies. Crit Rev Oncol Hematol. 2007;62:105–118.
  • Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480:480–489.
  • Cheever MA, Allison JP, Ferris AS, et al. The prioritization of cancer antigens: a National Cancer Institute pilot project for the acceleration of translational research. Clin Cancer Res off J Am Assoc Cancer Res. 2009;15:5323–5337.
  • Anguille S, Van Tendeloo VF, Berneman ZN. Leukemia-associated antigens and their relevance to the immunotherapy of acute myeloid leukemia. Leukemia. 2012;26:2186–2196.
  • Bendandi M. Idiotype vaccines for lymphoma: proof-of-principles and clinical trial failures. Nat Rev Cancer. 2009;9:675–681.
  • Dhodapkar MV, Sexton R, Das R, et al. Prospective analysis of antigen-specific immunity, stem-cell antigens, and immune checkpoints in monoclonal gammopathy. Blood. 2015;126:2475–2478.
  • Brooks SE, Bonney SA, Lee C, et al. Application of the pMHC array to characterise tumour antigen specific T cell populations in leukaemia patients at disease diagnosis. Plos One. 2015;10:e0140483.
  • Fichtner S, Hose D, Engelhardt M, et al. Association of antigen-specific T-cell responses with antigen expression and immunoparalysis in multiple myeloma. Clin Cancer Res off J Am Assoc Cancer Res. 2015;21:1712–1721.
  • Weng J, Rawal S, Chu F, et al. TCL1: a shared tumor-associated antigen for immunotherapy against B-cell lymphomas. Blood. 2012;120:1613–1623.
  • Carmon L, Avivi I, Kovjazin R, et al. Phase I/II study exploring ImMucin, a pan-major histocompatibility complex, anti-MUC1 signal peptide vaccine, in multiple myeloma patients. Br J Haematol. 2015;169:44–56.
  • Van Tendeloo VF, Van de Velde A, Van Driessche A, et al. Induction of complete and molecular remissions in acute myeloid leukemia by Wilms’ tumor 1 antigen-targeted dendritic cell vaccination. Proc Natl Acad Sci U S A. 2010;107:13824–13829.
  • Scanlan MJ, Gure AO, Jungbluth AA, et al. Cancer/testis antigens: an expanding family of targets for cancer immunotherapy. Immunol Rev. 2002;188:22–32.
  • Zilberberg J, Feinman R, Korngold R. Strategies for the identification of T cell-recognized tumor antigens in hematological malignancies for improved graft-versus-tumor responses after allogeneic blood and marrow transplantation. Biol Blood Marrow Transplant. 2015;21(6):1000–1007.
  • Fritsch EF, Hacohen N, Wu CJ. Personal neoantigen cancer vaccines: the momentum builds. Oncoimmunology. 2014;3:e29311.
  • Stroopinsky D, Rosenblatt J, Ito K, et al. MUC1 is a potential target for the treatment of acute myeloid leukemia stem cells. Cancer Res. 2013;73(17):5569–5579.
  • Gao L, Bellantuono I, Elsässer A, et al. Selective elimination of leukemic CD34(+) progenitor cells by cytotoxic T lymphocytes specific for WT1. Blood. 2000;95:2198–2203.
  • Allegra A, Russo S, Gerace D, et al. Vaccination strategies in lymphoproliferative disorders: failures and successes. Leuk Res. 2015;39:1006–1019.
  • Lynch RG, Graff RJ, Sirisinha S, et al. Myeloma proteins as tumor-specific transplantation antigens. Proc Natl Acad Sci U S A. 1972;69:1540–1544.
  • Kwak LW, Young HA, Pennington RW, et al. Vaccination with syngeneic, lymphoma-derived immunoglobulin idiotype combined with granulocyte/macrophage colony-stimulating factor primes mice for a protective T-cell response. Proc Natl Acad Sci U S A. 1996;93:10972–10977.
  • Kaminski MS, Kitamura K, Maloney DG, et al. Idiotype vaccination against murine B cell lymphoma. Inhibition of tumor immunity by free idiotype protein. J Immunol (Baltimore, Md: 1950). 1987;138:1289–1296.
  • 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 off J Am Soc Clin Oncol. 2011;29:2787–2794.
  • Freedman A, Neelapu SS, Nichols C, et al. Placebo-controlled phase III trial of patient-specific immunotherapy with mitumprotimut-T and granulocyte-macrophage colony-stimulating factor after rituximab in patients with follicular lymphoma. J Clin Oncol off J Am Soc Clin Oncol. 2009;27:3036–3043.
  • Levy R, Ganjoo KN, Leonard JP, et al. Active idiotypic vaccination versus control immunotherapy for follicular lymphoma. J Clin Oncol off J Am Soc Clin Oncol. 2014;32:1797–1803.
  • Bogen B. A mouse model for immunotherapy of myeloma. Hematol J off J Eur Haematol Assoc/EHA. 2002;3:224–229.
  • Li Y, Bendandi M, Deng Y, et al. Tumor-specific recognition of human myeloma cells by idiotype-induced CD8(+) T cells. Blood. 2000;96:2828–2833.
  • Yi Q, Osterborg A. Idiotype-specific T cells in multiple myeloma: targets for an immunotherapeutic intervention? Med Oncol. 1996;13:1–7.
  • Wen YJ, 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.
  • Abdalla AO, Kokhaei P, Hansson L, et al. Idiotype vaccination in patients with myeloma reduced circulating myeloma cells (CMC). Ann Oncol off J Eur Soc Med Oncol/ESMO. 2008;19:1172–1179.
  • Hansson L, Abdalla AO, Moshfegh A, et al. Long-term idiotype vaccination combined with interleukin-12 (IL-12), or IL-12 and granulocyte macrophage colony-stimulating factor, in early-stage multiple myeloma patients. Clin Cancer Res off J Am Assoc Cancer Res. 2007;13:1503–1510.
  • McCann KJ, Godeseth R, Chudley L, et al. Idiotypic DNA vaccination for the treatment of multiple myeloma: safety and immunogenicity in a phase I clinical study. Cancer Immunol Immunother. 2015;64:1021–1032.
  • 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;99:1517–1526.
  • Reichardt VL, Okada CY, Liso A, et al. Idiotype vaccination using dendritic cells after autologous peripheral blood stem cell transplantation for multiple myeloma – a feasibility study. Blood. 1999;93:2411–2419.
  • Curti A, Tosi P, Comoli P, et al. Phase I/II clinical trial of sequential subcutaneous and intravenous delivery of dendritic cell vaccination for refractory multiple myeloma using patient-specific tumour idiotype protein or idiotype (VDJ)-derived class I-restricted peptides. Br J Haematol. 2007;139:415–424.
  • Lacy MQ, Mandrekar S, Dispenzieri A, et al. Idiotype-pulsed antigen-presenting cells following autologous transplantation for multiple myeloma may be associated with prolonged survival. Am J Hematol. 2009;84:799–802.
  • Yi Q, Szmania S, Freeman J, et al. Optimizing dendritic cell-based immunotherapy in multiple myeloma: intranodal injections of idiotype-pulsed CD40 ligand-matured vaccines led to induction of type-1 and cytotoxic T-cell immune responses in patients. Br J Haematol. 2010;150:554–564.
  • Zahradova L, Mollova K, Ocadlikova D, et al. Efficacy and safety of Id-protein-loaded dendritic cell vaccine in patients with multiple myeloma – phase II study results. Neoplasma. 2012;59:440–449.
  • Garcia-Marquez MA, Wennhold K, Draube A, et al. Results of a phase II clinical trial with Id-protein-loaded dendritic cell vaccine in multiple myeloma: encouraging or discouraging? Immunotherapy. 2012;4:991–994.
  • Fritsch EF, Rajasagi M, Ott PA, et al. HLA-binding properties of tumor neoepitopes in humans. Cancer Immunol Res. 2014;2:522–529.
  • Oka Y, Tsuboi A, Taguchi T, et al. Induction of WT1 (Wilms’ tumor gene)-specific cytotoxic T lymphocytes by WT1 peptide vaccine and the resultant cancer regression. Proc Natl Acad Sci U S A. 2004;101:13885–13890.
  • Inoue K, Ogawa H, Yamagami T, et al. Long-term follow-up of minimal residual disease in leukemia patients by monitoring WT1 (Wilms tumor gene) expression levels. Blood. 1996;88:2267–2278.
  • Inoue K, Sugiyama H, Ogawa H, et al. WT1 as a new prognostic factor and a new marker for the detection of minimal residual disease in acute leukemia. Blood. 1994;84:3071–3079.
  • Bergmann L, Miething C, Maurer U, et al. High levels of Wilms’ tumor gene (wt1) mRNA in acute myeloid leukemias are associated with a worse long-term outcome. Blood. 1997;90:1217–1225.
  • Ohminami H, Yasukawa M, Fujita S. HLA class I-restricted lysis of leukemia cells by a CD8(+) cytotoxic T-lymphocyte clone specific for WT1 peptide. Blood. 2000;95:286–293.
  • Maslak PG, Dao T, Krug LM, et al. Vaccination with synthetic analog peptides derived from WT1 oncoprotein induces T-cell responses in patients with complete remission from acute myeloid leukemia. Blood. 2010;116:171–179.
  • Brayer J, Lancet JE, Powers J, et al. WT1 vaccination in AML and MDS: A pilot trial with synthetic analog peptides. Am J Hematol. 2015;90:602–607.
  • Keilholz U, Letsch A, Busse A, et al. A clinical and immunologic phase 2 trial of Wilms tumor gene product 1 (WT1) peptide vaccination in patients with AML and MDS. Blood. 2009;113:6541–6548.
  • Uttenthal B, Martinez-Davila I, Ivey A, et al. Wilms’ tumour 1 (WT1) peptide vaccination in patients with acute myeloid leukaemia induces short-lived WT1-specific immune responses. Br J Haematol. 2014;164:366–375.
  • Alatrash G, Molldrem JJ. Vaccines as consolidation therapy for myeloid leukemia. Expert Rev Hematol. 2011;4:37–50.
  • Rezvani K, Yong ASM, Mielke S, et al. Repeated PR1 and WT1 peptide vaccination in Montanide-adjuvant fails to induce sustained high-avidity, epitope-specific CD8+ T cells in myeloid malignancies. Haematologica. 2011;96:432–440.
  • Kuball J, de Boer K, Wagner E, et al. Pitfalls of vaccinations with WT1-, proteinase3- and MUC1-derived peptides in combination with MontanideISA51 and CpG7909. Cancer Immunol Immunother. 2011;60:161–171.
  • Wilde S, Sommermeyer D, Frankenberger B, et al. Dendritic cells pulsed with RNA encoding allogeneic MHC and antigen induce T cells with superior antitumor activity and higher TCR functional avidity. Blood. 2009;114:2131–2139.
  • Javorovic M, Pohla H, Frankenberger B, et al. RNA transfer by electroporation into mature dendritic cells leading to reactivation of effector-memory cytotoxic T lymphocytes: a quantitative analysis. Mol Ther J Am Soc Gene Ther. 2005;12:734–743.
  • Gilboa E, Vieweg J. Cancer immunotherapy with mRNA-transfected dendritic cells. Immunol Rev. 2004;199:251–263.
  • Bae J, Prabhala R, Voskertchian A, et al. A multiepitope of XBP1, CD138 and CS1 peptides induces myeloma-specific cytotoxic T lymphocytes in T cells of smoldering myeloma patients. Leukemia. 2015;29:218–229.
  • Burkhardt UE, Hainz U, Stevenson K, et al. Autologous CLL cell vaccination early after transplant induces leukemia-specific T cells. J Clin Invest. 2013;123:3756–3765.
  • Guièze R, Wu CJ. Genomic and epigenomic heterogeneity in chronic lymphocytic leukemia. Blood. 2015;126:445–453.
  • Rajasagi M, Shukla SA, Fritsch EF, et al. Systematic identification of personal tumor-specific neoantigens in chronic lymphocytic leukemia. Blood. 2014;124:453–462.
  • Banchereau J, Palucka AK. Dendritic cells as therapeutic vaccines against cancer. Nat Reviews Immunol. 2005;5:296–306.
  • Hsu FJ, Benike C, Fagnoni F, et al. Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed dendritic cells. Nat Med. 1996;2:52–58.
  • Spisek R, Chevallier P, Morineau N, et al. Induction of leukemia-specific cytotoxic response by cross-presentation of late-apoptotic leukemic blasts by autologous dendritic cells of nonleukemic origin. Cancer Res. 2002;62:2861–2868.
  • Ruben JM, van den Ancker W, Bontkes HJ, et al. Apoptotic blebs from leukemic cells as a preferred source of tumor-associated antigen for dendritic cell-based vaccines. Cancer Immunol Immunother. 2014;63:335–345.
  • Kokhaei P, Choudhury A, Mahdian R, et al. Apoptotic tumor cells are superior to tumor cell lysate, and tumor cell RNA in induction of autologous T cell response in B-CLL. Leukemia. 2004;18:1810–1815.
  • Palma M, Hansson L, Choudhury A, et al. Vaccination with dendritic cells loaded with tumor apoptotic bodies (Apo-DC) in patients with chronic lymphocytic leukemia: effects of various adjuvants and definition of immune response criteria. Cancer Immunol Immunother. 2012;61:865–879.
  • 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.
  • Sborov DW, Nuovo GJ, Stiff A, et al. A phase I trial of single-agent reolysin in patients with relapsed multiple myeloma. Clin Cancer Res off J Am Assoc Cancer Res. 2014;20:5946–5955.
  • Rosenblatt J, Kufe D, Avigan D. Dendritic cell fusion vaccines for cancer immunotherapy. Expert Opin Biol Ther. 2005;5:703–715.
  • Avigan D, Rosenblatt J, Kufe D. Dendritic/tumor fusion cells as cancer vaccines. Semin Oncol. 2012;39:287–295.
  • Vasir B, Borges V, Wu Z, et al. Fusion of dendritic cells with multiple myeloma cells results in maturation and enhanced antigen presentation. Br J Haematol. 2005;129:687–700.
  • Raje N, Hideshima T, Davies FE, et al. Tumour cell/dendritic cell fusions as a vaccination strategy for multiple myeloma. Br J Haematol. 2004;125:343–352.
  • Tanaka Y, Koido S, Ohana M, et al. Induction of impaired antitumor immunity by fusion of MHC class II-deficient dendritic cells with tumor cells. J Immunol (Baltimore, Md: 1950). 2005;174:1274–1280.
  • Gong J, Chen D, Kashiwaba M, et al. Induction of antitumor activity by immunization with fusions of dendritic and carcinoma cells. Nat Med. 1997;3:558–561.
  • Rosenblatt J, Vasir B, Uhl L, et al. Vaccination with dendritic cell/tumor fusion cells results in cellular and humoral antitumor immune responses in patients with multiple myeloma. Blood. 2011;117:393–402.
  • Rosenblatt J, Avivi I, Vasir B, et al. Vaccination with dendritic cell/tumor fusions following autologous stem cell transplant induces immunologic and clinical responses in multiple myeloma patients. Clin Cancer Res off J Am Assoc Cancer Res. 2013;19:3640–3648.
  • Lacy MQ, Gertz MA, Dispenzieri A, et al. Long-term results of response to therapy, time to progression, and survival with lenalidomide plus dexamethasone in newly diagnosed myeloma. Mayo Clinic Proc. 2007;82:1179–1184.
  • Zweegman S, van der Holt B, Mellqvist U-H, et al. Lenalidomide plus melphalan and prednisone, followed by lenalidomide maintenance versus thalidomide plus melphalan and prednisone, followed by thalidomide maintenance; results of the randomised phase 3 HOVON 87/NMSG18 trial. Blood. 2016;127:1109–1116.
  • Fehniger TA, Uy GL, Trinkaus K, et al. A phase 2 study of high-dose lenalidomide as initial therapy for older patients with acute myeloid leukemia. Blood. 2011;117:1828–1833.
  • Fehniger TA, Byrd JC, Marcucci G, et al. Single-agent lenalidomide induces complete remission of acute myeloid leukemia in patients with isolated trisomy 13. Blood. 2009;113:1002–1005.
  • Blum W, Klisovic RB, Becker H, et al. Dose escalation of lenalidomide in relapsed or refractory acute leukemias. J Clin Oncol off J Am Soc Clin Oncol. 2010;28:4919–4925.
  • Krönke J, Udeshi ND, Narla A, et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science (New York, NY). 2014;343:301–305.
  • Lu G, Middleton RE, Sun H, et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science (New York, NY). 2014;343:305–309.
  • Wong HK, Wilson AJ, Gibson HM, et al. Increased expression of CTLA-4 in malignant T-cells from patients with mycosis fungoides – cutaneous T cell lymphoma. J Invest Dermatol. 2006;126:212–219.
  • Luptakova K, Rosenblatt J, Glotzbecker B, et al. Lenalidomide enhances anti-myeloma cellular immunity. Cancer Immunol Immunother. 2013;62:39–49.
  • Sakamaki I, Kwak LW, Cha S-C, et al. Lenalidomide enhances the protective effect of a therapeutic vaccine and reverses immune suppression in mice bearing established lymphomas. Leukemia. 2014;28:329–337.
  • Görgün G, Samur MK, Cowens KB, et al. Lenalidomide enhances immune checkpoint blockade-induced immune response in multiple myeloma. Clin Cancer Res off J Am Assoc Cancer Res. 2015;21:4607–4618.
  • Noman MZ, Desantis G, Janji B, et al. PD-L1 is a novel direct target of HIF-1, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med. 2014;211:781–790.
  • Srivastava P, Paluch BE, Matsuzaki J, et al. Immunomodulatory action of SGI-110, a hypomethylating agent, in acute myeloid leukemia cells and xenografts. Leuk Res. 2014;38(11):1332–1341.
  • Goodyear O, Agathanggelou A, Novitzky-Basso I, et al. Induction of a CD8+ T-cell response to the MAGE cancer testis antigen by combined treatment with azacitidine and sodium valproate in patients with acute myeloid leukemia and myelodysplasia. Blood. 2010;116(11):1908–1918.
  • Pusic I, Choi J, Fiala MA, et al. Maintenance therapy with decitabine after allogeneic stem cell transplantation for acute myelogenous leukemia and myelodysplastic syndrome. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2015;21:1761–1769.
  • Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372:311–319.
  • Phan GQ, Yang JC, Sherry RM, et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci U S A. 2003;100:8372–8377.
  • Spain L, Diem S, Larkin J. Management of toxicities of immune checkpoint inhibitors. Cancer Treat Rev. 2016;44:51–60.
  • Michot JM, Bigenwald C, Champiat S, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer (Oxford, England: 1990). 2016;54:139–148.
  • Seya T, Shime H, Takeda Y, et al. Adjuvant for vaccine immunotherapy of cancer – focusing on TLR2 and TLR3 agonists for safely enhancing antitumor immunity. Cancer Sci. 2015;106:1659–1668.
  • Gollob JA, Veenstra KG, Parker RA, et al. Phase I trial of concurrent twice-weekly recombinant human interleukin-12 plus low-dose IL-2 in patients with melanoma or renal cell carcinoma. J Clin Oncol off J Am Soc Clin Oncol. 2003;21:2564–2573.
  • Lee P, Wang F, Kuniyoshi J, et al. Effects of interleukin-12 on the immune response to a multipeptide vaccine for resected metastatic melanoma. J Clin Oncol off J Am Soc Clin Oncol. 2001;19:3836–3847.
  • Heine A, Schilling J, Grünwald B, et al. The induction of human myeloid derived suppressor cells through hepatic stellate cells is dose-dependently inhibited by the tyrosine kinase inhibitors nilotinib, dasatinib and sorafenib, but not sunitinib. Cancer Immunol Immunother. 2016;65:273–282.
  • Sawant A, Schafer CC, Jin TH, et al. Enhancement of antitumor immunity in lung cancer by targeting myeloid-derived suppressor cell pathways. Cancer Res. 2013;73(22):6609–6620.
  • Rapoport AP, Aqui NA, Stadtmauer EA, et al. Combination immunotherapy after ASCT for multiple myeloma using MAGE-A3/Poly-ICLC immunizations followed by adoptive transfer of vaccine-primed and costimulated autologous T cells. Clin Cancer Res off J Am Assoc Cancer Res. 2014;20:1355–1365.
  • Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371:1507–1517.
  • Porter DL, Hwang W-T, Frey NV, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med. 2015;7:303ra139.
  • Wang X, Wong CW, Urak R, et al. CMVpp65 vaccine enhances the antitumor efficacy of adoptively transferred CD19-redirected CMV-specific T cells. Clin Cancer Res off J Am Assoc Cancer Res. 2015;21:2993–3002.

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