Recent developments in immunotherapy of acute myeloid leukemia

The advent of new immunotherapeutic agents in clinical practice has revolutionized cancer treatment in the past decade, both in oncology and hematology. The transfer of the immunotherapeutic concepts to the treatment of acute myeloid leukemia (AML) is hampered by various characteristics of the disease, including non-leukemia-restricted target antigen expression profile, low endogenous immune responses, and intrinsic resistance mechanisms of the leukemic blasts against immune responses. However, considerable progress has been made in this field in the past few years.Within this manuscript, we review the recent developments and the current status of the five currently most prominent immunotherapeutic concepts: (1) antibody-drug conjugates, (2) T cell-recruiting antibody constructs, (3) chimeric antigen receptor (CAR) T cells, (4) checkpoint inhibitors, and (5) dendritic cell vaccination. We focus on the clinical data that has been published so far, both for newly diagnosed and refractory/relapsed AML, but omitting immunotherapeutic concepts in conjunction with hematopoietic stem cell transplantation. Besides, we have included important clinical trials that are currently running or have recently been completed but are still lacking full publication of their results.While each of the concepts has its particular merits and inherent problems, the field of immunotherapy of AML seems to have taken some significant steps forward. Results of currently running trials will reveal the direction of further development including approaches combining two or more of these concepts.

[1]  H. Goossens,et al.  Induction of complete and molecular remissions in acute myeloid leukemia by Wilms’ tumor 1 antigen-targeted dendritic cell vaccination , 2010, Proceedings of the National Academy of Sciences.

[2]  G. Kvalheim,et al.  New generation dendritic cell vaccine for immunotherapy of acute myeloid leukemia , 2014, Cancer Immunology, Immunotherapy.

[3]  G. Zugmaier,et al.  Clinical overview of anti-CD19 BiTE(®) and ex vivo data from anti-CD33 BiTE(®) as examples for retargeting T cells in hematologic malignancies. , 2015, Molecular immunology.

[4]  C. Rader.  DARTs take aim at BiTEs. , 2011, Blood.

[5]  S. Parmar,et al.  Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents , 2013, Leukemia.

[6]  U. Testa,et al.  CD 123 is a membrane biomarker and a therapeutic target in hematologic malignancies , 2014, Biomarker Research.

[7]  Xiuli Wang,et al.  T cells expressing CD123-specific chimeric antigen receptors exhibit specific cytolytic effector functions and antitumor effects against human acute myeloid leukemia. , 2013, Blood.

[8]  G. Fey,et al.  Dual-targeting triplebody 33-3-19 mediates selective lysis of biphenotypic CD19+ CD33+ leukemia cells , 2016, Oncotarget.

[9]  H. Goossens,et al.  Transpresentation of interleukin-15 by IL-15/IL-15Rα mRNA-engineered human dendritic cells boosts antitumoral natural killer cell activity , 2015, Oncotarget.

[10]  Quan-shun Wang,et al.  Treatment of CD33-directed chimeric antigen receptor-modified T cells in one patient with relapsed and refractory acute myeloid leukemia. , 2015, Molecular therapy : the journal of the American Society of Gene Therapy.

[11]  D. Dimitrov,et al.  Preclinical Development of FLT3-Redirected Chimeric Antigen Receptor T Cell Immunotherapy for Acute Myeloid Leukemia , 2016 .

[12]  N. Cheung,et al.  Acute myeloid leukemia targets for bispecific antibodies , 2017, Blood Cancer Journal.

[13]  R. Lutz,et al.  The Antibody-Drug Conjugate (ADC) IMGN779 Is Highly Active in Vitro and in Vivo Against Acute Myeloid Leukemia (AML) with FLT3-ITD Mutations , 2014 .

[14]  P. Moore,et al.  Application of dual affinity retargeting molecules to achieve optimal redirected T-cell killing of B-cell lymphoma. , 2011, Blood.

[15]  A. Engert,et al.  The emerging role of immune checkpoint inhibition in malignant lymphoma , 2017, Haematologica.

[16]  A. Mackensen,et al.  T lymphocytes can be effectively recruited for ex vivo and in vivo lysis of AML blasts by a novel CD33/CD3-bispecific BiTE antibody construct , 2013, Leukemia.

[17]  C. Hourigan,et al.  Current Approaches in the Treatment of Relapsed and Refractory Acute Myeloid Leukemia , 2015, Journal of clinical medicine.

[18]  David L. Porter,et al.  Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia , 2015, Science Translational Medicine.

[19]  A. Scott,et al.  Persistence and efficacy of second generation CAR T cell against the LeY antigen in acute myeloid leukemia. , 2013, Molecular therapy : the journal of the American Society of Gene Therapy.

[20]  M. Carroll,et al.  Preclinical targeting of human acute myeloid leukemia and myeloablation using chimeric antigen receptor-modified T cells. , 2014, Blood.

[21]  M. Weiss,et al.  Immunotherapy in acute myeloid leukemia , 2015, Cancer.

[22]  Yvonne Y Chen,et al.  T Cells Expressing CD19/CD20 Bispecific Chimeric Antigen Receptors Prevent Antigen Escape by Malignant B Cells , 2016, Cancer Immunology Research.

[23]  Angel F. Lopez,et al.  Targeting of acute myeloid leukaemia by cytokine‐induced killer cells redirected with a novel CD123‐specific chimeric antigen receptor , 2013, British journal of haematology.

[24]  P. Moore,et al.  A CD3xCD123 bispecific DART for redirecting host T cells to myelogenous leukemia: Preclinical activity and safety in nonhuman primates , 2015, Science Translational Medicine.

[25]  C. Craddock,et al.  Mylotarg has potent anti-leukaemic effect: a systematic review and meta-analysis of anti-CD33 antibody treatment in acute myeloid leukaemia , 2014, Annals of Hematology.

[26]  E. Wang,et al.  Combining IMGN779, a Novel Anti-CD33 Antibody-Drug Conjugate (ADC), with the PARP Inhibitor, Olaparib, Results in Enhanced Anti-Tumor Activity in Preclinical Acute Myeloid Leukemia (AML) Models , 2016 .

[27]  E. Estey,et al.  Gemtuzumab ozogamicin in combination with vorinostat and azacitidine in older patients with relapsed or refractory acute myeloid leukemia: a phase I/II study , 2014, Haematologica.

[28]  Z. Eshhar,et al.  Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[29]  M. Carroll,et al.  CD33-specific chimeric antigen receptor T cells exhibit potent preclinical activity against human acute myeloid leukemia , 2015, Leukemia.

[30]  P. Chevallier,et al.  Persistence of CD33 expression at relapse in CD33+ acute myeloid leukaemia patients after receiving Gemtuzumab in the course of the disease , 2008, British journal of haematology.

[31]  H. Kantarjian,et al.  Monoclonal antibody therapy with rituximab for acute lymphoblastic leukemia. , 2009, Hematology/oncology clinics of North America.

[32]  E. Mittendorf,et al.  Targeting Immune Checkpoints in Hematologic Malignancies , 2016, Pharmacological Reviews.

[33]  K. Rezvani,et al.  A novel TCR-like CAR with specificity for PR1/HLA-A2 effectively targets myeloid leukemia in vitro when expressed in human adult peripheral blood and cord blood T cells. , 2016, Cytotherapy.

[34]  F. Ravandi,et al.  Vadastuximab Talirine Plus Hypomethylating Agents: A Well-Tolerated Regimen with High Remission Rate in Frontline Older Patients with Acute Myeloid Leukemia (AML) , 2016 .

[35]  D. Dimitrov,et al.  High affinity FRβ-specific CAR T cells eradicate AML and normal yeloid lineage without HSC toxicity , 2016, Leukemia.

[36]  M. Konopleva,et al.  A phase II study of decitabine and gemtuzumab ozogamicin in newly diagnosed and relapsed acute myeloid leukemia and high-risk myelodysplastic syndrome , 2016, Leukemia.

[37]  G. Ehninger,et al.  Distribution and levels of cell surface expression of CD33 and CD123 in acute myeloid leukemia , 2014, Blood Cancer Journal.

[38]  W. Hiddemann,et al.  Current strategies in immunotherapy for acute myeloid leukemia. , 2013, Immunotherapy.

[39]  D. Bonnet,et al.  Chimeric antigen receptors against CD33/CD123 antigens efficiently target primary acute myeloid leukemia cells in vivo , 2014, Leukemia.

[40]  A. Bagg,et al.  Leukemia Stem Cells Are Characterized By CLEC12A Expression and Chemotherapy Refractoriness That Can be Overcome By Targeting with Chimeric Antigen Receptor T Cells , 2016 .

[41]  A. Romanelli,et al.  IMGN779, a CD33-Targeted Antibody-Drug Conjugate (ADC) with a Novel DNA-Alkylating Effector Molecule, Induces DNA Damage, Cell Cycle Arrest, and Apoptosis in AML Cells. , 2015 .

[42]  R. Larson,et al.  Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. , 2015, The Lancet. Oncology.

[43]  A. Walker.  Dying a fiery death: pyroptosis in MDS. , 2016, Blood.

[44]  L. Naldini,et al.  CD44v6-targeted T cells mediate potent antitumor effects against acute myeloid leukemia and multiple myeloma. , 2013, Blood.

[45]  W. Hiddemann,et al.  Allogeneic transplantation versus chemotherapy as postremission therapy for acute myeloid leukemia: a prospective matched pairs analysis. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[46]  Christina Peters,et al.  Antibody–drug conjugates as novel anti-cancer chemotherapeutics , 2015, Bioscience reports.

[47]  S. Owen,et al.  Antibody Drug Conjugates: Design and Selection of Linker, Payload and Conjugation Chemistry , 2015, The AAPS Journal.

[48]  W. Hiddemann,et al.  CD33 target validation and sustained depletion of AML blasts in long-term cultures by the bispecific T-cell-engaging antibody AMG 330. , 2014, Blood.

[49]  H. Abken,et al.  The growing world of CAR T cell trials: a systematic review , 2016, Cancer Immunology, Immunotherapy.

[50]  A. Lawson,et al.  Chimeric receptors providing both primary and costimulatory signaling in T cells from a single gene product. , 1998, Journal of immunology.

[51]  R. Kischel,et al.  Cellular determinants for preclinical activity of a novel CD33/CD3 bispecific T-cell engager (BiTE) antibody, AMG 330, against human AML. , 2014, Blood.

[52]  U. Brinkmann,et al.  Corrigendum to "Bispecific antibodies" [Drug Discov. Today 20 (July (7)) (2015) 838-847]. , 2018, Drug discovery today.

[53]  M. Fanger,et al.  Bispecific antibodies. , 1992, Critical reviews in immunology.

[54]  H. Goossens,et al.  The tumor-associated antigen RHAMM (HMMR/CD168) is expressed by monocyte-derived dendritic cells and presented to T cells , 2016, Oncotarget.

[55]  A. Scott,et al.  Gene-modified T cells as immunotherapy for multiple myeloma and acute myeloid leukemia expressing the Lewis Y antigen , 2010, Gene Therapy.

[56]  P. Parren,et al.  ADCT-301, a Pyrrolobenzodiazepine (PBD) Dimer–Containing Antibody–Drug Conjugate (ADC) Targeting CD25-Expressing Hematological Malignancies , 2016, Molecular Cancer Therapeutics.

[57]  G. Ehninger,et al.  Costimulation improves the killing capability of T cells redirected to tumor cells expressing low levels of CD33: description of a novel modular targeting system , 2014, Leukemia.

[58]  G. Schuurhuis,et al.  C-Type Lectin-Like Molecule-1 , 2004, Cancer Research.

[59]  I. Aldoss,et al.  Redirecting T cells to eradicate B-cell acute lymphoblastic leukemia: bispecific T-cell engagers and chimeric antigen receptors , 2017, Leukemia.

[60]  P. Loo,et al.  Preclinical Evaluation of MCLA117, a CLEC12AxCD3 Bispecific Antibody Efficiently Targeting a Novel Leukemic Stem Cell Associated Antigen in AML , 2015 .

[61]  X. H. Chen,et al.  Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[62]  N. Bartlett,et al.  Phase 1 Results of ZUMA-1: A Multicenter Study of KTE-C19 Anti-CD19 CAR T Cell Therapy in Refractory Aggressive Lymphoma , 2017, Molecular therapy : the journal of the American Society of Gene Therapy.

[63]  A. Biondi,et al.  Acute Myeloid Leukemia Targeting by Chimeric Antigen Receptor T Cells: Bridging the Gap from Preclinical Modeling to Human Studies. , 2017, Human gene therapy.

[64]  Carsten Reinhardt,et al.  Bispecific T-cell engaging antibodies for cancer therapy. , 2009, Cancer research.

[65]  F. Ravandi,et al.  Vadastuximab Talirine Monotherapy in Older Patients with Treatment Naive CD33-Positive Acute Myeloid Leukemia (AML) , 2016 .

[66]  Tamara J Laskowski,et al.  Redirecting Specificity of T cells Using the Sleeping Beauty System to Express Chimeric Antigen Receptors by Mix-and-Matching of VL and VH Domains Targeting CD123+ Tumors , 2016, PloS one.

[67]  R. Larson,et al.  A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia. , 2013, Blood.

[68]  R. Walter,et al.  Antigen-specific immunotherapies for acute myeloid leukemia. , 2015, Hematology. American Society of Hematology. Education Program.

[69]  M. Subklewe,et al.  Effects of TLR agonists on maturation and function of 3-day dendritic cells from AML patients in complete remission , 2011, Journal of Translational Medicine.

[70]  W. Hiddemann,et al.  Blockade of the PD-1/PD-L1 axis augments lysis of AML cells by the CD33/CD3 BiTE antibody construct AMG 330: reversing a T-cell-induced immune escape mechanism , 2016, Leukemia.

[71]  T. Migone,et al.  A novel antibody–drug conjugate targeting SAIL for the treatment of hematologic malignancies , 2015, Blood Cancer Journal.

[72]  R. Berger,et al.  Phase I Safety and Pharmacokinetic Study of CT-011, a Humanized Antibody Interacting with PD-1, in Patients with Advanced Hematologic Malignancies , 2008, Clinical Cancer Research.

[73]  A. Hagemeijer,et al.  Gemtuzumab Ozogamicin Versus Best Supportive Care in Older Patients With Newly Diagnosed Acute Myeloid Leukemia Unsuitable for Intensive Chemotherapy: Results of the Randomized Phase III EORTC-GIMEMA AML-19 Trial. , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[74]  D. Campana,et al.  A chimeric receptor with NKG2D specificity enhances natural killer cell activation and killing of tumor cells. , 2013, Cancer research.

[75]  W. Kavanaugh,et al.  Abstract A203: CD3-EGFR bispecific Probody™ therapeutics induced tumor regressions and increased therapeutic window in preclinical studies , 2015 .

[76]  H. Kantarjian,et al.  Phase 1 study of an anti-CD33 immunotoxin, humanized monoclonal antibody M195 conjugated to recombinant gelonin (HUM-195/rGEL), in patients with advanced myeloid malignancies , 2013, Haematologica.

[77]  E. Estey,et al.  Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomised controlled trials. , 2014, The Lancet. Oncology.

[78]  I. Bernstein,et al.  SGN-CD33A: a novel CD33-targeting antibody-drug conjugate using a pyrrolobenzodiazepine dimer is active in models of drug-resistant AML. , 2013, Blood.

[79]  Raphael Sandaltzopoulos,et al.  Chimeric Antigen Receptor T Cells with Dissociated Signaling Domains Exhibit Focused Antitumor Activity with Reduced Potential for Toxicity In Vivo , 2013, Cancer Immunology Research.

[80]  G. Schuurhuis,et al.  Targeting of CLEC12A In Acute Myeloid Leukemia by Antibody-Drug-Conjugates and Bispecific CLL-1×CD3 BiTE Antibody , 2010 .

[81]  W. Hiddemann,et al.  CD86 and IL-12p70 Are Key Players for T Helper 1 Polarization and Natural Killer Cell Activation by Toll-Like Receptor-Induced Dendritic Cells , 2012, PloS one.

[82]  M. Linenberger,et al.  CD33-directed therapy with gemtuzumab ozogamicin in acute myeloid leukemia: progress in understanding cytotoxicity and potential mechanisms of drug resistance , 2005, Leukemia.

[83]  M. Liedtke,et al.  Inotuzumab Ozogamicin versus Standard Therapy for Acute Lymphoblastic Leukemia. , 2016, The New England journal of medicine.

[84]  R. Schlenk,et al.  The European LeukemiaNet AML Working Party consensus statement on allogeneic HSCT for patients with AML in remission: an integrated-risk adapted approach , 2012, Nature Reviews Clinical Oncology.

[85]  J. Medin,et al.  Engineering Hematopoietic Cells for Cancer Immunotherapy: Strategies to Address Safety and Toxicity Concerns , 2016, Journal of immunotherapy.

[86]  P. Sharma,et al.  Phase IB/II Study of Nivolumab in Combination with Azacytidine (AZA) in Patients (pts) with Relapsed Acute Myeloid Leukemia (AML) , 2016 .

[87]  S. Tippmer,et al.  Generation of Th1-Polarizing Dendritic Cells Using the TLR7/8 Agonist CL075 , 2010, The Journal of Immunology.

[88]  T G Berger,et al.  Dendritic cell-based immunotherapy. , 2003, Current topics in microbiology and immunology.

[89]  J. Heiber,et al.  Anti-CD33 chimeric antigen receptor targeting of acute myeloid leukemia , 2015, Haematologica.

[90]  A. Varki,et al.  Myeloid precursors and acute myeloid leukemia cells express multiple CD33-related Siglecs. , 2006, Experimental hematology.

[91]  E. Meyer,et al.  Type I interferon causes thrombotic microangiopathy by a dose-dependent toxic effect on the microvasculature. , 2016, Blood.

[92]  Scott E. Smith,et al.  A Phase 1b Study of Vadastuximab Talirine in Combination with 7+3 Induction Therapy for Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) , 2016 .

[93]  T. Knösel,et al.  Increase of PD-L1 expressing B-precursor ALL cells in a patient resistant to the CD19/CD3-bispecific T cell engager antibody blinatumomab , 2015, Journal of Hematology & Oncology.

[94]  J. Desjarlais,et al.  Immunotherapy with Long-Lived Anti-CD123 × Anti-CD3 Bispecific Antibodies Stimulates Potent T Cell-Mediated Killing of Human AML Cell Lines and of CD123+ Cells in Monkeys: A Potential Therapy for Acute Myelogenous Leukemia , 2014 .

[95]  G. V. van Dongen,et al.  The novel AML stem cell associated antigen CLL-1 aids in discrimination between normal and leukemic stem cells. , 2005, Blood.

[96]  J. F. Nemeth,et al.  Development of a CD123xCD3 Bispecific Antibody (JNJ-63709178) for the Treatment of Acute Myeloid Leukemia (AML) , 2016 .

[97]  D. Howard,et al.  A phase 2 trial of azacitidine and gemtuzumab ozogamicin therapy in older patients with acute myeloid leukemia. , 2013, Blood.

[98]  W. Klapper,et al.  Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia , 2017, The New England journal of medicine.

[99]  H. Lowman,et al.  Probody therapeutics for targeting antibodies to diseased tissue , 2014, Expert opinion on biological therapy.

[100]  D. Neuberg,et al.  Individualized vaccination of AML patients in remission is associated with induction of antileukemia immunity and prolonged remissions , 2016, Science Translational Medicine.

[101]  J. Guenot,et al.  Characterization of CD33/CD3 Tetravalent Bispecific Tandem Diabodies (TandAbs) for the Treatment of Acute Myeloid Leukemia , 2016, Clinical Cancer Research.

[102]  Daniel Li,et al.  CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. , 2016, The Journal of clinical investigation.

[103]  G. Ehninger,et al.  Improved Killing of AML Blasts By Dual-Targeting of CD123 and CD33 Via Unitarg a Novel Antibody-Based Modular T Cell Retargeting System , 2015 .

[104]  J. Dipersio,et al.  Targeting CD123 In Leukemic Stem Cells Using Dual Affinity Re-Targeting Molecules (DARTs®) , 2013 .