The emerging role of immune checkpoint based approaches in AML and MDS

References

• Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252–264.
   PubMed Web of Science ®Google Scholar
• Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol. 2008;8:467–477.
   PubMed Web of Science ®Google Scholar
• Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol. 2013;13:227–242.
   PubMed Web of Science ®Google Scholar
• Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science. 1996;271:1734–1736.
   PubMed Web of Science ®Google Scholar
• Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–723.
   PubMed Web of Science ®Google Scholar
• O'Day SJ, Maio M, Chiarion-Sileni V, et al. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann Oncol. 2010;21:1712–1717.
   PubMed Web of Science ®Google Scholar
• Sui X, Ma J, Han W, et al. The anticancer immune response of anti-PD-1/PD-L1 and the genetic determinants of response to anti-PD-1/PD-L1 antibodies in cancer patients. Oncotarget. 2015;6:19393–19404.
   PubMed Web of Science ®Google Scholar
• Nishimura H, Okazaki T, Tanaka Y, et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science. 2001;291:319–322.
   PubMed Web of Science ®Google Scholar
• Nishimura H, Nose M, Hiai H, et al. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity. 1999;11:141–151.
   PubMed Web of Science ®Google Scholar
• Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192:1027–1034.
   PubMed Web of Science ®Google Scholar
• Yokosuka T, Takamatsu M, Kobayashi-Imanishi W, et al. Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. J Exp Med. 2012;209:1201–1217.
   PubMed Web of Science ®Google Scholar
• Alatrash G, Daver N, Mittendorf EA. Targeting immune checkpoints in hematologic malignancies. Pharmacol Rev. 2016;68:1014–1025.
   PubMed Web of Science ®Google Scholar
• Costello RT, Mallet F, Sainty D, et al. Regulation of CD80/B7-1 and CD86/B7-2 molecule expression in human primary acute myeloid leukemia and their role in allogenic immune recognition. Eur J Immunol. 1998;28:90–103.
   PubMed Web of Science ®Google Scholar
• Re F, Arpinati M, Testoni N, et al. Expression of CD86 in acute myelogenous leukemia is a marker of dendritic/monocytic lineage. Exp Hematol. 2002;30:126–134.
   PubMed Web of Science ®Google Scholar
• Vollmer M, Li L, Schmitt A, et al. Expression of human leucocyte antigens and co-stimulatory molecules on blasts of patients with acute myeloid leukaemia. Br J Haematol. 2003;120:1000–1008.
   PubMed Web of Science ®Google Scholar
• Whiteway A, Corbett T, Anderson R, et al. Expression of co-stimulatory molecules on acute myeloid leukaemia blasts may effect duration of first remission. Br J Haematol. 2003;120:442–451.
   PubMed Web of Science ®Google Scholar
• Graf M, Reif S, Hecht K, et al. High expression of costimulatory molecules correlates with low relapse-free survival probability in acute myeloid leukemia (AML). Ann Hematol. 2005;84:287–297.
   PubMed Web of Science ®Google Scholar
• Zhang L, Chen X, Liu X, et al. CD40 ligation reverses T cell tolerance in acute myeloid leukemia. J Clin Invest. 2013;123:1999–2010.
   PubMed Web of Science ®Google Scholar
• Teague RM, Kline J. Immune evasion in acute myeloid leukemia: current concepts and future directions. J Immunother Cancer. 2013;1:13.
   Google Scholar
• Vidriales MB, Orfao A, López-Berges MC, et al. Lymphoid subsets in acute myeloid leukemias: increased number of cells with NK phenotype and normal T-cell distribution. Ann Hematol. 1993;67:217–222.
   PubMed Web of Science ®Google Scholar
• Naval Daver SB, Garcia-Manero G, Cortes JE, et al. Defining the immune checkpoint landscape in patients (pts) with acute myeloid leukemia. ASH Session. 2016;617: abstract 2900.
   Google Scholar
• Le Dieu R, Taussig DC, Ramsay AG, et al. Peripheral blood T cells in acute myeloid leukemia (AML) patients at diagnosis have abnormal phenotype and genotype and form defective immune synapses with AML blasts. Blood. 2009;114:3909–3916.
   PubMed Web of Science ®Google Scholar
• Van den Hove LE, Vandenberghe P, Van Gool SW, et al. Peripheral blood lymphocyte subset shifts in patients with untreated hematological tumors: evidence for systemic activation of the T cell compartment. Leuk Res. 1998;22:175–184.
   PubMed Web of Science ®Google Scholar
• Schnorfeil FM, Lichtenegger FS, Emmerig K, et al. T cells are functionally not impaired in AML: increased PD-1 expression is only seen at time of relapse and correlates with a shift towards the memory T cell compartment. J Hematol Oncol. 2015;8:93.
   PubMed Web of Science ®Google Scholar
• Wendelbo O, Nesthus I, Sjo M, et al. Functional characterization of T lymphocytes derived from patients with acute myelogenous leukemia and chemotherapy-induced leukopenia. Cancer Immunol Immunother. 2004;53:740–747.
   PubMed Web of Science ®Google Scholar
• Adam Lamble YK, Huang F, Sasser K, et al. Mass cytometry as a modality to identify candidates for immune checkpoint inhibitor therapy within acute myeloid leukemia. ASH Abstract #2829; 2016.
   Google Scholar
• Page DB, Postow MA, Callahan MK, et al. Immune modulation in cancer with antibodies. Annu Rev Med. 2014;65:185–202.
   PubMed Web of Science ®Google Scholar
• Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517–2526.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Green MR, Rodig S, Juszczynski P, et al. Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: implications for targeted therapy. Clin Cancer Res. 2012;18:1611–1618.
   PubMed Web of Science ®Google Scholar
• Ansell SM, Iwamoto FM, LaCasce A, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med. 2015;372:311–319.
   PubMed Web of Science ®Google Scholar
• Moskowitz C, Ribrag V, Michot JM, et al. PD-1 blockade with the monoclonal antibody pembrolizumab (MK-3475) in patients with classical Hodgkin lymphoma after brentuximab vedotin failure: preliminary results from a phase 1b study (KEYNOTE-013). 56th ASH Annual Meeting and Exposition; 2014; San Francisco, CA.
   Google Scholar
• 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;14:3044–3051.
   PubMed Web of Science ®Google Scholar
• Westin JR, Chu F, Zhang M, et al. Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label, phase 2 trial. Lancet Oncol. 2014;15:69–77.
   PubMed Web of Science ®Google Scholar
• Armand P, Nagler A, Weller EA, et al. Disabling immune tolerance by programmed death-1 blockade with pidilizumab after autologous hematopoietic stem-cell transplantation for diffuse large B-cell lymphoma: results of an international phase II trial. J Clin Oncol. 2013;31:4199–4206.
   PubMed Web of Science ®Google Scholar
• Lesokhin AM, Ansell SM, Armand P, et al. Nivolumab in patients with relapsed or refractory hematologic malignancy: preliminary results of a phase Ib study. JCO. 2016;34:2698–2704.
   PubMed Web of Science ®Google Scholar
• San Miguel J, Siegel D, Shah JJ, et al. Pembrolizumab in combination with lenalidomide and low-dose dexamethasone for relapsed/refractory multiple myeloma (RRMM): keynote-023. American Society of Hematology Annual Meeting; 2015.
   Google Scholar
• Zhang L, Gajewski TF, Kline J. PD-1/PD-L1 interactions inhibit antitumor immune responses in a murine acute myeloid leukemia model. Blood. 2009;114:1545–1552.
   PubMed Web of Science ®Google Scholar
• Zhou Q, Munger ME, Veenstra RG, et al. Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia. Blood. 2011;117:4501–4510.
   PubMed Web of Science ®Google Scholar
• Daver N, et al. Defining the immune checkpoint landscape in patients (pts) with acute myeloid leukemia (AML). Blood. 2016;128: abstract 2900.
   PubMed Web of Science ®Google Scholar
• Mumprecht S, Schürch C, Schwaller J, et al. Programmed death 1 signaling on chronic myeloid leukemia-specific T cells results in T-cell exhaustion and disease progression. Blood. 2009;114:1528–1536.
   PubMed Web of Science ®Google Scholar
• Shi L, Chen S, Yang L, et al. The role of PD-1 and PD-L1 in T-cell immune suppression in patients with hematological malignancies. J Hematol Oncol. 2013;6:74.
   PubMed Web of Science ®Google Scholar
• Chen X, Liu S, Wang L, et al. Clinical significance of B7-H1 (PD-L1) expression in human acute leukemia. Cancer Biol Ther. 2008;7:622–627.
   PubMed Web of Science ®Google Scholar
• Fourcade J, Sun Z, Benallaoua M, et al. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. J Exp Med. 2010;207:2175–2186.
   PubMed Web of Science ®Google Scholar
• Zhou Q, Munger ME, Highfill SL, et al. Program death-1 signaling and regulatory T cells collaborate to resist the function of adoptively transferred cytotoxic T lymphocytes in advanced acute myeloid leukemia. Blood. 2010;116:2484–2493.
   PubMed Web of Science ®Google Scholar
• Dolen Y, Esendagli G. Myeloid leukemia cells with a B7-2(+) subpopulation provoke Th-cell responses and become immuno-suppressive through the modulation of B7 ligands. Eur J Immunol. 2013;43:747–757.
   PubMed Web of Science ®Google Scholar
• Marketwired. U.S. FDA Lifts Partial Clinical Hold on Medivation's Pidilizumab. March 9; 2016.
   Google Scholar
• Garcia-Manero G, Tallman MS, Martinelli G, et al. Pembrolizumab, a PD-1 inhibitor, in Patients with Myelodysplastic Syndrome (MDS) after Failure of Hypomethylating Agent Treatment. American Society of Hematology, Dec 2016 (abstract); 2016.
   Google Scholar
• Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006;108:419–425.
   PubMed Web of Science ®Google Scholar
• Riley JL, Mao M, Kobayashi S, et al. Modulation of TCR-induced transcriptional profiles by ligation of CD28, ICOS, and CTLA-4 receptors. Proc Natl Acad Sci USA. 2002;99:11790–11795.
   PubMed Web of Science ®Google Scholar
• Linsley PS, Greene JL, Brady W, et al. Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors. Immunity. 1994;1:793–801.
   PubMed Web of Science ®Google Scholar
• Schneider H, Downey J, Smith A, et al. Reversal of the TCR stop signal by CTLA-4. Science. 2006;313:1972–1975.
   PubMed Web of Science ®Google Scholar
• Egen JG, Allison JP. Cytotoxic T lymphocyte antigen-4 accumulation in the immunological synapse is regulated by TCR signal strength. Immunity. 2002;16:23–35.
   PubMed Web of Science ®Google Scholar
• Saudemont A, Quesnel B. In a model of tumor dormancy, long-term persistent leukemic cells have increased B7-H1 and B7.1 expression and resist CTL-mediated lysis. Blood. 2004;104:2124–2133.
   PubMed Web of Science ®Google Scholar
• Laurent S, Palmisano GL, Martelli AM, et al. CTLA-4 expressed by chemoresistant, as well as untreated, myeloid leukaemia cells can be targeted with ligands to induce apoptosis. Br J Haematol. 2007;136:597–608.
   PubMed Web of Science ®Google Scholar
• Ribas A. Tumor immunotherapy directed at PD-1. N Engl J Med. 2012;366:2517–2519.
   PubMed Web of Science ®Google Scholar
• Zeidan AM, Kharfan-Dabaja MA, Komrokji RS. Stabilization of myelodysplastic syndromes (MDS) following hypomethylating agent (HMAs) failure using the immune checkpoint inhibitor ipilimumab: a phase I trial. Blood. 2015;126:1666–1666.
   Web of Science ®Google Scholar
• Wrangle J, Wang W, Koch A, et al. Alterations of immune response of non-small cell lung cancer with azacytidine. Oncotarget. 2013;4:2067–2079.
   PubMed Web of Science ®Google Scholar
• Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009;10:223–232.
   PubMed Web of Science ®Google Scholar
• Dombret H, Seymour JF, Butrym A, et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015;126:291–299.
   PubMed Web of Science ®Google Scholar
• Fenaux P, Mufti GJ, Hellström-Lindberg E, et al. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol. 2010;28:562–569.
   PubMed Web of Science ®Google Scholar
• Guo H, Miao H, Gerber L, et al. Disruption of EphA2 receptor tyrosine kinase leads to increased susceptibility to carcinogenesis in mouse skin. Cancer Res. 2006;66:7050–7058.
   PubMed Web of Science ®Google Scholar
• Srivastava P, Paluch BE, Matsuzaki J, et al. Induction of cancer testis antigen expression in circulating acute myeloid leukemia blasts following hypomethylating agent monotherapy. Oncotarget. 2016;7:12840–12856.
   PubMed Web of Science ®Google Scholar
• Coral S, Sigalotti L, Altomonte M, et al. 5-Aza-2′-deoxycytidine-induced expression of functional cancer testis antigens in human renal cell carcinoma: immunotherapeutic implications. Clin Cancer Res. 2002;8:2690–2695.
   PubMed Web of Science ®Google Scholar
• Coral S, Sigalotti L, Gasparollo A, et al. Prolonged upregulation of the expression of HLA class I antigens and costimulatory molecules on melanoma cells treated with 5-aza-2′-deoxycytidine (5-AZA-CdR). J Immunother. 1999;22:16–24.
   PubMed Web of Science ®Google Scholar
• Serrano A, Tanzarella S, Lionello I, et al. Rexpression of HLA class I antigens and restoration of antigen-specific CTL response in melanoma cells following 5-aza-2′-deoxycytidine treatment. Int J Cancer. 2001;94:243–251.
   PubMed Web of Science ®Google Scholar
• Garcia-Manero G, Daver NG, Montalban-Bravo G, et al. A phase II study evaluating the combination of nivolumab or ipilimumab with azacitidine in patients with previously treated or untreated myelodysplastic syndromes. American Society of Hematology, Dec 2016 (oral presentation).
   Google Scholar
• Yang H, Bueso-Ramos C, DiNardo C, et al. Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. Leukemia. 2014;28:1280–1288.
   PubMed Web of Science ®Google Scholar
• Naval Daver SBG, Garcia-Manero JE, Cortes F, et al. Phase IB/II study of nivolumab in combination with azacytidine in patients with relapsed acute myeloid leukemia. American Society of Hematology, Dec 2016 (abstract); 2016.
   Google Scholar
• Vereecque R, Saudemont A, Quesnel B. Cytosine arabinoside induces costimulatory molecule expression in acute myeloid leukemia cells. Leukemia. 2004;18:1223–1230.
   PubMed Web of Science ®Google Scholar
• Saha A, Aoyama K, Taylor PA, et al. Host programmed death ligand 1 is dominant over programmed death ligand 2 expression in regulating graft-versus-host disease lethality. Blood. 2013;122:3062–3073.
   PubMed Web of Science ®Google Scholar
• Blazar BR, Carreno BM, Panoskaltsis-Mortari A, et al. Blockade of programmed death-1 engagement accelerates graft-versus-host disease lethality by an IFN-gamma-dependent mechanism. J Immunol. 2003;171:1272–1277.
   PubMed Web of Science ®Google Scholar
• Blazar BR, et al. Opposing roles of CD28:B7 and CTLA-4:B7 pathways in regulating in vivo alloresponses in murine recipients of MHC disparate T cells. J Immunol. 1999;162:6368–6377.
   PubMed Web of Science ®Google Scholar
• Davids MS, Haesook T, Bachireddy P, et al. Ipilimumab for patients with relapse after allogeneic transplantation. N Engl J Med. 2016;375:143–153.
   PubMed Web of Science ®Google Scholar
• Herbaux C, Gauthier J, Brice P, et al. Efficacy and tolerability of nivolumab after allogeneic transplantation for relapsed Hodgkin's lymphoma. Blood. 2017;129:2471--2478.
   PubMed Web of Science ®Google Scholar
• Saudemont A, Buffenoir G, Denys A, et al. Gene transfer of CD154 and IL12 cDNA induces an anti-leukemic immunity in a murine model of acute leukemia. Leukemia. 2002;16:1637–1644.
   PubMed Web of Science ®Google Scholar
• Workman CJ, Rice DS, Dugger KJ, et al. Phenotypic analysis of the murine CD4-related glycoprotein, CD223 (LAG-3). Eur J Immunol. 2002;32:2255–2263.
   PubMed Web of Science ®Google Scholar
• Huang CT, Workman CJ, Flies D, et al. Role of LAG-3 in regulatory T cells. Immunity. 2004;21:503–513.
   PubMed Web of Science ®Google Scholar
• Grosso JF, Goldberg MV, Getnet D, et al. Functionally distinct LAG-3 and PD-1 subsets on activated and chronically stimulated CD8 T cells. J Immunol. 2009;182:6659–6669.
   PubMed Web of Science ®Google Scholar
• Berrien-Elliott MM, Jackson SR, Meyer JM, et al. Durable adoptive immunotherapy for leukemia produced by manipulation of multiple regulatory pathways of CD8+ T-cell tolerance. Cancer Res. 2013;73:605–616.
   PubMed Web of Science ®Google Scholar
• Zhu C, Anderson AC, Schubart A, et al. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol. 2005;6:1245–1252.
   PubMed Web of Science ®Google Scholar
• Wang C, Lin GH, McPherson AJ, et al. Immune regulation by 4-1BB and 4-1BBL: complexities and challenges. Immunol Rev. 2009;229:192–215.
   PubMed Web of Science ®Google Scholar
• Richter G, Hayden-Ledbetter M, Irgang M, et al. Tumor necrosis factor-alpha regulates the expression of inducible costimulator receptor ligand on CD34(+) progenitor cells during differentiation into antigen presenting cells. J Biol Chem. 2001;276:45686–45693.
   PubMed Web of Science ®Google Scholar
• Richter G, Burdach S. ICOS: a new costimulatory ligand/receptor pair and its role in T-cell activation. Onkologie. 2004;27:91–95.
   PubMedGoogle Scholar
• Lucia Masarova HK, Daver N. Immune checkpoint approaches in AML and MDS: a next frontier? Target Oncol. 2017 [published online March 06, 2017].
   Google Scholar