Immunotherapeutic strategies for relapse control in acute myeloid leukemia

Blood Reviews 27 (2013) 209–216

Contents lists available at ScienceDirect

Blood Reviews journal homepage: www.elsevier.com/locate/blre

REVIEW

Immunotherapeutic strategies for relapse control in acute myeloid leukemia Anna Martner, Fredrik Bergh Thorén, Johan Aurelius, Kristoffer Hellstrand ⁎ Sahlgrenska Cancer Center, University of Gothenburg, Box 405, 40530 Gothenburg, Sweden

a r t i c l e

i n f o

Keywords: Acute myeloid leukemia Maintenance therapy Leukemia-related immunosuppression

a b s t r a c t Despite that the initial phases of chemotherapy induce disappearance of leukemic cells in many patients with acute myeloid leukemia (AML), the prevention of life-threatening relapses in the post-remission phase remains a significant clinical challenge. Allogeneic bone marrow transplantation, which is available for a minority of patients, efficiently prevents recurrences of leukemia by inducing immune-mediated elimination of leukemic cells, and over the past decades, numerous immunotherapeutic protocols have been developed aiming to mimic the graft-versus-leukemia reaction for the prevention of relapse. Here we review past and present strategies for relapse control with focus on overcoming leukemia-related immunosuppression in AML. We envisage future treatment protocols, in which systemic immune activators, such as vaccines, dendritic cell-based therapies, engineered variants of IL-2, or IL-15, are combined with agents that counter immunosuppression mediated by, e.g., the PD/PDL interaction, CTLA-4, CD200, reactive oxygen species, IDO expression, CXCR4, or the KIR/class I interaction, based on characteristics of the prevailing malignant clone. This combinatorial approach may pave the way for individualized immunotherapy in AML. © 2013 Elsevier Ltd. All rights reserved.

1. Introduction Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults with an incidence of approximately 4/100,000 [1,2]. Upon diagnosis, patients receive induction chemotherapy aiming to achieve complete remission (CR), which is defined as absence of microscopically detectable malignant cells along with the return of normal hematopoiesis. The post-remission therapy comprises consolidation chemotherapy with the goal of eradicating remaining undetectable leukemic cells [3,4]. This phase of therapy is critical for a favorable long-term outcome as nearly all patients will experience recurrence of leukemia (relapse) if consolidation is not provided [5]. The risk of relapse varies with several well-defined prognostic factors, in particular the patients' age and genetic aberrations of the leukemic clone, as reviewed in detail elsewhere [6–8]. Despite successful induction therapy and completed consolidation therapy, relapse occurs in 60–70% of patients within five years [9]. In the first relapse, the likelihood of achieving a renewed CR is lower than at onset of disease, and the duration the second CR is almost invariably shorter than the first [10]. The median survival of relapsing patients is in the range of 6 months with few long-term survivors [11]. Relapse is a significant reason why the overall prognosis of adult patients with AML remains poor with a 20–30% likelihood of 5-year survival after diagnosis [1,12].

⁎ Corresponding author at: Sahlgrenska Cancer Center, University of Gothenburg, Box 425, 40530 Gothenburg, Sweden. Tel.: + 46 706 204358. E-mail address: [email protected] (K. Hellstrand). 0268-960X/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.blre.2013.06.006

Patients with unfavorable genetic aberrations in leukemic cells are candidates for allogeneic stem cell transplantation, which is used in the consolidation phase or as intensification therapy. Allo-transplantation was earlier offered primarily to younger otherwise healthy patients, but in recent years the development of protocols using reduced intensity conditioning has enabled its use also among patients in their 70's and among those with significant co-morbidities [13,14]. For the majority of AML patients however, i.e. those who are not candidates for allo-transplantation, the consensual standard of care has been no further anti-leukemic treatment. An exception is that several centers in Germany practice repeated courses of chemotherapy also in the post-consolidation phase, which appears beneficial in terms of relapse protection in elderly patients [15,16]; however the toxicity of this treatment has limited its wide-spread use. A relapse is assumed to result from expansion of malignant cells that have escaped the cytotoxic action of chemotherapy, and the goal of AML treatment beyond consolidation is to eradicate these remaining cells (“minimal residual disease”, MRD) to cure patients. In this overview, we present past and present strategies to maintain CR in the postconsolidation phase of AML with particular focus on the utility of immunotherapy to achieve immune-mediated elimination of residual leukemic cells. 2. Immune reactivity in AML Measurable adaptive immune responses evolve in most patients with AML, as evidenced by the demonstration of antibodies [17–19] as well as by CD4+ and CD8+ T cell responses directed against leukemia-related antigens (reviewed in [20]). In addition, AML cells are frequently sensitive

210

A. Martner et al. / Blood Reviews 27 (2013) 209–216

to the cytotoxic action of natural killer (NK) cells [21–23]. While the impact of humoral immune response for the outcome of AML remains unknown, a large body of evidence suggests that T and NK cell functions are pivotal for leukemia-free survival after the completion of chemotherapy. In the following section we review the purported role of these immune effector cells with focus on their impact for remission maintenance. 2.1. T cells in immune surveillance The surveilling role of T cells is founded on experiences from allo-transplantation in AML and related diseases. For example, several studies demonstrate that transplanted patients with low-grade or absent T cell-dependent graft-versus-host disease show a higher probability of relapse [24,25]. In addition, elimination of T cells from the transplant increases the relapse risk in AML [4,26], and the re-infusion of donor T cells can induce CR in a small but significant fraction of patients [23]. While the role of transplanted T cells for remission maintenance is well established, relatively few investigators have addressed the clinical relevance of anti-leukemic T-cell responses in non-transplanted patients. In a study of pediatric patients with AML, who had either received only chemotherapy or an autologous transplant, Montagna and co-workers showed that the emergence of anti-leukemic cytotoxic T cell precursors (CTLp's) in bone marrow and blood was associated with long-term remission maintenance: no relapses were observed among 8 non-transplanted patients in CR in whom CTLp's were detected, whereas 7/8 patients with absence of CTLp's experienced relapse. Interestingly, in patients with absence of anti-leukemic CTLp's sizeable levels of EBV-specific CTLs were detected, thus suggesting a specific deficiency to mount an anti-leukemic T cell response [27]. Similarly, Greiner et al. demonstrated a significant correlation between a strong mRNA expression of leukemia-related T cell antigens and survival of patients with AML [28]. Despite the relative scarcity of clinical correlates between T-cell function and outcome in AML, several studies point to an impaired cytotoxic T-cell response in AML, partly due to a deficiency of antigen exposure on MHC class I by leukemic cells. AML blasts thus have been reported to display a skewed balance of co-inhibitory vs. co-stimulatory receptors [29] and recent data also imply a deficiency of T cell/AML blast immune synapse formation [30]. A striking, albeit indirect support for the role of T cells for outcome was provided in a report by Chamuleau and co-workers in their study of the indoleamine 2,3-dioxygenase (IDO) immunosuppressive pathway. IDO degrades tryptophan, which is essential for T cell expansion, and high expression of INDO mRNA by leukemic blasts was shown to herald poor prognosis. High INDO expression was associated with both a higher frequency of relapse among patients in CR and a significantly lower rate of CR, thus implying that INDO/IDO determines the outcome of AML by multiple mechanisms [31]. 2.2. NK cells in immune surveillance The role of autologous NK cells as potential anti-leukemic effector cells in AML has been studied extensively, as reviewed in detail elsewhere [32]. The number of circulating NK cells, an intact anti-tumor cytotoxicity of NK cells, a maintained cytokine-producing function of NK cells, and a preserved expression of activating receptors by NK cells all herald a favorable outcome of AML [23,33–38]. The correlation between NK cell functional integrity and outcome largely reflects a dysfunction of the NK cell population in AML. While the mechanisms are only partly understood, convincing data point to the possibility that NK cells may be inactivated by cells of the leukemic clone, which have been reported to secrete various soluble NK-cell inhibitory factors such as TGF-beta and reactive oxygen species [35,39–42] as well as to inhibit NK cells by cell-to-cell interaction

[43–45]. Table 1 summarizes aspects on lymphocyte dysfunction in AML. The lytic activity of NK cells is governed by their expression of inhibitory and activating receptors [46–48]. Inhibitory killer immunoglobulinlike receptors (KIRs) recognize HLA-A, HLA-B and HLA-C proteins leading to inactivation of NK cells that encounter self-HLA molecules on putative target cells. This mechanism of NK cell inactivation is proposed to explain how NK cells avoid attacking autologous cells, but is assumed to have relevance also for the outcome of allo-transplantation in AML. Retrospective analyses of the KIR status of donor NK cells vs. HLA class I molecules of the recipient thus revealed that mismatches of KIR/class I – which predict allo-reactivity of grafted NK cells – were strongly associated with a reduced risk of relapse after allo-transplantation [49]. Similar results were reported in a subsequent study [50] but disputed by others [51–53]. Additional studies are warranted to define the value of KIR ligand mismatching in AML (for further review, see [32,48,54]). Recent studies propose a protective role also for activating KIRs in AML in the context of allo-transplantation. KIR2DS1 recognizes HLA-C2 molecules, and NK cells expressing KIR2DS1 that are derived from HLA-C1 subjects (HLA-C1/C1 or C1/C2) secrete interferon-γ and efficiently lyse target cells, in particular those expressing HLA-C2. In contrast KIR2DS1+ NK cells from subjects who are homozygous for HLA-C2 (HLA-C2/C2) – thus expressing the ligand for KIR2DS1 as a self-molecule – are hyporesponsive in terms of cytotoxicity and capacity to produce cytokines. With this background, Venstrom and co-workers [55] studied the impact of KIR2DS1 on the relapse rate of allo-transplanted patients. It was observed that the risk of relapse was significantly lower when donors were KIR2DS1+, but only when donors also were homo- or heterozygous for HLA-C1. Patients receiving KIR2DS1+ transplants from HLA-C2/C2 donors thus showed a frequency of relapse similar to that observed with KIR2DS1− transplants. These findings are consistent with the notion that KIR2DS1 is an activating KIR in HLA-C1/C1 or HLA C1/C2 donors, and that KIR2DS1-expressing NK cells are tolerized in HLA-C2/C2 donors [56–58]. Importantly, the results support that donor NK cells significantly contribute to the graft-versus-leukemia reaction with ensuing reduction of relapse risk. 3. Immunotherapy for remission maintenance The notion that immune cells participate in surveillance of leukemic cells in AML, specifically that (1) endogenous T cells and NK cells are endowed with significant anti-leukemic function in AML and (2) both of these lymphocyte subsets significantly contribute to the graftversus-leukemia effect after allo-transplantation, has inspired the evaluation of systemic T cell and NK cell activating agents for relapse control. In addition, the favorable effects of monoclonal antibodies against antigens expressed by malignant cells, in particular in the treatment of B cell malignancies [59–62], have encouraged the development of therapeutic antibodies against AML cells. A potential advantage of immunotherapy is that LSCs, which due to their non-proliferating state ostensibly escape chemotherapy, may be targeted by antibodies and cytotoxic immune cells. 3.1. Monoclonal antibodies Strategies to target leukemic cells using monoclonal antibodies have significantly improved treatment of chronic lymphatic leukemia (CLL) and lymphoma, where CD20 antibodies such as rituximab are routinely used [59–62]. Similar strategies are currently evaluated also in AML. Antibodies binding to leukemic cells are assumed to facilitate clearance of the malignant cells via antibody-dependent cellular cytotoxicity (ADCC), presumably exerted by CD16+ NK cells, or complement activation. Antibodies may also be conjugated to cytotoxic drugs and radioisotopes for directed actions on leukemic cells.

A. Martner et al. / Blood Reviews 27 (2013) 209–216

211

Table 1 Leukemia-related immunosuppression in AML. Immunosuppressive mechanism

Mode of action and rationale

Therapy

Clinical development

Reactive oxygen species (ROS)

ROS produced by malignant and non-malignant myeloid cells inactive cytotoxic lymphocytes in a PARP-1/ AIF-dependent fashion with ensuing lymphocyte apoptosis.

Histamine dihydrochloride (HDC), a ROS formation inhibitor

Ipilimumab (anti-CTLA-4)

Post-consolidation immunotherapy with [39,112,113,115,117] HDC in conjunction with low-dose IL-2 significantly improved leukemia-free survival in a phase III trial. Post hoc analyses suggested pronounced clinical benefit in monocytic leukemias, where malignant cells express histamine H2-receptors and ROS-producing enzymes. HDC/IL-2 is approved for relapse prevention within EU and in Israel. Early-stage trials are ongoing. [79,83,84]

Anti-PD-L1

Early-stage trials are ongoing.

[43,76]

Preclinical stage.

[133,134,31]

Preclinical stage.

[135,136]

Preclinical stage.

[45,91,137,138]

CTLA-4

CTLA-4 (CD152) on Tregs impairs T-cell function, partly by down-regulating CD80 and CD86 on APCs. CTLA-4 also negatively regulates CD4+ and CD8+ T cells. Programmed cell PD-1 down-modulates T cell function after death-1 (PD-1) interaction with PD-L1, which is expressed by a fraction of AML cells. IDO depletes tryptophan, which is essential Indoleamine for T cell expansion. IDO also induces Tregs 2,3-dioxygenase (IDO) via the tryptophan metabolite 3-HAA. High expression of INDO (encoding IDO) predicts poor prognosis in AML. Fas-ligand (FasL) FasL is expressed by subgroups of AML cells and triggers apoptosis of Fas+ T cells in vitro. FasL is also present in immunosuppressive tumor-derived exosomes (TEX) obtained from AML patients. CD200 CD200R on T cells/NK cells transduces immunosuppressive signals by targeting CD200 expressed by AML cells. CD200 expression by AML cells entails poor prognosis. NK cells from patients with CD200-positive AML are reduced in number and function. Inhibitory KIRs suppress NK cells by transKiller-cell immunoglobulin-like mitting a “self”-signal after binding to HLA class I. Mismatches of KIR/class I may be a receptors (KIR) positive prognostic marker after allo-BMT. Blocking of KIR using IPH2101 has shown promise in a phase I trial.

Anti-CD200

1. SCT with mismatched KIR/class I Early-phase clinical trials. 2. Anti-KIR (IPH2101)

3.1.1. Anti-CD33 Most studies of monoclonal antibodies in AML therapy have focused on CD33 as the target antigen. CD33 is expressed on 85–90% of leukemic blasts as well as by multipotent myeloid precursors, monocytes and neutrophils. The antigen is absent from pluripotent hematopoietic stem cells. Unconjugated anti-CD33 antibodies have shown little clinical benefit in CD33+ non-APL AML [63], but conjugation of anti-CD33 antibodies to cytotoxic drugs or radioisotopes has proven a more efficacious strategy (reviewed in [64]). Gemtuzumab ozogamicin (GO), where anti-CD33 is conjugated to the cytotoxic agent calicheamicin, was approved in 2000 by the FDA as a single-agent induction therapy in elderly patients with relapsed AML [65]. In 2010, GO was withdrawn from the market due to post-approval clinical trials that failed to verify sufficient clinical benefit along with liver toxicity [66,67]. GO is currently undergoing further clinical evaluation, and the use of fractionated lower doses of GO was recently reported to allow the safe delivery of higher cumulative doses along with significantly improved outcome [68]. In APL, cells of the leukemic clone homogenously express CD33, and GO appears to efficiently target these leukemic cells [69,70]. 3.1.2. Antibodies targeting LSC A disadvantage of anti-CD33 antibodies is that less differentiated leukemic cells, not expressing CD33, are not targeted. Although controversies still exist, accumulating evidence indicates that AML cells are organized as a cellular hierarchy, initiated and maintained by self-renewing leukemic stem cells (LSC) [71]. Thus, the LSC most probably need to be eliminated for a permanent cure of AML.

Reference

[48,49,55,85]

The phenotype, maturation stage and expression of cell-surface molecules on the LSC are likely to differ between subtypes of AML. Studies aiming at identifying cell-surface antigens preferentially expressed by LSC, but not by normal hematopoietic stem cells (HSC), have revealed several promising targets including the adhesion molecule CD44, the anti-phagocytic molecule CD47 and the high affinity IL-3 receptor IL3RAP or CD123 (reviewed in [72]). Monoclonal antibodies targeting CD44 [73], CD47 [74] and CD123 [75] have demonstrated efficacy against LSC expressing these surface antigens in murine xenotransplantation models, and anti-CD123 antibodies are currently undergoing investigation in a phase I trial (NCT01632852). 3.1.3. Antibodies targeting PD-L1, PD-L2 and PD-1 Expression of PD-L1 and PD-L2 by cancer cells has been proposed to represent an immune escape mechanism as interactions between these receptors and PD-1, expressed by T cells and NK cells, conveys inhibitory signals to these lymphocytes. In a murine model of AML, blocking of either PD-1 or PD-L1 led to improved T cell responses, rejection of PD-L1 expressing AML cells and increased survival [76]. In a study of 79 AML patients, 18% had B7-H1+ (PD-L1+) blasts [43]; this study also demonstrated that the expression of PD-L1 on leukemic cells was inducible by IFN-γ, and that expression of PD-L1 protected AML cells from CTL lysis [43]. No clinical trials evaluating the usefulness of antibodies inhibiting interactions between PD-L1/ PD-L2 and PD-1 have been completed for AML patients, but trials in other forms of cancer (NCT00729664, NCT00730639) imply that targeting the PD/PD-L interaction is a potentially efficacious strategy

212

A. Martner et al. / Blood Reviews 27 (2013) 209–216

[77,78]. Since expression of PD-L1 and PD-L2 is induced during immune responses, in part due to the secretion of by IFN-* by lymphocytes, antibodies targeting the PD-1/PD-L1/2 axis may be useful in particular as adjuncts to immunostimulatory therapies. An ongoing trial in AML evaluates the efficacy of blocking PD-1 in conjunction with a DC vaccine (NCT01096602). However, treatments blocking interactions between PD-L1/PD-L2 and PD-1 entail considerable toxicity that may limit its putative use for remission maintenance in AML [77,78]. 3.1.4. Antibodies targeting CTLA-4 In analogy with antibodies targeting PD-1, antibodies against the negative T cell regulator CTLA-4 have been considered in the treatment of AML. CTLA-4 inhibits T cell activation via two principal mechanisms; firstly, when T cells are activated these cells up-regulate expression of CTLA-4, which conveys T cell inhibition upon interaction with its receptors CD80 and CD86. Secondly, CTLA-4 is constitutively expressed by regulatory T cells (Tregs) and plays a critical role for the immunosuppression exerted by these cells [79]. Thus, Tregs down-modulate CD80 and CD86 by DCs in a CTLA-4 dependent manner, rendering the DCs less capable of initiating immune responses [79,80]. The CTLA-4 antibody ipilimumab has been approved for treatment of metastatic malignant melanoma on the basis of several trials showing improved overall survival [81,82]. There are reports showing a correlation between high frequencies of Tregs and unfavorable outcome of AML [83,84] and early-stage trials targeting CTLA-4 in AML are underway (NCT01757639, NCT00060372). 3.1.5. Anti-KIR As discussed in Section 2.2, allo-transplantation with KIR-HLAmismatched donors has highlighted the importance of NK cell function for outcome. A fraction of grafted NK cells cannot be inhibited due to the KIR/KIR ligand mismatch, which enhances NK cell cytotoxicity against leukemic cells. With this background, attempts are being made in non-transplanted patients to treat patients with antibodies directed against inhibitory KIRs on NK cells. In a phase I trial, the administration of the antibody IPH2101, which blocks the major inhibitory KIRs, was shown to be feasible and potentially efficacious in elderly AML patients in first CR [85]. An ongoing randomized phase II trial evaluates IPH2101 for remission maintenance (NCT01687387). 3.1.6. CXCR4 inhibitors and antibodies The interaction of myeloid leukemic blasts with the bone marrow environment is postulated to keep leukemic cells in a dormant stage. The chemokine receptor CXCR4, which is expressed by approximately 50% of AML blasts, binds to CXCL12 produced by bone marrow stromal cells [86]. Targeting the CXCR4/CXCL12 interaction therefore may favor stem cell mobilization and cell cycle entry, thus resulting in enhanced sensitivity to chemotherapy [87]. Early-stage trials have been performed using the CXCR4 inhibitor plerixafor in combination with chemotherapy [88]. Preclinical studies have shown that also other small molecule antagonists and humanized antibodies targeting CXCR4 exhibit potent CXCR4dependent cytotoxicity [89,90], and a phase I study has been initiated using anti-CXCR4 in AML (NCT01120457). 3.1.7. Targeting CD200 CD200 is an immunosuppressive glycoprotein that transduces inhibitory signals upon interaction with CD200R. CD200 is expressed by several subsets of leukocytes including T cells, B cells and dendritic cells as well as by subsets of AML cells [44]. Over-expression of CD200 by AML cells has been associated with increased relapse risk, in particular in non-core binding factor leukemias [91]. NK cells from patients with CD200hi AML cells are reduced in number and function [45] and in vitro analyses imply that CD200+ AML cells suppress NK cell function, which is prevented by CD200 blockade [45]. Notably, anti-CD200 of the IgG1, but not IgG2 or IgG4, isotypes yielded depletion of activated

human T cells in vitro by mediating antibody-dependent cellular cytotoxicity by NK cells [92]. 3.2. Immunotherapy with systemic cytokines 3.2.1. Cell cycle induction A limitation of chemotherapy is that only dividing cells are targeted, thus dormant leukemic stem cells (LSC) may escape the cytotoxic action of such therapy. A means to enable targeting also of LSC may be to induce cell-cycle progression of resting AML cells. Induction therapy regimens in China and Japan frequently combine cytarabine and aclarubin with G-CSF, where the latter drug aims to trigger proliferation of resting leukemic cells. A meta-analysis of thirty-five trials with a total of 1029 AML and MDS patients showed that the CR rate of regimens where G-CSF was included was significantly higher than regimens without G-CSF [93]. 3.2.2. NK and T cell activators An early form of immunotherapy in AML comprised stimulation with bacillus Calmette-Guérin (BCG), which triggers the formation of immune-enhancing cytokines such as interleukin-2 (IL-2), IL-12 and IL-18 in addition to polyclonally activating subsets of T cells. No randomized evaluation of the putative efficacy of BCG administration in the post-chemotherapy phase of AML treatment has been performed, but meta-analyses suggested that this treatment did not impact on relapse risk or survival [94]. More recent studies have used interferon-α, which efficiently activates NK cell-mediated cytotoxicity and improves antigen presentation [95], for remission maintenance; a randomized AML trial by Goldstone and co-workers did not, however, show a benefit in terms of relapse protection by this treatment [96]. In the late 1990's linomide, a quinoline derivative with pleiotropic immunostimulatory properties, including NK cell activation, was evaluated for relapse prevention in AML in a randomized phase III trial, again with disappointing results [97]. Despite the failure of these earlier efforts to avoid relapses by boosting immunity in the post-chemotherapy phase, there were significant expectations of successful AML immunotherapy in the form of IL-2, a T cell-derived cytokine that activates several subsets of T cells and, additionally, strongly boosts the cytotoxic activity of NK cells [98]. However, IL-2 monotherapy for relapse control has yielded disappointment: six randomized trials using IL-2 have failed to demonstrate significant relapse prevention or prolongation of time in CR [99–104]. The inefficiency of IL-2 to prevent relapse has been confirmed in two meta-analyses comprising a total of N 1400 patients [105,106]. The lack of in vivo efficacy of NK and T stimulatory therapies may be due to leukemia-related immunosuppressive mechanisms that counter the desired induction of cell-mediated, anti-leukemic immunity. Several immunosuppressive pathways have been described in AML [33,34,40] and thus immunostimulatory agents may need to be combined with counter-suppressive strategies to unravel their anti-leukemic potential. A mechanism of immunosuppression of potential relevance to the efficiency of IL-2 treatment in AML relates to the capacity of myeloid cells (i.e. normal and malignant monocyte/macrophages and granulocytes) to produce reactive oxygen species (ROS) via the NADPH oxidase (NOX-2) [107–109]. Extracellular, myeloid cell-derived ROS down-regulate functions of NK cells and T cells and trigger significant cell death in these lymphocyte subsets. A NOX-2 inhibitor, histamine dihydrochloride (HDC), acting via H2 type histamine receptors expressed by myeloid cells, rescues NK cells and T cells from ROS-induced inhibition and apoptosis, and promotes anti-leukemic functions of IL-2 [110–114]. HDC has been used together with IL-2 for relapse prevention in AML in several clinical trials, and a phase III study of 320 patients in the post-consolidation phase showed a significantly improved leukemia-free survival in patients receiving HDC/IL-2 [115]. In 2009, the combination of HDC and IL-2 was approved within EU as maintenance remission therapy in AML [113,114,116].

A. Martner et al. / Blood Reviews 27 (2013) 209–216

Recently, it was reported that the clinical benefit of HDC/IL-2 may be preferential to or restricted to subtypes of AML. Aurelius et al. performed post hoc analyses of phase III trial results pointing to a pronounced relapse-protective among patients with monocytic AML (FAB classes M4 and M5), but no apparent benefit in FAB-M2 (myeloblastic) AML [117]. These authors also reported that FAB-M4/M5 AML cells, but not FAB-M2 cells, triggered extensive apoptosis in adjacent NK cells by producing ROS via NOX-2. FAB-M4/M5 cells expressed functional H2Rs that mediated inhibition of ROS production by HDC, which rescued NK cells from AML cell-induced apoptosis. These findings thus imply that monocytic AML cells utilize ROS as a strategy to avoid destruction by NK cells, and that the value of HDC/IL-2 therapy may be explained by H2R-dependent inhibition of ROS-production by leukemic cells, as depicted in Fig. 1 [39,117]. A potential disadvantage with the use of IL-2 as an immunostimulatory agent is that this cytokine induces Tregs [79,118–121]. These cells express the high-affinity IL-2 receptor CD25 (IL-2Rα), and the IL-2-induced expansion of Tregs in AML immunotherapy may thus compromise anti-leukemic efficacy. Recently, modified variants of IL-2 were developed that activate T cells irrespective of interaction with CD25. One such IL-2 variant was superior to IL-2 in expanding the population of cytotoxic T cells; it also showed improved anti-tumor responses in vivo and elicited less expansion of Treg cells [122]. A similar approach was adopted by Klein and co-workers, who developed an IL-2 variant with abolished CD25 binding, fused to the C-terminus of a tumor-specific IgG1 antibody [123]. IL-15 shares several immunostimulatory properties of IL-2, but does not induce Treg responses. Thus, IL-15 preferentially drives expansion of CD8+ central and effector memory T cells and NK cells, with no apparent effect on Tregs [124]. Two phase I trials are currently determining the safety of IL-15 monotherapy in metastatic malignant melanoma and renal cell carcinoma, and in combination with adoptive transfer of haploidentical NK cells in AML (NCT01369888, NCT01021059, NCT01385423). 3.3. Strategies for vaccination in AML As recently reviewed by Anguille and co-authors [20], a large number of T-cell antigens have been identified in AML. These antigens are leukemia-specific (LSA), i.e. uniquely expressed by AML cells, or leukemia-associated (LAA), i.e. expressed at low levels also by non-malignant cells.

213

Several of the LSAs are proteins that arise from chromosomal translocations and include fusion proteins such as AML1-ETO (t(8;21)), DEK-CAN (t(6;9)) and promyelocytic leukemia-retinoic receptor alpha (PML-RARα; t (15;17)). Mutant proteins with properties of LSA have also been identified in Flt3-ITD+ and NPM1+ AML. The development of LSAs for AML immunotherapy has hitherto been hampered by the fact that these antigens typically are relevant to small groups of patients, and the current information on the clinical utility of LSA-based immunotherapy is scarce. Recently, immunogenic properties of the protein encoded by the mutated nucleophosmin gene (NPMmut) were described; this mutation is found in approximately 30% of all patients with AML and in 50–60% of those with normal karyotype. Greiner et al. [125] found that 30–40% of AML patients showed T cell responses to NPMmut-derived epitopes, implying that this LSA may constitute a target for T-cell based therapy in a relatively large patient group. Immunogenic LAAs, in particular those expressed by a wider range of AML subtypes, have been more extensively studied. Induction of T cell immunity has been achieved either by vaccination with LAA-associated peptides or observed in the context of allo-transplantation with CD8+ responses occurring against, e.g., BMI1, HOXA9, hTERT, MUC1, myeloperoxidase, proteinase 3, and RHAMM, but the information about the clinical relevance of induction of respective T cell subsets is mostly anecdotal. The Wilm's tumor 1 antigen (WT1), which is overexpressed by AML cells, is arguably the best characterized LAA. The antigen is expressed across FAB classes of AML and expressed by LSCs, and several WT1-derived peptides have been assessed for in vivo immunogenicity in patients with AML [126] (reviewed in Angullie et al. [20]). Recently, Van Tendeloo et al. [127] introduced full-length WT1 mRNA into dendritic cells (DCs) and observed reductions of WT1 transcript levels (as a marker of residual leukemia) in five WT1/DC-vaccinated AML patients in parallel with the development of WT1-specific CD8+ T cells. Several clinical trials are in process to evaluate the potential benefit of WT1/DC immunotherapy in AML [128]. In addition to immunity evoked by vaccination or allo-transplantation, non-transplanted patients may display natural T and B cell reactivity against AML-derived antigens. A study by Greiner et al. [28] showed that approximately one third of AML patients develop antibodies against several AML antigens, and Scheibenbogen et al. [129] reported the induction of CD8+ T cell responses to WT1 and proteinase 3 among newly diagnosed patients and those in CR. Additional studies from the

Fig. 1. Schematic representation of ROS-induced suppression of NK cells and its regulation by HDC and IL-2. (A) Mature monocytic AML cells produce ROS via the NADPH-oxidase, which triggers apoptotic cell death in adjacent NK cells. (B) HDC inhibits ROS production acting via H2-receptors on monocytic AML cells and thus preserves NK cell viability and function, including responsiveness to IL-2.

214

A. Martner et al. / Blood Reviews 27 (2013) 209–216

Greiner group demonstrated that 7/10 patients in CR displayed T cell responses against the oncofetal antigen preferentially expressed antigen of melanoma (PRAME), and that mRNA expression in AML cells of at least 1 of the 3 LAAs RHAMM/HMMR, PRAME, or G250/CA9 was associated with a significant survival advantage [28]. 4. Future immunotherapeutic strategies Most immunotherapeutic protocols in AML have been developed for relapse prevention in the post-consolidation phase, but immune-based strategies appear to play a significant role also in earlier stages of disease. The example of GO is likely to inspire further development of conjugated antibodies, and the relicensing of GO for use in CD33+ AML seems probable. An additional strategy, i.e. the adoptive transfer of T cells retrovirally transfected to express an antibody against leukemic cells along with co-stimulatory molecules (chimeric antigen receptors, CAR) has shown promise in B cell malignancies, including refractory ALL [130], and most likely will be evaluated also in AML. Also, a more widespread use of cell cycle inducers, such as G-CSF and/or the CXCR4 inhibitor plerixafor, during induction therapy may result in higher rates of patients achieving complete remission and lower incidence of relapses. In addition, the use of adoptively transferred NK cells to treat hematopoietic malignancies is currently expanding, as reviewed in [131]. There is a high demand for improved strategies to prevent relapses in the post-remission stage, in particular for patients who are not eligible for allo-transplantation. HDC/IL-2 is currently the only approved post-remission treatment (in EU and Israel), but the current pace of development is likely to bring about additional immunotherapeutics. Lessons from the past decades teach that single-agent NK cell- or T cell-activators are likely to be inefficacious, as exemplified by the unexpected failure of post-remission IL-2 therapy for relapse control. Future protocols may comprise a counter-suppressive component aiming to reduce or neutralize leukemia-related immunosuppression (as listed in Table 1) with, for example, a T- or NK-cell activating component such as a vaccine, engineered variants of IL-2, IL-15, or an antibody mediating ADCC against leukemic cells. In addition, biomarkers that predict efficacy need to be developed in parallel with the immunotherapies, not least because several counter-suppressive strategies, including anti-PD/PDL or anti-CTLA-4, entail significant immune-related toxicity [78,132]. Ideally, this development results in personalized immunotherapy that controls relapse of AML as efficiently as allo-transplantation, but with reduced treatment-related morbidity. Conflict of interest Author KH holds issued and pending patents on the use of histamine dihydrochloride and related compounds in cancer. References [1] Tallman MS, Gilliland DG, Rowe JM. Drug therapy for acute myeloid leukemia. Blood 2005;106:1154–63. [2] Astrom M, Bodin L, Tidefelt U. Adjustment of incidence rates after an estimate of completeness and accuracy in registration of acute leukemias in a Swedish population. Leuk Lymphoma 2001;41:559–70. [3] Schiller G, Gajewski J, Territo M, Nimer S, Lee M, Belin T, et al. Long-term outcome of high-dose cytarabine-based consolidation chemotherapy for adults with acute myelogenous leukemia. Blood 1992;80:2977–82. [4] Kolb HJ. Graft-versus-leukemia effects of transplantation and donor lymphocytes. Blood 2008;112:4371–83. [5] Breems DA, Van Putten WL, Huijgens PC, Ossenkoppele GJ, Verhoef GE, Verdonck LF, et al. Prognostic index for adult patients with acute myeloid leukemia in first relapse. J Clin Oncol 2005;23:1969–78. [6] Estey EH. Acute myeloid leukemia: 2012 update on diagnosis, risk stratification, and management. Am J Hematol 2012;87:89–99. [7] Martelli MP, Sportoletti P, Tiacci E, Martelli MF, Falini B. Mutational landscape of AML with normal cytogenetics: biological and clinical implications. Blood Rev 2013;27:13–22.

[8] Smith ML, Hills RK, Grimwade D. Independent prognostic variables in acute myeloid leukaemia. Blood Rev 2011;25:39–51. [9] Byrd JC, Mrozek K, Dodge RK, Carroll AJ, Edwards CG, Arthur DC, et al. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood 2002;100:4325–36. [10] Forman SJ, Rowe JM. The myth of the second remission of acute leukemia in the adult. Blood 2013;121:1077–82. [11] Rowe J, LI X, Cassileth PA. Very poor survival of patients with AML who relapse after achieving a first complete remission: the Eastern Cooperative Oncology Group Experience. ASH Annual Meeting Abstracts, 106; 2005. p. 546. [12] Pulte D, Gondos A, Brenner H. Improvements in survival of adults diagnosed with acute myeloblastic leukemia in the early 21st century. Haematologica 2008;93:594–600. [13] Gyurkocza B, Storb R, Storer BE, Chauncey TR, Lange T, Shizuru JA, et al. Nonmyeloablative allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia. J Clin Oncol 2010;28:2859–67. [14] Mohty M, de Lavallade H, Ladaique P, Faucher C, Vey N, Coso D, et al. The role of reduced intensity conditioning allogeneic stem cell transplantation in patients with acute myeloid leukemia: a donor vs no donor comparison. Leukemia 2005;19:916–20. [15] Buchner T, Hiddemann W, Wormann B, Loffler H, Gassmann W, Haferlach T, et al. Double induction strategy for acute myeloid leukemia: the effect of high-dose cytarabine with mitoxantrone instead of standard-dose cytarabine with daunorubicin and 6-thioguanine: a randomized trial by the German AML Cooperative Group. Blood 1999;93:4116–24. [16] Buchner T, Urbanitz D, Hiddemann W, Ruhl H, Ludwig WD, Fischer J, et al. Intensified induction and consolidation with or without maintenance chemotherapy for acute myeloid leukemia (AML): two multicenter studies of the German AML Cooperative Group. J Clin Oncol 1985;3:1583–9. [17] Greiner J, Ringhoffer M, Taniguchi M, Schmitt A, Kirchner D, Krahn G, et al. Receptor for hyaluronan acid-mediated motility (RHAMM) is a new immunogenic leukemia-associated antigen in acute and chronic myeloid leukemia. Exp Hematol 2002;30:1029–35. [18] Greiner J, Ringhoffer M, Taniguchi M, Hauser T, Schmitt A, Dohner H, et al. Characterization of several leukemia-associated antigens inducing humoral immune responses in acute and chronic myeloid leukemia. Int J Cancer 2003;106:224–31. [19] Elisseeva OA, Oka Y, Tsuboi A, Ogata K, Wu F, Kim EH, et al. Humoral immune responses against Wilms tumor gene WT1 product in patients with hematopoietic malignancies. Blood 2002;99:3272–9. [20] Anguille S, Van Tendeloo VF, Berneman ZN. Leukemia-associated antigens and their relevance to the immunotherapy of acute myeloid leukemia. Leukemia 2012;26:2186–96. [21] Brune M, Hellstrand K. Remission maintenance therapy with histamine and interleukin-2 in acute myelogenous leukaemia. Br J Haematol 1996;92:620–6. [22] Smits EL, Berneman ZN, Van Tendeloo VF. Immunotherapy of acute myeloid leukemia: current approaches. Oncologist 2009;14:240–52. [23] Lowdell MW, Koh MB. Immunotherapy of AML: future directions. J Clin Pathol 2000;53:49–54. [24] Appelbaum FR. Haematopoietic cell transplantation as immunotherapy. Nature 2001;411:385–9. [25] Damiani D, Tiribelli M, Geromin A, Cerno M, Sperotto A, Toffoletti E, et al. Donor compatibility and performance status affect outcome of allogeneic haematopoietic stem cell transplant in patients with relapsed or refractory acute myeloid leukaemia. Ann Hematol 2012;91:1937–43. [26] Horowitz MM, Gale RP, Sondel PM, Goldman JM, Kersey J, Kolb HJ, et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood 1990;75: 555–62. [27] Montagna D, Maccario R, Locatelli F, Montini E, Pagani S, Bonetti F, et al. Emergence of antitumor cytolytic T cells is associated with maintenance of hematologic remission in children with acute myeloid leukemia. Blood 2006;108:3843–50. [28] Greiner J, Schmitt M, Li L, Giannopoulos K, Bosch K, Schmitt A, et al. Expression of tumor-associated antigens in acute myeloid leukemia: implications for specific immunotherapeutic approaches. Blood 2006;108:4109–17. [29] van Luijn MM, van den Ancker W, Chamuleau ME, Ossenkoppele GJ, van Ham SM, van de Loosdrecht AA. Impaired antigen presentation in neoplasia: basic mechanisms and implications for acute myeloid leukemia. Immunotherapy 2010;2:85–97. [30] Le Dieu R, Taussig DC, Ramsay AG, Mitter R, Miraki-Moud F, Fatah R, 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;114:3909–16. [31] Chamuleau ME, van de Loosdrecht AA, Hess CJ, Janssen JJ, Zevenbergen A, Delwel R, et al. High INDO (indoleamine 2,3-dioxygenase) mRNA level in blasts of acute myeloid leukemic patients predicts poor clinical outcome. Haematologica 2008;93: 1894–8. [32] Lion E, Willemen Y, Berneman ZN, Van Tendeloo VF, Smits EL. Natural killer cell immune escape in acute myeloid leukemia. Leukemia 2012;26:2019–26. [33] Costello RT, Sivori S, Marcenaro E, Lafage-Pochitaloff M, Mozziconacci MJ, Reviron D, et al. Defective expression and function of natural killer cell-triggering receptors in patients with acute myeloid leukemia. Blood 2002;99:3661–7. [34] Fauriat C, Just-Landi S, Mallet F, Arnoulet C, Sainty D, Olive D, et al. Deficient expression of NCR in NK cells from acute myeloid leukemia: evolution during leukemia treatment and impact of leukemia cells in NCRdull phenotype induction. Blood 2007;109:323–30.

A. Martner et al. / Blood Reviews 27 (2013) 209–216 [35] Orleans-Lindsay JK, Barber LD, Prentice HG, Lowdell MW. Acute myeloid leukaemia cells secrete a soluble factor that inhibits T and NK cell proliferation but not cytolytic function—implications for the adoptive immunotherapy of leukaemia. Clin Exp Immunol 2001;126:403–11. [36] Sanchez-Correa B, Morgado S, Gayoso I, Bergua JM, Casado JG, Arcos MJ, et al. Human NK cells in acute myeloid leukaemia patients: analysis of NK cell-activating receptors and their ligands. Cancer Immunol Immunother 2011;60:1195–205. [37] Tajima F, Kawatani T, Endo A, Kawasaki H. Natural killer cell activity and cytokine production as prognostic factors in adult acute leukemia. Leukemia 1996;10:478–82. [38] Costello RT, Fauriat C, Sivori S, Marcenaro E, Olive D. NK cells: innate immunity against hematological malignancies? Trends Immunol 2004;25:328–33. [39] Aurelius J, Thoren FB, Akhiani A, Brune M, Palmqvist L, Hansson M, et al. Monocytic AML cells inactivate anti-leukemic lymphocytes: role of NADPH oxidase/gp91phox expression and the PARP-1/PAR pathway of apoptosis. Blood 2012;119:5832–7. [40] Buggins AG, Milojkovic D, Arno MJ, Lea NC, Mufti GJ, Thomas NS, et al. Microenvironment produced by acute myeloid leukemia cells prevents T cell activation and proliferation by inhibition of NF-kappaB, c-Myc, and pRb pathways. J Immunol 2001;167:6021–30. [41] Groh V, Wu J, Yee C, Spies T. Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature 2002;419:734–8. [42] Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ. Natural innate and adaptive immunity to cancer. Annu Rev Immunol 2011;29:235–71. [43] Berthon C, Driss V, Liu J, Kuranda K, Leleu X, Jouy N, et al. In acute myeloid leukemia, B7-H1 (PD-L1) protection of blasts from cytotoxic T cells is induced by TLR ligands and interferon-gamma and can be reversed using MEK inhibitors. Cancer Immunol Immunother 2010;59:1839–49. [44] Barclay AN, Wright GJ, Brooke G, Brown MH. CD200 and membrane protein interactions in the control of myeloid cells. Trends Immunol 2002;23:285–90. [45] Coles SJ, Wang EC, Man S, Hills RK, Burnett AK, Tonks A, et al. CD200 expression suppresses natural killer cell function and directly inhibits patient anti-tumor response in acute myeloid leukemia. Leukemia 2011;25:792–9. [46] Lanier LL. NK cell recognition. Annu Rev Immunol 2005;23:225–74. [47] Long EO, Sik Kim H, Liu D, Peterson ME, Rajagopalan S. Controlling natural killer cell responses: integration of signals for activation and inhibition. Annu Rev Immunol 2013;31:227–58. [48] Babor F, Fischer JC, Uhrberg M. The role of KIR genes and ligands in leukemia surveillance. Front Immunol 2013;4:27. [49] Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 2002;295:2097–100. [50] Giebel S, Locatelli F, Lamparelli T, Velardi A, Davies S, Frumento G, et al. Survival advantage with KIR ligand incompatibility in hematopoietic stem cell transplantation from unrelated donors. Blood 2003;102:814–9. [51] Miller JS, Cooley S, Parham P, Farag SS, Verneris MR, McQueen KL, et al. Missing KIR ligands are associated with less relapse and increased graft-versus-host disease (GVHD) following unrelated donor allogeneic HCT. Blood 2007;109:5058–61. [52] Hsu KC, Gooley T, Malkki M, Pinto-Agnello C, Dupont B, Bignon JD, et al. KIR ligands and prediction of relapse after unrelated donor hematopoietic cell transplantation for hematologic malignancy. Biol Blood Marrow Transplant 2006;12: 828–36. [53] Davies SM, Ruggieri L, DeFor T, Wagner JE, Weisdorf DJ, Miller JS, et al. Evaluation of KIR ligand incompatibility in mismatched unrelated donor hematopoietic transplants. Killer immunoglobulin-like receptor. Blood 2002;100:3825–7. [54] Verheyden S, Demanet C. NK cell receptors and their ligands in leukemia. Leukemia 2008;22:249–57. [55] Venstrom JM, Pittari G, Gooley TA, Chewning JH, Spellman S, Haagenson M, et al. HLA-C-dependent prevention of leukemia relapse by donor activating KIR2DS1. N Engl J Med 2012;367:805–16. [56] Sivori S, Carlomagno S, Falco M, Romeo E, Moretta L, Moretta A. Natural killer cells expressing the KIR2DS1-activating receptor efficiently kill T-cell blasts and dendritic cells: implications in haploidentical HSCT. Blood 2011;117:4284–92. [57] Biassoni R, Cantoni C, Pende D, Sivori S, Parolini S, Vitale M, et al. Human natural killer cell receptors and co-receptors. Immunol Rev 2001;181:203–14. [58] Stewart CA, Laugier-Anfossi F, Vely F, Saulquin X, Riedmuller J, Tisserant A, et al. Recognition of peptide-MHC class I complexes by activating killer immunoglobulin-like receptors. Proc Natl Acad Sci U S A 2005;102:13224–9. [59] Bauer K, Rancea M, Roloff V, Elter T, Hallek M, Engert A, et al. Rituximab, ofatumumab and other monoclonal anti-CD20 antibodies for chronic lymphocytic leukaemia. Cochrane Database Syst Rev 2012;11:CD008079. [60] Cang S, Mukhi N, Wang K, Liu D. Novel CD20 monoclonal antibodies for lymphoma therapy. J Hematol Oncol 2012;5:64. [61] Kantarjian H, Thomas D, Wayne AS, O'Brien S. Monoclonal antibody-based therapies: a new dawn in the treatment of acute lymphoblastic leukemia. J Clin Oncol 2012;30:3876–83. [62] Cheson BD. Monoclonal antibody therapy of chronic lymphocytic leukaemia. Best Pract Res Clin Haematol 2010;23:133–43. [63] Feldman EJ, Brandwein J, Stone R, Kalaycio M, Moore J, O'Connor J, et al. Phase III randomized multicenter study of a humanized anti-CD33 monoclonal antibody, lintuzumab, in combination with chemotherapy, versus chemotherapy alone in patients with refractory or first-relapsed acute myeloid leukemia. J Clin Oncol 2005;23:4110–6. [64] Walter RB, Appelbaum FR, Estey EH, Bernstein ID. Acute myeloid leukemia stem cells and CD33-targeted immunotherapy. Blood 2012;119:6198–208. [65] Bross PF, Beitz J, Chen G, Chen XH, Duffy E, Kieffer L, et al. Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin Cancer Res 2001;7:1490–6.

215

[66] McKoy JM, Angelotta C, Bennett CL, Tallman MS, Wadleigh M, Evens AM, et al. Gemtuzumab ozogamicin-associated sinusoidal obstructive syndrome (SOS): an overview from the research on adverse drug events and reports (RADAR) project. Leuk Res 2007;31:599–604. [67] Kopecky KJ, Stuart RK, Larson RA, Nevill TJ, Stenke S, Slovak ML, et al. Preliminary Results of Southwest Oncology Group Study S0106: An International Intergroup Phase 3 Randomized Trial Comparing the Addition of Gemtuzumab Ozogamicin to Standard Induction Therapy Versus Standard Induction Therapy Followed by a Second Randomization to Post-Consolidation Gemtuzumab Ozogamicin Versus No Additional Therapy for Previously Untreated Acute Myeloid Leukemia. Blood 2009;114 [Abstract 790]. [68] Castaigne S, Pautas C, Terre C, Raffoux E, Bordessoule D, Bastie JN, et al. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet 2012;379:1508–16. [69] Estey EH, Giles FJ, Beran M, O'Brien S, Pierce SA, Faderl SH, et al. Experience with gemtuzumab ozogamycin (“mylotarg”) and all-trans retinoic acid in untreated acute promyelocytic leukemia. Blood 2002;99:4222–4. [70] Lo-Coco F, Cimino G, Breccia M, Noguera NI, Diverio D, Finolezzi E, et al. Gemtuzumab ozogamicin (Mylotarg) as a single agent for molecularly relapsed acute promyelocytic leukemia. Blood 2004;104:1995–9. [71] Eppert K, Takenaka K, Lechman ER, Waldron L, Nilsson B, van Galen P, et al. Stem cell gene expression programs influence clinical outcome in human leukemia. Nat Med 2011;17:1086–93. [72] Majeti R. Monoclonal antibody therapy directed against human acute myeloid leukemia stem cells. Oncogene 2011;30:1009–19. [73] Jin L, Hope KJ, Zhai Q, Smadja-Joffe F, Dick JE. Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat Med 2006;12:1167–74. [74] Majeti R, Chao MP, Alizadeh AA, Pang WW, Jaiswal S, Gibbs Jr KD, et al. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell 2009;138:286–99. [75] Jin L, Lee EM, Ramshaw HS, Busfield SJ, Peoppl AG, Wilkinson L, et al. Monoclonal antibody-mediated targeting of CD123, IL-3 receptor alpha chain, eliminates human acute myeloid leukemic stem cells. Cell Stem Cell 2009;5:31–42. [76] Zhang L, Gajewski TF, Kline J. PD-1/PD-L1 interactions inhibit antitumor immune responses in a murine acute myeloid leukemia model. Blood 2009;114:1545–52. [77] Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012;366:2455–65. [78] Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366:2443–54. [79] Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science 2008;322:271–5. [80] Qureshi OS, Zheng Y, Nakamura K, Attridge K, Manzotti C, Schmidt EM, et al. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science 2011;332:600–3. [81] Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363:711–23. [82] Lipson EJ, Drake CG. Ipilimumab: an anti-CTLA-4 antibody for metastatic melanoma. Clin Cancer Res 2011;17:6958–62. [83] Szczepanski MJ, Szajnik M, Czystowska M, Mandapathil M, Strauss L, Welsh A, et al. Increased frequency and suppression by regulatory T cells in patients with acute myelogenous leukemia. Clin Cancer Res 2009;15:3325–32. [84] Shenghui Z, Yixiang H, Jianbo W, Kang Y, Laixi B, Yan Z, et al. Elevated frequencies of CD4(+) CD25(+) CD127lo regulatory T cells is associated to poor prognosis in patients with acute myeloid leukemia. Int J Cancer 2011;129:1373–81. [85] Vey N, Bourhis JH, Boissel N, Bordessoule D, Prebet T, Charbonnier A, et al. A phase 1 trial of the anti-inhibitory KIR mAb IPH2101 for AML in complete remission. Blood 2012;120:4317–23. [86] Zhang Y, Patel S, Abdelouahab H, Wittner M, Willekens C, Shen S, et al. CXCR4 inhibitors selectively eliminate CXCR4-expressing human acute myeloid leukemia cells in NOG mouse model. Cell Death Dis 2012;3:e396. [87] Peled A, Tavor S. Role of CXCR4 in the pathogenesis of acute myeloid leukemia. Theranostics 2013;3:34–9. [88] Uy GL, Rettig MP, Motabi IH, McFarland K, Trinkaus KM, Hladnik LM, et al. A phase 1/2 study of chemosensitization with the CXCR4 antagonist plerixafor in relapsed or refractory acute myeloid leukemia. Blood 2012;119:3917–24. [89] Beider K, Begin M, Abraham M, Wald H, Weiss ID, Wald O, et al. CXCR4 antagonist 4F-benzoyl-TN14003 inhibits leukemia and multiple myeloma tumor growth. Exp Hematol 2011;39:282–92. [90] Kuhne MR, Mulvey T, Belanger B, Chen S, Pan C, Chong C, et al. BMS-936564/MDX-1338: a fully human anti-CXCR4 antibody induces apoptosis in vitro and shows antitumor activity in vivo in hematologic malignancies. Clin Cancer Res 2013;19:357–66. [91] Tonks A, Hills R, White P, Rosie B, Mills KI, Burnett AK, et al. CD200 as a prognostic factor in acute myeloid leukaemia. Leukemia 2007;21:566–8. [92] Kretz-Rommel A, Qin F, Dakappagari N, Cofiell R, Faas SJ, Bowdish KS. Blockade of CD200 in the presence or absence of antibody effector function: implications for anti-CD200 therapy. J Immunol 2008;180:699–705. [93] Wei G, Ni W, Chiao JW, Cai Z, Huang H, Liu D. A meta-analysis of CAG (cytarabine, aclarubicin, G-CSF) regimen for the treatment of 1029 patients with acute myeloid leukemia and myelodysplastic syndrome. J Hematol Oncol 2011;4:46. [94] Foon KA, Smalley RV, Riggs CW, Gale RP. The role of immunotherapy in acute myelogenous leukemia. Arch Intern Med 1983;143:1726–31.

216

A. Martner et al. / Blood Reviews 27 (2013) 209–216

[95] Anguille S, Lion E, Willemen Y, Van Tendeloo VF, Berneman ZN, Smits EL. Interferon-alpha in acute myeloid leukemia: an old drug revisited. Leukemia 2011;25:739–48. [96] Goldstone AH, Burnett AK, Wheatley K, Smith AG, Hutchinson RM, Clark RE. Attempts to improve treatment outcomes in acute myeloid leukemia (AML) in older patients: the results of the United Kingdom Medical Research Council AML11 trial. Blood 2001;98:1302–11. [97] Simonsson B, Totterman T, Hokland P, Lauria F, Carella AM, Fernandez MN, et al. Roquinimex (Linomide) vs placebo in AML after autologous bone marrow transplantation. Bone Marrow Transplant 2000;25:1121–7. [98] Foa R, Meloni G, Guarini A, Vignetti M, Marchis D, Tosti S, et al. Interleukin 2 (IL2) in the management of acute myeloid leukemia: clinical and biological findings. Leukemia 1992;6(Suppl. 3):115S–6S. [99] Baer MR, George SL, Caligiuri MA, Sanford BL, Bothun SM, Mrozek K, et al. Low-dose interleukin-2 immunotherapy does not improve outcome of patients age 60 years and older with acute myeloid leukemia in first complete remission: Cancer and Leukemia Group B Study 9720. J Clin Oncol 2008;26:4934–9. [100] Blaise D, Attal M, Reiffers J, Michallet M, Bellanger C, Pico JL, et al. Randomized study of recombinant interleukin-2 after autologous bone marrow transplantation for acute leukemia in first complete remission. Eur Cytokine Netw 2000;11:91–8. [101] Kolitz JE, Hars V, DeAngelo DJ, Allen SL, Shea TC, Vij R, et al. Phase III trial of immunotherapy with recombinant interleukin-2 (rIL-2) versus observation in patients b 60 years with acute myeloid leukemia (AML) in first remission (CR1): preliminary results from Cancer and Leukemia Group B (CALGB) 19808. ASH Annual Meeting Abstracts, 110; 2007. p. 157. [102] Lange BJ, Smith FO, Feusner J, Barnard DR, Dinndorf P, Feig S, et al. Outcomes in CCG-2961, a children's oncology group phase 3 trial for untreated pediatric acute myeloid leukemia: a report from the children's oncology group. Blood 2008;111: 1044–53. [103] Lotzova E, Savary CA, Herberman RB. Induction of NK cell activity against fresh human leukemia in culture with interleukin 2. J Immunol 1987;138:2718–27. [104] Pautas C, Merabet F, Thomas X, Raffoux E, Gardin C, Corm S, et al. Randomized study of intensified anthracycline doses for induction and recombinant interleukin-2 for maintenance in patients with acute myeloid leukemia age 50 to 70 years: results of the ALFA-9801 study. J Clin Oncol 2010;28:808–14. [105] Berry SM, Broglio KR, Berry DA. Addressing the incremental benefit of histamine dihydrochloride when added to interleukin-2 in treating acute myeloid leukemia: a Bayesian meta-analysis. Cancer Invest 2011;29:293–9. [106] Buyse M, Squifflet P, Lucchesi KJ, Brune ML, Castaigne S, Rowe JM. Assessment of the consistency and robustness of results from a multicenter trial of remission maintenance therapy for acute myeloid leukemia. Trials 2011;12:86. [107] Hansson M, Asea A, Ersson U, Hermodsson S, Hellstrand K. Induction of apoptosis in NK cells by monocyte-derived reactive oxygen metabolites. J Immunol 1996;156: 42–7. [108] Thoren FB, Romero AI, Hellstrand K. Oxygen radicals induce poly(ADP-ribose) polymerase-dependent cell death in cytotoxic lymphocytes. J Immunol 2006;176: 7301–7. [109] Kono K, Salazar-Onfray F, Petersson M, Hansson J, Masucci G, Wasserman K, et al. Hydrogen peroxide secreted by tumor-derived macrophages down-modulates signal-transducing zeta molecules and inhibits tumor-specific T cell-and natural killer cell-mediated cytotoxicity. Eur J Immunol 1996;26:1308–13. [110] Hellstrand K, Hermodsson S. Cell-to-cell mediated inhibition of natural killer cell proliferation by monocytes and its regulation by histamine H2-receptors. Scand J Immunol 1991;34:741–52. [111] Mellqvist UH, Hansson M, Brune M, Dahlgren C, Hermodsson S, Hellstrand K. Natural killer cell dysfunction and apoptosis induced by chronic myelogenous leukemia cells: role of reactive oxygen species and regulation by histamine. Blood 2000;96: 1961–8. [112] Romero AI, Thoren FB, Brune M, Hellstrand K. NKp46 and NKG2D receptor expression in NK cells with CD56dim and CD56bright phenotype: regulation by histamine and reactive oxygen species. Br J Haematol 2006;132:91–8. [113] Martner A, Thoren FB, Aurelius J, Soderholm J, Brune M, Hellstrand K. Immunotherapy with histamine dihydrochloride for the prevention of relapse in acute myeloid leukemia. Expert Rev Hematol 2010;3:381–91. [114] Romero AI, Thoren FB, Aurelius J, Askarieh G, Brune M, Hellstrand K. Postconsolidation immunotherapy with histamine dihydrochloride and interleukin-2 in AML. Scand J Immunol 2009;70:194–205. [115] Brune M, Castaigne S, Catalano J, Gehlsen K, Ho AD, Hofmann WK, et al. Improved leukemia-free survival after postconsolidation immunotherapy with

[116]

[117]

[118] [119] [120] [121] [122] [123]

[124]

[125]

[126]

[127]

[128]

[129]

[130]

[131]

[132] [133]

[134]

[135]

[136] [137]

[138]

histamine dihydrochloride and interleukin-2 in acute myeloid leukemia: results of a randomized phase 3 trial. Blood 2006;108:88–96. Thoren FB, Romero AI, Brune M, Hellstrand K. Histamine dihydrochloride and low-dose interleukin-2 as post-consolidation immunotherapy in acute myeloid leukemia. Expert Opin Biol Ther 2009;9:1217–23. Aurelius J, Martner A, Brune M, Palmqvist L, Hansson M, Hellstrand K, et al. Remission maintenance in acute myeloid leukemia: impact of functional histamine H2 receptors expressed by leukemic cells. Haematologica 2012;97:1904–8. Sakaguchi S. Regulatory T, cells: key controllers of immunologic self-tolerance. Cell 2000;101:455–8. Long SA, Buckner JH, Greenbaum CJ. IL-2 therapy in type 1 diabetes: “trials” and tribulations. Clin Immunol 2013 (epub ahead of print). Liao W, Lin JX, Leonard WJ. Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy. Immunity 2013;38:13–25. Beyer M. Interleukin-2 treatment of tumor patients can expand regulatory T cells. Oncoimmunology 2012;1:1181–2. Levin AM, Bates DL, Ring AM, Krieg C, Lin JT, Su L, et al. Exploiting a natural conformational switch to engineer an interleukin-2 ‘superkine’. Nature 2012;484:529–33. Klein C, Inja W, Nicolini V, Claire D, Freimoser A, Herter S, et al. Novel tumor-targeted, engineered IL-2 variant (IL-2v)-based immunocytokines for immunotherapy of cancer. AACR Special Conference on Tumor Immunology; 2012 (Abstract:55). Waldmann TA, Lugli E, Roederer M, Perera LP, Smedley JV, Macallister RP, et al. Safety (toxicity), pharmacokinetics, immunogenicity, and impact on elements of the normal immune system of recombinant human IL-15 in rhesus macaques. Blood 2011;117:4787–95. Greiner J, Ono Y, Hofmann S, Schmitt A, Mehring E, Gotz M, et al. Mutated regions of nucleophosmin 1 elicit both CD4(+) and CD8(+) T-cell responses in patients with acute myeloid leukemia. Blood 2012;120:1282–9. Maslak PG, Dao T, Krug LM, Chanel S, Korontsvit T, Zakhaleva V, 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;116:171–9. Van Tendeloo VF, Van de Velde A, Van Driessche A, Cools N, Anguille S, Ladell K, 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;107:13824–9. Van Driessche A, Berneman ZN, Van Tendeloo VF. Active specific immunotherapy targeting the Wilms' tumor protein 1 (WT1) for patients with hematological malignancies and solid tumors: lessons from early clinical trials. Oncologist 2012;17: 250–9. Scheibenbogen C, Letsch A, Thiel E, Schmittel A, Mailaender V, Baerwolf S, et al. CD8 T-cell responses to Wilms tumor gene product WT1 and proteinase 3 in patients with acute myeloid leukemia. Blood 2002;100:2132–7. Brentjens RJ, Davila ML, Riviere I, Park J, Wang X, Cowell LG, et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapyrefractory acute lymphoblastic leukemia. Sci Transl Med 2013;5:177ra38. McKenna DH, Kadidlo DM, Cooley S, Miller JS. Clinical production and therapeutic applications of alloreactive natural killer cells. Methods Mol Biol 2012;882: 491–507. Di Giacomo AM, Biagioli M, Maio M. The emerging toxicity profiles of anti-CTLA-4 antibodies across clinical indications. Semin Oncol 2010;37:499–507. Yan Y, Zhang GX, Gran B, Fallarino F, Yu S, Li H, et al. IDO upregulates regulatory T cells via tryptophan catabolite and suppresses encephalitogenic T cell responses in experimental autoimmune encephalomyelitis. J Immunol 2010;185:5953–61. Curti A, Pandolfi S, Valzasina B, Aluigi M, Isidori A, Ferri E, et al. Modulation of tryptophan catabolism by human leukemic cells results in the conversion of CD25- into CD25+ T regulatory cells. Blood 2007;109:2871–7. Buzyn A, Petit F, Ostankovitch M, Figueiredo S, Varet B, Guillet JG, et al. Membrane-bound Fas (Apo-1/CD95) ligand on leukemic cells: a mechanism of tumor immune escape in leukemia patients. Blood 1999;94:3135–40. Whiteside TL. Immune modulation of T-cell and NK (natural killer) cell activities by TEXs (tumour-derived exosomes). Biochem Soc Trans 2013;41:245–51. Coles SJ, Hills RK, Wang EC, Burnett AK, Man S, Darley RL, et al. Expression of CD200 on AML blasts directly suppresses memory T-cell function. Leukemia 2012;26:2148–51. Coles SJ, Hills RK, Wang EC, Burnett AK, Man S, Darley RL, et al. Increased CD200 expression in acute myeloid leukemia is linked with an increased frequency of FoxP3+ regulatory T cells. Leukemia 2012;26:2146–8.