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Review ArticleReview Article

Targeting Immune Checkpoints in Hematologic Malignancies

Gheath Alatrash, Naval Daver and Elizabeth A. Mittendorf
Michael G. Rosenblum, ASSOCIATE EDITOR
Pharmacological Reviews October 2016, 68 (4) 1014-1025; DOI: https://doi.org/10.1124/pr.116.012682
Gheath Alatrash
Departments of Stem Cell Transplantation and Cellular Therapy (G.A., E.A.M.), Leukemia (N.D.), and Breast Surgical (E.A.M.) Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
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Naval Daver
Departments of Stem Cell Transplantation and Cellular Therapy (G.A., E.A.M.), Leukemia (N.D.), and Breast Surgical (E.A.M.) Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
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Elizabeth A. Mittendorf
Departments of Stem Cell Transplantation and Cellular Therapy (G.A., E.A.M.), Leukemia (N.D.), and Breast Surgical (E.A.M.) Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
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Michael G. Rosenblum
Departments of Stem Cell Transplantation and Cellular Therapy (G.A., E.A.M.), Leukemia (N.D.), and Breast Surgical (E.A.M.) Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
Roles: ASSOCIATE EDITOR
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Abstract

The use of antibodies that target immune checkpoint molecules on the surface of T-lymphocytes and/or tumor cells has revolutionized our approach to cancer therapy. Cytotoxic-T-lymphocyte antigen (CTLA-4) and programmed cell death protein 1 (PD-1) are the two most commonly targeted immune checkpoint molecules. Although the role of antibodies that target CTLA-4 and PD-1 has been established in solid tumor malignancies and Food and Drug Administration approved for melanoma and non-small cell lung cancer, there remains a desperate need to incorporate immune checkpoint inhibition in hematologic malignancies. Unlike solid tumors, a number of considerations must be addressed to appropriately employ immune checkpoint inhibition in hematologic malignancies. For example, hematologic malignancies frequently obliterate the bone marrow and lymph nodes, which are critical immune organs that must be restored for appropriate response to immune checkpoint inhibition. On the other hand, hematologic malignancies are the quintessential immune responsive tumor type, as proven by the success of allogeneic stem cell transplantation (allo-SCT) in hematologic malignancies. Also, sharing an immune cell lineage, malignant hematologic cells often express immune checkpoint molecules that are absent in solid tumor cells, thereby offering direct targets for immune checkpoint inhibition. A number of clinical trials have demonstrated the potential for immune checkpoint inhibition in hematologic malignancies before and after allo-SCT. The ongoing clinical studies and complimentary immune correlatives are providing a growing body of knowledge regarding the role of immune checkpoint inhibition in hematologic malignancies, which will likely become part of the standard of care for hematologic malignancies.

I. Introduction

Targeting immune checkpoint molecules on the surface of tumor cells or immune cells has proven to be a highly effective approach in cancer immunotherapy. A number of clinical trials in a variety of tumor types have been conducted using antibodies that target immune checkpoint molecules. Although there are several immune checkpoint pathways that regulate immune cells, to date, the two major approaches to immune checkpoint blockade that have been investigated clinically have targeted cytotoxic-T-lymphocyte antigen (CTLA-4) and the programmed cell death pathway. The programmed cell death pathway includes programmed cell death protein 1 (PD-1) and its ligands programmed death ligands 1 (PD-L1) and 2 (PD-L2). To date, melanoma and non-small cell lung cancer (NSCLC) are the two tumor types for which the use of immune checkpoint inhibition has received Food and Drug Administration approval. However, there is great interest in investigating these agents in hematologic malignancies, which are known to express immune checkpoint molecules and to be susceptible to immune modulation. In addition, there is a desperate need for novel agents to treat a number of hematologic malignancies, because these remain some of the most aggressive tumors to afflict adults and children. This review will provide an update on the current state of immune checkpoint based approaches in the treatment of hematologic malignancies, including stem cell transplantation.

II. T Cell Inhibitory Pathways: Cytotoxic-T-lymphocyte Antigen 4, Programmed Death Protein 1, and Programmed Death Protein Ligand 1

Upon initial encounter with its antigen in a lymphoid organ, there are a number of signaling pathways that must be triggered within the T cell to achieve adequate activation. T cells require binding of their T cell receptor (TCR) to the peptide/human leukocyte antigen complex (pHLA) that is expressed on the target, as well as binding of the T cell costimulatory receptors to their cognate ligands that are expressed by the tumor or antigen presenting cell (APC). CD28 is an important costimulatory molecule expressed on the T cell surface. There are two known ligands for CD28, CD80 (B7.1) and CD86 (B7.2), both expressed on APCs. CD80 and CD86 are also ligands for CTLA-4, an inhibitory molecule expressed on the T cell surface. CTLA-4 binds with a higher affinity to CD80 and CD86 on the APCs, and in effect competes with CD28 for binding to these molecules (Linsley et al., 1994; Leach et al., 1996; Egen and Allison, 2002; Riley et al., 2002; Schneider et al., 2006). In addition, CTLA-4 activates phosphatases such as Src-homology 2 domain-containing phosphatase 2, which counteract the phosphorylation steps that ensue after TCR binding to pHLA and are critical for T cell activation (Rudd et al., 2009). CTLA-4 is expressed by CD8+ and CD4+ T cells; however, the effects of CTLA-4 are primarily seen in the CD4+ T cell population, including helper T cells and regulatory T cells (TReg). Engagement of CTLA-4 with its ligands results in the downregulation of helper T cell activities and upregulation of TReg cell activities. Together, competition for binding with CD80 and CD86, the attenuation of helper T cell functions, and the enhancement of TReg activities result in a “break” on effector T cell activation that is critical for controlling the immune response and maintaining normal immune homeostasis.

Although CTLA-4 plays a major role in regulating the initial stages of T cell activation, another T cell inhibitory mechanism, PD-1, plays a critical role in abrogating T cell functions during the later stages of the immune response (Nishimura et al., 1999; Freeman et al., 2000; Nishimura et al., 2001). The PD-1 pathway, which involves the T cell inhibitory molecule PD-1 and its ligands PD-L1/PD-L2, modulates the immune response after T cells exit the circulation and home into inflamed and tumor tissues. This mechanism regulates and contains the immune response to prevent tissue damage and autoimmunity that can be deleterious to the host. PD-1 and PD-L1/PD-L2 therefore play an important role in peripheral tolerance. Like CTLA-4, signaling through PD-1 affects phosphatases like Src-homology 2 domain-containing phosphatase 2, which offset the activity of the kinases that mediate T cell activation after TCR/pHLA engagement and CD28 activation (Freeman et al., 2000; Yokosuka et al., 2012). PD-1 signaling also promotes TReg proliferation and immune suppressive functions (Francisco et al., 2009).

III. Targeting Immune Checkpoint Molecules in Cancer

A number of antibodies that block the interaction between immune checkpoint receptors on T cells and their ligands on tumor cells have been developed and have proven to be efficacious in the setting of solid tumor. Several of these are currently being evaluated in hematologic malignancies (Table 1). The rationale for a therapeutic strategy employing antibodies that target immune checkpoint molecules stems from the concept that impeding the interaction between the immune checkpoint receptor on the T cell and its ligand on the tumor cell releases the inhibitory brakes that abrogate T cells functions and antitumor immune response. There are a number of critical issues to be considered when employing immune checkpoint blockade in cancer immunotherapy. The first is that T cells must be present within the tumor microenvironment. This is indeed a critical consideration, because it may dictate the timing of administration of the immune checkpoint blockade in relation to other systemic cancer therapies. The majority of systemic cancer therapies is lymphodepleting and can affect the number of lymphocytes within the tumor microenvironment.

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TABLE 1

Immune checkpoint antibodies used in hematologic malignancies

The second consideration is that the T cells within the tumor microenvironment need to possess specificity to distinct antigens expressed by tumor cells. The characteristics of the antigens targeted by tumor infiltrating lymphocytes (TIL) have been heavily investigated. Antigens expressed by tumor cells generally fall into two broad categories: 1) mutated antigens that oftentimes account for neoantigens or 2) tumor-associated antigens that are routinely expressed by normal tissues but are differentially expressed by the tumor. In one of the original studies using the anti-CTLA-4 antibody ipilimumab, the response in patients with melanoma directly correlated with a higher number of neoantigens in tumors with a higher mutational load (Snyder et al., 2014). This was confirmed in NSCLC studies where PD-1 blockade with pembrolizumab was used. In that setting, the mutational and neoantigen load, as well as the detection of neoantigen-specific TILs, highly correlated with response to pembrolizumab (Rizvi et al., 2015; McGranahan et al., 2016).

The third consideration is the expression of immune checkpoint receptors on TIL and the presence of their cognate ligands on tumor cells or other immune cells within the tumor microenvironment. A number of studies have demonstrated better efficacy with immune checkpoint blockade in patients who have high levels of CTLA-4 and PD-1 on TIL and high expression of CTLA-4 and PD-L1 ligands on the tumor cells (Taube et al., 2014; Van Allen et al., 2015; McGranahan et al., 2016). However, clinical data have also demonstrated the efficacy of immune checkpoint inhibitors in tumors that have a lower expression of immune checkpoint molecules. For example, a clinical trial testing the efficacy of nivolumab, ipilimumab, and the combination in patients with untreated melanoma, demonstrated clinical response to immune checkpoint blockade even among patients with tumors that expressed a low level of PD-L1, although the response rate was higher in patients with higher baseline PD-L1 expression (Larkin et al., 2015). Similar results have been observed in a clinical trial in patients with NSCLC (Garon et al., 2015). Although this remains an area of active investigation, the inconsistencies in responses to checkpoint blockade, based on the expression of the immune checkpoint molecules, may be attributable to heterogeneity in the tumor that is not adequately reflected by tumor sampling or to other components of the tumor microenvironment that regulate response to immune checkpoint blockade. These data suggest that the presence of PD-L1 expression may not be an accurate biomarker of response to therapy and many trials no longer use tumor PD-L1 expression as an eligibility criterion.

IV. Immune Checkpoint Inhibition in Hematologic Tumors

There are a number of factors to be considered with the use of immune checkpoint blockade in the treatment of patients with hematologic malignancies, including leukemia, lymphoma, and multiple myeloma (MM). Because they share a common cell lineage, malignant hematologic tumor cells often express markers typically associated with antigen presenting cells, specifically CD80 and CD86, hence making them direct targets for antibodies against CTLA-4. This is different from nonhematologic malignancies wherein CTLA-4 targeting is aimed at removing tolerance to the immune priming events that occur within the lymphoid organs. In addition, because they originate and reside within lymphoid organs, either the bone marrow or lymph nodes, hematologic malignancies could be more susceptible to regulation by targeting CTLA-4 (Fig. 1). On the other hand, the timing of the application of immune checkpoint blockade may be more critical in the setting of hematologic malignancies, especially leukemia, where the tumor itself oftentimes obliterates host immunity. Although the clinical application of immune checkpoint blockade for hematologic malignancies is clearly lagging behind its use in solid tumors, a number of studies have demonstrated encouraging results with immune checkpoint inhibition in hematologic malignancies.

Fig. 1.
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Fig. 1.

Malignant hematologic cells express ligand for CTLA-4 and PD-1 and are therefore direct targets for immune checkpoint blockade. (A) Malignant solid tumor cells express PD-L1 and PD-L2 and can attenuate the antitumor immune response through direct interactions with PD-1 on the tumor specific T cells. Immune checkpoint blockade in solid tumor malignancies that interferes with the PD-1/PD-L1 pathway directly removes this inhibition. (B) Anti-CTLA-4 is effective in solid tumor malignancies through its influence on antigen presenting cells (APC) during immune priming. (C) Malignant hematologic cells express PD-L1 and PD-L2, but also express CTLA-4. Because malignant hematologic cells can act as APC, the use of anti-CTLA-4 antibodies in this setting therefore can directly modulate the immune response against the malignant hematologic cell.

A. Lymphoma

The success of anti-PD-1 therapy in Hodgkin’s lymphoma (HL) has been the major achievement supporting the use of immune checkpoint blockade in hematologic malignancies. There is a compelling rationale for the use of anti-PD-1 therapy in HL. Firstly, chromosome 9 abnormalities, which contain the PD-L1 and PD-L2 gene loci, are often encountered in HL and lead to overexpression of these ligands (Green et al., 2010). Secondly, there is often a dense immune infiltrate surrounding Reed-Sternberg cells in HL, which if activated could theoretically eliminate the malignant cells. Thirdly, there is a known association between HL and Epstein-Barr virus, which is known to upregulate PD-L1 and PD-L2 (Green et al., 2012). In essence, these observations provided a strong justification for the use of immune checkpoint blockade targeting PD-1 in HL, which was subsequently validated in the clinical setting. In a phase I trial, 23 patients with HL who were heavily pretreated, including 78% who relapsed after autologous (auto) stem cell transplantation (SCT) and 78% who relapsed after therapy with anti-CD30 (brentuximab vedotin), were administered the anti-PD1 antibody nivolumab (Ansell et al., 2015b). Twenty patients (87%) achieved an objective response, including 17% achieving complete response (CR) and 70% partial response (PR). Three patients had stable disease. Tumor samples were available for 10 patients, all of whom demonstrated expression of PD-L1 and PD-L2. Similar results were reported in a phase Ib study using the anti-PD-1 antibody pembrolizumab (Moskowitz et al., 2014). In that study of 15 patients with classic HL, all previously treated with brentuximab vedotin, 3 patients (20%) achieved CR and 5 patients (33%) achieved PR; the overall response rate was 53%. Anti-CTLA-4 therapy with ipilimumab has also been evaluated in patients with HL after allogeneic (allo) SCT. In a study by Bashey et al. (2009), ipilimumab was administered to 29 patients with a variety of relapsed hematologic malignancies after allo-SCT, including 14 patients (48%) with HL. Of the patients with HL, four patients responded to ipilimumab: two achieved CR and two had disease stabilization.

There is also promise for using immune checkpoint blockade in non-Hodgkin lymphoma (NHL). PD-L1 is expressed by subtypes of NHL (Green et al., 2010; Andorsky et al., 2011), and immune cell infiltrates in lymphoma tissue have been correlated with clinical outcomes (Lippman et al., 1990; Grogan and Miller, 1993; Ansell et al., 2001). Based on these observations, immune checkpoint blockade has been tested in NHL, with the most encouraging data in the setting of follicular lymphoma (FL) with the use of the anti-PD-1 antibody pidilizumab. In a phase I clinical trial that enrolled 17 patients with lymphoma and leukemia, including 4 patients with NHL [two diffuse large B cell lymphoma (DLBCL), 1 FL and 1 acute lymphocytic cell lymphoma], Berger et al. (2008) showed elimination of tumor masses in the FL patient after pidilizumab treatment. This observation led to a nonrandomized, single center phase II clinical trial in 32 patients with relapsed rituximab-sensitive FL (Westin et al., 2014). In that trial, patients were treated with the combination of pidilizumab and rituximab. Results from the study showed safety of the combination of pidilizumab and rituximab and activity in 29 evaluable patients, which included 15 patients (52%) achieving CR and 4 (14%) achieving PR. Furthermore, the investigators identified immune gene signatures that could predict for response to therapy and showed that the frequency of pre-therapy PD-1 expressing effector T cells within the tumor correlated positively with both tumor response and progression-free survival (PFS). These signatures have not yet been validated. Nevertheless, the identified genes extend beyond immune checkpoint molecules, highlighting the complexity of modulating the antitumor immune response with checkpoint antibodies in NHL.

There has also been encouraging data with the use of pidilizumab in the setting of DLBCL after auto-SCT (Armand et al., 2013). In a phase II study, 66 patients with NHL (49 patients with DLBCL, 4 patients with primary mediastinal B cell lymphoma and 13 patients with transformed indolent B cell NHL) were given pidilizumab within 3 months after auto-SCT. CT and PET scans documented CR in 31 patients (47%) and 45 patients (68%), respectively, before administration of pidilizumab. The overall response rate after pidilizumab treatment in the 35 eligible patients who had measurable disease after auto-SCT was 51% and the 16-month overall survival and PFS were 0.85 (90% CI, 0.74 to 0.92) and 0.72 (90% CI, 0.60 to 0.82), respectively, and were not affected by disease status at the time of administration of pidilizumab. The PFS in the study cohort compared favorably with the PFS of historical controls treated in the same institution, 0.52 (90% CI, 0.39 to 0.63). Unfortunately, the investigators did not have access to tumor tissue and therefore could not provide an analysis of PD-L1 or PD-L2 expression by the tumor cells, which is critical in NHL, because immune checkpoint molecules are not ubiquitously expressed by malignant NHL cells but are often restricted to subgroups of tumors (Green et al., 2010; Andorsky et al., 2011). The investigators did show an increase in the T cell memory subsets in the peripheral blood over the course of treatment and showed an increase in PD-L1 expression in subsets of immune cells in the peripheral blood; however, no clear patterns or correlations were identified.

A number of studies have shown expression of CD80 and CD86 by lymphoma cells, including DLBCL and FL, hence providing the rationale for targeting CTLA-4 in NHL (Dorfman et al., 1997; Tsukada et al., 1997; Chaperot et al., 1999). Promising results in NHL have been seen with the use of the anti-CTLA-4 antibody ipilimumab. In a phase I study of 18 patients with NHL, including 14 patients with FL, 3 with DLBCL and 1 with mantle cell lymphoma, clinical responses were seen in 3 patients, including PR in 1 patient with FL and CR in 1 patient with DLBCL (Ansell et al., 2009). A summary of the aforementioned studies is included in Table 2.

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TABLE 2

Summary of key studies of immune checkpoint inhibition according to disease type

Furthermore, the investigators demonstrated an increase in T cell proliferation to recall antigens after ipilimumab therapy in five patients (31%). Other studies that investigated the use of ipilimumab in the lymphoma setting were conducted after allo-SCT and are discussed in more detail in the following sections. Ongoing clinical trials of immune checkpoint inhibition in lymphoma are listed in Table 3.

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TABLE 3

Select ongoing trials of immune checkpoint inhibition in Hodgkin and non-Hodgkin lymphomas

Data compiled from ClinicalTrials.gov (https://clinicaltrials.gov), 7/2016.

B. Multiple Myeloma

The importance of immunotherapy in MM is exemplified by the curative potential of allo-SCT in patients with MM. Despite the potential benefit of allo-SCT, the high risk of toxicity has limited its applicability in these patients (Mehta and Singhal, 1998; Bensinger et al., 2001; Bruno et al., 2007; Blade et al., 2010; Bjorkstrand et al., 2011; Roddie and Peggs, 2011). Antigen specific T cell clones that target MM cells have been identified after allo-SCT, again highlighting the immunogenicity of MM and the potential to target this disease by immune modulating agents (Atanackovic et al., 2007; Tyler et al., 2013). Furthermore, studies have shown the expression of PD-L1 on MM cells and immune cells and expression of PD-1 on T and natural killer cells within the MM microenvironment (Gorgun et al., 2015; Ray et al., 2015). In addition, T cell exhaustion, primarily in the CD8+ T cell compartment, was demonstrated in patients with MM after autologous stem cell transplantation and correlated with disease relapse. Together, these data provide a rationale for targeting immune checkpoint molecules in patients with MM after auto-SCT (Chung et al., 2016).

However, to date, there is limited clinical data of immune checkpoint blockade in MM. In the phase I study of pidilizumab in 17 patients with various hematologic malignancies discussed in the previous section, there was one MM patient enrolled who demonstrated long-term stable disease after treatment (Berger et al., 2008). However, in an interim analysis of a phase I study that tested nivolumab in patients with relapsed or refractory lymphoid malignancies, there were no objective responses in any of the 27 MM patients included (Lesokhin et al., 2014). A number of hypotheses have been postulated to explain the discouraging results of immune checkpoint blockade in MM. Clonal T cells have been shown to play an important role in the anti-MM immune response; however, these clonal T cells were shown to have low PD-1 expression (Suen et al., 2015). Another study demonstrated that clonal T cells in MM are not exhausted; rather they exhibit a telomere-independent senescent phenotype or senescence-associated secretory phenotype, which would not be expected to respond to immune checkpoint blockade (Suen et al., 2014). A summary of these studies is included in Table 2.

Nevertheless, despite this somewhat discouraging data, a recent study demonstrated a 76% objective response rate when pembrolizumab was combined with lenalidomide and low-dose dexamethasone for the treatment of patients (n = 34) with relapsed/refractory MM (San Miguel et al., 2015). There are currently a number of clinical trials ongoing evaluating checkpoint blockade strategies for MM (Table 4).

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TABLE 4

Ongoing trials of immune checkpoint blockade in multiple myeloma

Data compiled from ClinicalTrials.gov (https://clinicaltrials.gov) 7/2016.

C. Leukemia

Even though the majority of clinical studies blocking PD-1 and CTLA-4 using humanized monoclonal antibodies have been conducted in solid tumors and lymphoma, PD-1 and CTLA-4 have also been shown to play a role in leukemia, graft versus leukemia (GVL) and graft versus host disease (GVHD) (Blazar et al., 1994, 1995, 1997; Fevery et al., 2007). Although CD80 and CD86 expression is not expected in solid tumors, both molecules have been detected in acute myeloid leukemia (AML), chronic myeloid leukemia, and myelodysplastic syndrome (MDS), owing to a common lineage shared by leukemia cells and APC, which naturally express CD80 and CD86 (Costello et al., 1998; Re et al., 2002; Vollmer et al., 2003; Whiteway et al., 2003; Graf et al., 2005; Yang et al., 2014). In addition, PD-L1 expression has also been detected in these malignancies and was shown to be associated with aggressive disease (Mumprecht et al., 2009; Yang et al., 2014). Furthermore, PD-1+ T cells are significantly increased in the bone marrow of patients with relapsed AML compared with healthy adult donor bone marrow (Daver et al., 2016).

Previous studies have demonstrated an important role for blocking CTLA-4 in leukemia immunity. Fevery et al. (2007) showed that blocking CTLA-4 augmented the antileukemia immune response in a murine model. Similarly, blocking the PD-1/PD-L1 pathway using anti-PD-L1 antibody enhanced the graft versus leukemia response in murine models (Zhou et al., 2010; Koestner et al., 2011). The aforementioned studies correlating the expression of CTLA-4 and PD-1 ligands with poor outcomes in AML and the preclinical studies showing improved antileukemia activities after blocking CTLA-4 and the PD-1/PD-L1 pathway together support the potential role of immune checkpoint blockade in enhancing the antileukemia immunity.

Another interesting concept that is being explored in checkpoint-based therapies for AML and MDS is the ability of epigenetic therapy to modulate immune checkpoint molecule expression on TIL and tumor cells (Zhang et al., 2011; Wrangle et al., 2013). Azacytidine is an epigenetic drug that is approved by the Food and Drug Administration for the treatment of MDS and approved by the European Medical Agency for the treatment of MDS and elderly AML. Azacytidine upregulates PD-1 and PD-L1 in MDS/AML, and the upregulation of these genes may be associated with emergence of resistance to azacytidine and inferior overall survival (Yang et al., 2014). These data have resulted in clinical trials combining epigenetic therapy with PD-1/PDL-1 blockade to improve response rates and durability of response in AML and MDS (NCT02397720, NCT02530463).

However, the application of immune checkpoint blockade in the setting of leukemia is more challenging in comparison with solid tumors and lymphoma. One significant obstacle in leukemia is that the underlying disease abrogates, and at times may completely obliterate, the immune system. Also, in the case of acute leukemia, the tumor burden and the rate of tumor proliferation suggest that the disease may progress before the checkpoint antibodies have had sufficient time to activate an immune response, especially if these agents are given alone. The timing of checkpoint therapy administration and identification of ideal combinations is critical, and best results may be achieved in the maintenance setting when there is minimal residual disease and a fully competent immune system that can be manipulated with immune checkpoint blockade or when immune checkpoint agents are combined with potentially synergistic standard anti-leukemic therapy. Identification of immune-checkpoint pathways beyond PD-1/PDL-1 and CTLA-4 that dominate in AML may further guide the rational selection of specific antibodies for clinical trials. Clinically targetable checkpoint receptors including PD-1, OX40, and ICOS appear to be overexpressed in the bone marrows of patients with AML (Daver et al., 2016). These findings need to be validated in larger studies.

In a phase I study of pidilizumab in patients with various hematologic malignancies, which included eight patients with AML and one patient with MDS, minimal response was seen in one patient with AML that was manifested by a decrease in the blast percentage from 50% to 5% (Berger et al., 2008). Four deaths were reported in that study, all of which occurred in AML patients and were attributed to leukemia progression. A summary of these studies is included in Table 2. There are a number of clinical trials currently ongoing to test checkpoint antibodies as single agents and in combination with standard antileukemia therapies in newly diagnosed and relapsed leukemia, including AML and MDS, as well as maintenance in AML (Table 5).

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TABLE 5

Ongoing trials of immune checkpoint blockade in acute myeloid leukemia

Data were compiled from ClinicalTrials.gov (https://clinicaltrials.gov) 7/2016.

D. Immune Checkpoint Inhibition after Stem Cell Transplantation: Timing Is Everything

Clinical trials of immune checkpoint blockade have been conducted after SCT with promising results. Effective immune reconstitution and the low disease burden that are characteristic after SCT provide an ideal setting to enhance the antileukemia/lymphoma immune response by eliminating the direct immunosuppressive effects of the tumor and by providing a microenvironment for the emergence of antigen specific cytotoxic T lymphocytes (CTL) (Guillaume et al., 1998; Molldrem et al., 2000; Atanackovic et al., 2007; Armand et al., 2013; Tyler et al., 2013; Chung et al., 2016). Studies in lymphoma after auto-SCT are discussed in previous sections and appear to be encouraging. However, immune checkpoint blockade in the allo-SCT setting carries the potential risk of flaring GVHD (Saha et al., 2013) and, as a result, there have been fewer clinical studies evaluating immune checkpoint blockade after allo-SCT. The precise timing of T cell reconstitution, including CD8+ T cells, CD4+ helper T cells, and TReg, within the first 2 years after allo-SCT has been correlated with promoting GVL activity or inciting GVHD (Dutt et al., 2007; Zheng et al., 2009; Alho et al., 2016). Moreover, although the antigens that drive GVL and GVHD are largely unknown, minor antigens that are common to leukemia and normal tissue have been shown to play a critical role in both processes, and oftentimes patients with GVHD show no evidence of disease. Therefore, it is possible that immune checkpoint blockade could eliminate the underlying leukemia, albeit at the risk of flaring GVHD. Lastly, most patients who receive allo-SCTs are placed on immunosuppressive medications to prevent GVHD for approximately 6 months after the allo-SCT. Together, the particulars of post-SCT immune reconstitution, the target antigens of GVL/GVHD, and the use of immunosuppressive medications after allo-SCT highlight the critical role of the timing in implementing immune checkpoint inhibitors after allo-SCT.

The few reported clinical trials have proven the complexity of immune checkpoint inhibition and the GVL/GVHD balance after allo-SCT. In the study by Bashey et al. (2009), which enrolled 29 patients with lymphoid and myeloid malignancies, ipilimumab given within 125–2368 days (median = 366 days) after allo-SCT did not precipitate GVHD in any of the patients. As discussed in the previous sections, responses were noted in five patients, four of whom had HL and one NHL. There is currently an ongoing study at the Dana Farber Cancer Institute that is testing increasing doses of ipilimumab administered to patients with relapsed malignancy after allo-SCT. Results from this phase I/Ib study of 28 patients with relapsed lymphoid and myeloid malignancies after allo-SCT who received two different dose levels of ipilimumab (3 or 10 mg/kg) showed efficacy of immune checkpoint inhibition in the patients treated at the higher dose level (Davids et al., 2016). Interestingly, patients with extramedullary AML seemed to respond particularly well to the therapy. Of note, acute (n = 1) and chronic (n = 3) GVHD were observed during treatment at the 10 mg/kg dose level. In addition to blocking CTLA-4 with ipilimumab, there is one report that shows the safety of blocking PD-1 after allo-SCT. In a case report by Angenendt et al. (2016), one patient with HD received nivolumab 19 months after allo-SCT without inciting GVHD, hence suggesting the possibility of using immune checkpoint blockade in the post-allo-SCT.

In contrast to these encouraging results suggesting the safety of immune checkpoint blockade after allo-SCT, other studies have confirmed the risk of GVHD after immune checkpoint inhibition. In the phase I trial by Berger et al. (2008), previously discussed, 4 of 17 patients who were treated with pidilizumab had received allo-SCT. One of the four patients had received pidilizumab 8 weeks after allo-SCT and subsequently experienced grade 4 GVHD of the gastrointestinal tract and died of persistent AML and GVHD. Because this patient already had evidence of skin GVHD at study entry, it was difficult for the investigators to determine whether the gastrointestinal GVHD was spontaneous or secondary to pidilizumab. Although these studies provide a compelling, nonetheless guarded, rationale to further evaluate immune checkpoint inhibition after allo-SCT, the major advance in this area should be to define the role of immune checkpoint inhibition in patients with evidence of disease after allo-SCT and to delineate the immune mechanisms that can be modulated by immune checkpoint inhibition to favor GVL over GVHD.

E. Immune Checkpoint Inhibition in the Setting of Engineered T Cell Therapy

Chimeric antigen receptor (CAR) T cells made their debut clinically in the setting of hematologic malignancies. A CAR combines a single-chain variable fragment antigen-specific extracellular region from a monoclonal antibody fused to intracellular domains providing T cell activation (i.e., CD3-ζ) and costimulation (i.e., CD28, 4-1BB, or OX40). CAR T cells therefore combine the specificity of monoclonal antibodies with the effector functions of T cells. The CD19 CAR T cell is the quintessential example demonstrating the potential of this technology. The efficacy of CD19 CAR T cells was first shown in chronic lymphocytic leukemia (Porter et al., 2011) and recently in acute lymphoblastic leukemia (Grupp et al., 2013; Maude et al., 2015). CAR T cell therapy is rapidly advancing for the treatment of patients with hematologic malignancies (Porter et al., 2011, 2015; Grupp et al., 2013; Maude et al., 2015); however, there remains room for improving the efficacy and safety of CAR T cell therapy.

One approach that could further potentiate the activity of CAR T cells is to combine CAR T cells with immune checkpoint blockade. John et al. (2013) demonstrated the feasibility of this approach in a HER-2 transgenic mouse model. In that study, the combination of anti-HER-2 CAR T cells and anti-PD-1 therapy enhanced the efficacy of the CAR T cells against HER-2-overexpressing tumors. As expected, mice treated with CAR T cells and anti-PD-1 demonstrated higher antitumor activities, but additionally, there was a decrease in myeloid derived suppressor cells in tumors treated with anti-PD-1. The combination of immune checkpoint inhibition and CAR T cell therapy using antibodies or engineered T cells that have modified immune checkpoint receptors (Shin et al., 2012; Ankri et al., 2013) have yet to be tested in preclinical models of hematologic malignances or in the clinical setting but may provide an essential synergy that could improve the outcomes beyond those seen with each individual therapy. Arguably, hematologic malignancies provide the ideal setting for this approach, because they are cured by immunotherapy, including allo-SCT, CAR T cells, and immune checkpoint inhibition, and the underlying disease itself causes major deficiencies in the immune system, suggesting that an approach that provides both an immune system and an immune modulatory drug may be more effective.

VI. Conclusion and Future Directions

Immune checkpoint inhibition for the treatment of cancer is undoubtedly a great breakthrough in cancer therapy (Couzin-Frankel, 2013; Dizon et al., 2016). The first clinical trial of immune checkpoint inhibition was conducted almost 15 years ago (Tchekmedyian et al., 2002), and the differences these approaches have made in the therapy of previously untreatable solid tumors and hematologic malignances have been striking. Through the application of immune checkpoint inhibition, we have learned much about cancer biology and the way tumors shape the immune response. As we gain a better understanding of the intricacies of the tumor microenvironment and the expression of immune checkpoint molecules by the tumor cells and the T cells, beyond CTLA-4 and PD-1 pathways, targeted clinical trials will be designed that take advantage of therapies that target immune checkpoint molecules combined with immune-based therapies, chemotherapies, vaccines, and small molecule targeting therapies (Fig. 2) to induce synergy with an intent to fully eradicate the underlying malignancy and provide long-lasting cures.

Fig. 2.
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Fig. 2.

The timing of the administration of immune checkpoint blockade is critical in determining treatment success in hematologic malignancies. The immune system is often attenuated in patients with active leukemia because of the accumulation of malignant cells in the bone marrow microenvironment. Before, or concomitant with, the administration of immune checkpoint inhibition, the underlying leukemia must be reduced to allow for some degree of immune reconstitution. One such approach includes the administration of immune checkpoint inhibitors to leukemia patients in remission or with a low leukemia burden. At this point, immune checkpoint inhibition can be administered (A) as an adjunct to cellular therapy, including stem cell transplantation, (B) in conjunction with vaccines, or (C) as a single agent.

Acknowledgments

Figures were designed by David M. Aten, M.A. (MD Anderson Cancer Center).

Author Contributions:

Wrote or contributed to the writing of the manuscript: Alatrash, Mittendorf, and Daver.

Footnotes

  • G.A. is supported by a grant from the Leukemia & Lymphoma Society. N.D. is supported by grants from the Ladies Leukemia League and the Anderson Cancer Center Leukemia SPORE. E.A.M. is an R. Lee Clark Fellow of the University of Texas Anderson Cancer Center supported by the Jeanne F. Shelby Scholarship Fund.

  • dx.doi.org/10.1124/pr.116.012682.

Abbreviations

allo
allogeneic
AML
acute myeloid leukemia
APC
antigen presenting cell
CAR
chimeric antigen receptor
CR
complete response
CTLA-4
cytotoxic-T-lymphocyte antigen
DLBCL
diffuse large B cell lymphoma
FL
follicular lymphoma
GVHD
graft versus host disease
GVL
graft versus leukemia
HL
Hodgkin’s lymphoma
MDS
myelodysplastic syndrome
MM
multiple myeloma
NHL
non-Hodgkin lymphoma
NSCLC
non-small cell lung cancer
PD-1
programmed cell death protein 1
PFS
progression-free survival
pHLA
peptide/human leukocyte antigen complex
PR
partial response
SCT
stem cell transplantation
TCR
T cell receptor
TIL
tumor infiltrating lymphocytes
TReg
regulatory T cells
  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics

References

  1. ↵
    1. Alho AC,
    2. Kim HT,
    3. Chammas MJ,
    4. Reynolds CG,
    5. Matos TR,
    6. Forcade E,
    7. Whangbo J,
    8. Nikiforow S,
    9. Cutler CS,
    10. Koreth J,
    11. et al.
    (2016) Unbalanced recovery of regulatory and effector T cells after allogeneic stem cell transplantation contributes to chronic GVHD. Blood 127:646–657.
    OpenUrlAbstract/FREE Full Text
  2. ↵
    1. Andorsky DJ,
    2. Yamada RE,
    3. Said J,
    4. Pinkus GS,
    5. Betting DJ, and
    6. Timmerman JM
    (2011) Programmed death ligand 1 is expressed by non-hodgkin lymphomas and inhibits the activity of tumor-associated T cells. Clin Cancer Res 17:4232–4244.
    OpenUrlAbstract/FREE Full Text
  3. ↵
    1. Angenendt L,
    2. Schliemann C,
    3. Lutz M,
    4. Rebber E,
    5. Schulze AB,
    6. Weckesser M,
    7. Stegger L,
    8. Schäfers M,
    9. Groth C,
    10. Kessler T,
    11. et al.
    (2016) Nivolumab in a patient with refractory Hodgkin’s lymphoma after allogeneic stem cell transplantation. Bone Marrow Transplant 51:443–445.
    OpenUrlCrossRef
  4. ↵
    1. Ankri C,
    2. Shamalov K,
    3. Horovitz-Fried M,
    4. Mauer S, and
    5. Cohen CJ
    (2013) Human T cells engineered to express a programmed death 1/28 costimulatory retargeting molecule display enhanced antitumor activity. J Immunol 191:4121–4129.
    OpenUrlAbstract/FREE Full Text
  5. Ansell S, Armand P, Timmerman JM, Shipp MA, Bradley-Garelik MB, Zhu L, and Lesokhin AM (2015a) Nivolumab in Patients (Pts) with relapsed or refractory classical Hodgkin lymphoma (R/R cHL): Clinical outcomes from extended follow-up of a phase 1 study (CA209-039), in American Society of Hematology Annual Meeting; 2015 December 5–12; Orlando, FL. Abstract 583, American Society of Hematology, Washington, D.C.
  6. ↵
    1. Ansell SM,
    2. Hurvitz SA,
    3. Koenig PA,
    4. LaPlant BR,
    5. Kabat BF,
    6. Fernando D,
    7. Habermann TM,
    8. Inwards DJ,
    9. Verma M,
    10. Yamada R,
    11. et al.
    (2009) Phase I study of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with relapsed and refractory B-cell non-Hodgkin lymphoma. Clin Cancer Res 15:6446–6453.
    OpenUrlAbstract/FREE Full Text
  7. ↵
    1. Ansell SM,
    2. Lesokhin AM,
    3. Borrello I,
    4. Halwani A,
    5. Scott EC,
    6. Gutierrez M,
    7. Schuster SJ,
    8. Millenson MM,
    9. Cattry D,
    10. Freeman GJ,
    11. et al.
    (2015b) PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med 372:311–319.
    OpenUrlCrossRefPubMed
  8. ↵
    1. Ansell SM,
    2. Stenson M,
    3. Habermann TM,
    4. Jelinek DF, and
    5. Witzig TE
    (2001) Cd4+ T-cell immune response to large B-cell non-Hodgkin’s lymphoma predicts patient outcome. J Clin Oncol 19:720–726.
    OpenUrlAbstract/FREE Full Text
  9. ↵
    1. Armand P,
    2. Nagler A,
    3. Weller EA,
    4. Devine SM,
    5. Avigan DE,
    6. Chen YB,
    7. Kaminski MS,
    8. Holland HK,
    9. Winter JN,
    10. Mason JR,
    11. et al.
    (2013) 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 31:4199–4206.
    OpenUrlAbstract/FREE Full Text
  10. ↵
    1. Atanackovic D,
    2. Arfsten J,
    3. Cao Y,
    4. Gnjatic S,
    5. Schnieders F,
    6. Bartels K,
    7. Schilling G,
    8. Faltz C,
    9. Wolschke C,
    10. Dierlamm J,
    11. et al.
    (2007) Cancer-testis antigens are commonly expressed in multiple myeloma and induce systemic immunity following allogeneic stem cell transplantation. Blood 109:1103–1112.
    OpenUrlAbstract/FREE Full Text
  11. ↵
    1. Bashey A,
    2. Medina B,
    3. Corringham S,
    4. Pasek M,
    5. Carrier E,
    6. Vrooman L,
    7. Lowy I,
    8. Solomon SR,
    9. Morris LE,
    10. Holland HK,
    11. et al.
    (2009) CTLA4 blockade with ipilimumab to treat relapse of malignancy after allogeneic hematopoietic cell transplantation. Blood 113:1581–1588.
    OpenUrlAbstract/FREE Full Text
  12. ↵
    1. Bensinger WI,
    2. Maloney D, and
    3. Storb R
    (2001) Allogeneic hematopoietic cell transplantation for multiple myeloma. Semin Hematol 38:243–249.
    OpenUrlCrossRefPubMed
  13. ↵
    1. Berger R,
    2. Rotem-Yehudar R,
    3. Slama G,
    4. Landes S,
    5. Kneller A,
    6. Leiba M,
    7. Koren-Michowitz M,
    8. Shimoni A, and
    9. Nagler A
    (2008) 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 14:3044–3051.
    OpenUrlAbstract/FREE Full Text
  14. ↵
    1. Björkstrand B,
    2. Iacobelli S,
    3. Hegenbart U,
    4. Gruber A,
    5. Greinix H,
    6. Volin L,
    7. Narni F,
    8. Musto P,
    9. Beksac M,
    10. Bosi A,
    11. et al.
    (2011) Tandem autologous/reduced-intensity conditioning allogeneic stem-cell transplantation versus autologous transplantation in myeloma: long-term follow-up. J Clin Oncol 29:3016–3022.
    OpenUrlAbstract/FREE Full Text
  15. ↵
    1. Bladé J,
    2. Rosiñol L,
    3. Cibeira MT,
    4. Rovira M, and
    5. Carreras E
    (2010) Hematopoietic stem cell transplantation for multiple myeloma beyond 2010. Blood 115:3655–3663.
    OpenUrlAbstract/FREE Full Text
  16. ↵
    1. Blazar BR,
    2. Taylor PA,
    3. Boyer MW,
    4. Panoskaltsis-Mortari A,
    5. Allison JP, and
    6. Vallera DA
    (1997) CD28/B7 interactions are required for sustaining the graft-versus-leukemia effect of delayed post-bone marrow transplantation splenocyte infusion in murine recipients of myeloid or lymphoid leukemia cells. J Immunol 159:3460–3473.
    OpenUrlAbstract
  17. ↵
    1. Blazar BR,
    2. Taylor PA,
    3. Linsley PS, and
    4. Vallera DA
    (1994) In vivo blockade of CD28/CTLA4: B7/BB1 interaction with CTLA4-Ig reduces lethal murine graft-versus-host disease across the major histocompatibility complex barrier in mice. Blood 83:3815–3825.
    OpenUrlAbstract/FREE Full Text
  18. ↵
    1. Blazar BR,
    2. Taylor PA,
    3. Panoskaltsis-Mortari A,
    4. Gray GS, and
    5. Vallera DA
    (1995) Coblockade of the LFA1:ICAM and CD28/CTLA4:B7 pathways is a highly effective means of preventing acute lethal graft-versus-host disease induced by fully major histocompatibility complex-disparate donor grafts. Blood 85:2607–2618.
    OpenUrlAbstract/FREE Full Text
  19. ↵
    1. Bruno B,
    2. Rotta M,
    3. Patriarca F,
    4. Mordini N,
    5. Allione B,
    6. Carnevale-Schianca F,
    7. Giaccone L,
    8. Sorasio R,
    9. Omedè P,
    10. Baldi I,
    11. et al.
    (2007) A comparison of allografting with autografting for newly diagnosed myeloma. N Engl J Med 356:1110–1120.
    OpenUrlCrossRefPubMed
  20. ↵
    1. Chaperot L,
    2. Plumas J,
    3. Jacob MC,
    4. Bost F,
    5. Molens JP,
    6. Sotto JJ, and
    7. Bensa JC
    (1999) Functional expression of CD80 and CD86 allows immunogenicity of malignant B cells from non-Hodgkin’s lymphomas. Exp Hematol 27:479–488.
    OpenUrlCrossRefPubMed
  21. ↵
    1. Chung DJ,
    2. Pronschinske KB,
    3. Shyer JA,
    4. Sharma S,
    5. Leung S,
    6. Curran SA,
    7. Lesokhin AM,
    8. Devlin SM,
    9. Giralt SA, and
    10. Young JW
    (2016) T-cell Exhaustion in Multiple Myeloma Relapse after Autotransplant: Optimal Timing of Immunotherapy. Cancer Immunol Res 4:61–71.
    OpenUrlAbstract/FREE Full Text
  22. ↵
    1. Costello RT,
    2. Mallet F,
    3. Sainty D,
    4. Maraninchi D,
    5. Gastaut JA, and
    6. Olive D
    (1998) 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 28:90–103.
    OpenUrlCrossRefPubMed
  23. ↵
    1. Couzin-Frankel J
    (2013) Breakthrough of the year 2013. Cancer immunotherapy. Science 342:1432–1433.
    OpenUrlAbstract/FREE Full Text
  24. ↵
    1. Daver N,
    2. Basu S,
    3. Garcia-Manero G,
    4. Cortes J,
    5. Ravandi F,
    6. Kornblau S,
    7. Konopleva M,
    8. Andreeff M,
    9. Borthakur G,
    10. Jain N,
    11. et al.
    (2016) Defining the immune checkpoint landscape of acute myeloid leukemia (AML), in American Association for Cancer Research Annual Meeting; 2016 April 16–20; New Orleans, LA. American Association for Cancer Research, Philadelphia.
  25. ↵
    1. Davids MS,
    2. Kim HT,
    3. Bachireddy P,
    4. Costello C,
    5. Liguori R,
    6. Savell A,
    7. Lukez AP,
    8. Avigan D,
    9. Chen YB,
    10. McSweeney P,
    11. et al., and
    12. Leukemia and Lymphoma Society Blood Cancer Research Partnership
    (2016) Ipilimumab for Patients with Relapse after Allogeneic Transplantation. N Engl J Med 375:143–153.
    OpenUrlCrossRefPubMed
  26. ↵
    1. Dizon DS,
    2. Krilov L,
    3. Cohen E,
    4. Gangadhar T,
    5. Ganz PA,
    6. Hensing TA,
    7. Hunger S,
    8. Krishnamurthi SS,
    9. Lassman AB,
    10. Markham MJ,
    11. et al.
    (2016) Clinical Cancer Advances 2016: Annual Report on Progress Against Cancer From the American Society of Clinical Oncology. J Clin Oncol 34:987–1011.
    OpenUrlFREE Full Text
  27. ↵
    1. Dorfman DM,
    2. Schultze JL,
    3. Shahsafaei A,
    4. Michalak S,
    5. Gribben JG,
    6. Freeman GJ,
    7. Pinkus GS, and
    8. Nadler LM
    (1997) In vivo expression of B7-1 and B7-2 by follicular lymphoma cells can prevent induction of T-cell anergy but is insufficient to induce significant T-cell proliferation. Blood 90:4297–4306.
    OpenUrlAbstract/FREE Full Text
  28. ↵
    1. Dutt S,
    2. Tseng D,
    3. Ermann J,
    4. George TI,
    5. Liu YP,
    6. Davis CR,
    7. Fathman CG, and
    8. Strober S
    (2007) Naive and memory T cells induce different types of graft-versus-host disease. J Immunol 179:6547–6554.
    OpenUrlAbstract/FREE Full Text
  29. ↵
    1. Egen JG and
    2. Allison JP
    (2002) Cytotoxic T lymphocyte antigen-4 accumulation in the immunological synapse is regulated by TCR signal strength. Immunity 16:23–35.
    OpenUrlCrossRefPubMed
  30. ↵
    1. Fevery S,
    2. Billiau AD,
    3. Sprangers B,
    4. Rutgeerts O,
    5. Lenaerts C,
    6. Goebels J,
    7. Landuyt W,
    8. Kasran A,
    9. Boon L,
    10. Sagaert X,
    11. et al.
    (2007) CTLA-4 blockade in murine bone marrow chimeras induces a host-derived antileukemic effect without graft-versus-host disease. Leukemia 21:1451–1459.
    OpenUrlCrossRefPubMed
  31. ↵
    1. Francisco LM,
    2. Salinas VH,
    3. Brown KE,
    4. Vanguri VK,
    5. Freeman GJ,
    6. Kuchroo VK, and
    7. Sharpe AH
    (2009) PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med 206:3015–3029.
    OpenUrlAbstract/FREE Full Text
  32. ↵
    1. Freeman GJ,
    2. Long AJ,
    3. Iwai Y,
    4. Bourque K,
    5. Chernova T,
    6. Nishimura H,
    7. Fitz LJ,
    8. Malenkovich N,
    9. Okazaki T,
    10. Byrne MC,
    11. et al.
    (2000) Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 192:1027–1034.
    OpenUrlAbstract/FREE Full Text
  33. ↵
    1. Garon EB,
    2. Rizvi NA,
    3. Hui R,
    4. Leighl N,
    5. Balmanoukian AS,
    6. Eder JP,
    7. Patnaik A,
    8. Aggarwal C,
    9. Gubens M,
    10. Horn L,
    11. et al., and
    12. KEYNOTE-001 Investigators
    (2015) Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 372:2018–2028.
    OpenUrlCrossRefPubMed
  34. ↵
    1. Görgün G,
    2. Samur MK,
    3. Cowens KB,
    4. Paula S,
    5. Bianchi G,
    6. Anderson JE,
    7. White RE,
    8. Singh A,
    9. Ohguchi H,
    10. Suzuki R,
    11. et al.
    (2015) Lenalidomide enhances immune checkpoint blockade-induced immune response in multiple myeloma. Clin Cancer Res 21:4607–4618.
    OpenUrlAbstract/FREE Full Text
  35. ↵
    1. Graf M,
    2. Reif S,
    3. Hecht K,
    4. Pelka-Fleischer R,
    5. Kroell T,
    6. Pfister K, and
    7. Schmetzer H
    (2005) High expression of costimulatory molecules correlates with low relapse-free survival probability in acute myeloid leukemia (AML). Ann Hematol 84:287–297.
    OpenUrlCrossRefPubMed
  36. ↵
    1. Green MR,
    2. Monti S,
    3. Rodig SJ,
    4. Juszczynski P,
    5. Currie T,
    6. O’Donnell E,
    7. Chapuy B,
    8. Takeyama K,
    9. Neuberg D,
    10. Golub TR,
    11. et al.
    (2010) 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 116:3268–3277.
    OpenUrlAbstract/FREE Full Text
  37. ↵
    1. Green MR,
    2. Rodig S,
    3. Juszczynski P,
    4. Ouyang J,
    5. Sinha P,
    6. O’Donnell E,
    7. Neuberg D, and
    8. Shipp MA
    (2012) Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: implications for targeted therapy. Clin Cancer Res 18:1611–1618.
    OpenUrlAbstract/FREE Full Text
  38. ↵
    1. Grogan TM and
    2. Miller TP
    (1993) Immunobiologic correlates of prognosis in lymphoma. Semin Oncol 20(5, Suppl 5)58–74.
    OpenUrlPubMed
  39. ↵
    1. Grupp SA,
    2. Kalos M,
    3. Barrett D,
    4. Aplenc R,
    5. Porter DL,
    6. Rheingold SR,
    7. Teachey DT,
    8. Chew A,
    9. Hauck B,
    10. Wright JF,
    11. et al.
    (2013) Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 368:1509–1518.
    OpenUrlCrossRefPubMed
  40. ↵
    1. Guillaume T,
    2. Rubinstein DB, and
    3. Symann M
    (1998) Immune reconstitution and immunotherapy after autologous hematopoietic stem cell transplantation. Blood 92:1471–1490.
    OpenUrlFREE Full Text
  41. ↵
    1. John LB,
    2. Devaud C,
    3. Duong CP,
    4. Yong CS,
    5. Beavis PA,
    6. Haynes NM,
    7. Chow MT,
    8. Smyth MJ,
    9. Kershaw MH, and
    10. Darcy PK
    (2013) Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells. Clin Cancer Res 19:5636–5646.
    OpenUrlAbstract/FREE Full Text
  42. ↵
    1. Koestner W,
    2. Hapke M,
    3. Herbst J,
    4. Klein C,
    5. Welte K,
    6. Fruehauf J,
    7. Flatley A,
    8. Vignali DA,
    9. Hardtke-Wolenski M,
    10. Jaeckel E,
    11. et al.
    (2011) PD-L1 blockade effectively restores strong graft-versus-leukemia effects without graft-versus-host disease after delayed adoptive transfer of T-cell receptor gene-engineered allogeneic CD8+ T cells. Blood 117:1030–1041.
    OpenUrlAbstract/FREE Full Text
  43. ↵
    1. Larkin J,
    2. Chiarion-Sileni V,
    3. Gonzalez R,
    4. Grob JJ,
    5. Cowey CL,
    6. Lao CD,
    7. Schadendorf D,
    8. Dummer R,
    9. Smylie M,
    10. Rutkowski P,
    11. et al.
    (2015) Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med 373:23–34.
    OpenUrlCrossRefPubMed
  44. ↵
    1. Leach DR,
    2. Krummel MF, and
    3. Allison JP
    (1996) Enhancement of antitumor immunity by CTLA-4 blockade. Science 271:1734–1736.
    OpenUrlAbstract
  45. ↵
    Lesokhin AM, Ansell SM, Armand P, Scott EC, Halwani A, Gutierrez M, Millenson MM, Cohen AD, Schuster SJ, Lebovic D, et al. (2014) Preliminary results of a phase I study of Nivolumab (BMS-936558) in patients with relapsed or refractory lymphoid malignancies, in American Society of Hematology Annual Meeting; 2014 December 6–9; San Francisco, CA. Abstract 291, American Society of Hematology, Washington, D.C.
  46. ↵
    1. Linsley PS,
    2. Greene JL,
    3. Brady W,
    4. Bajorath J,
    5. Ledbetter JA, and
    6. Peach R
    (1994) Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors. Immunity 1:793–801.
    OpenUrlCrossRefPubMed
  47. ↵
    1. Lippman SM,
    2. Spier CM,
    3. Miller TP,
    4. Slymen DJ,
    5. Rybski JA, and
    6. Grogan TM
    (1990) Tumor-infiltrating T-lymphocytes in B-cell diffuse large cell lymphoma related to disease course. Mod Pathol 3:361–367.
    OpenUrlPubMed
  48. ↵
    1. Maude SL,
    2. Teachey DT,
    3. Porter DL, and
    4. Grupp SA
    (2015) CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Blood 125:4017–4023.
    OpenUrlAbstract/FREE Full Text
  49. ↵
    1. McGranahan N,
    2. Furness AJ,
    3. Rosenthal R,
    4. Ramskov S,
    5. Lyngaa R,
    6. Saini SK,
    7. Jamal-Hanjani M,
    8. Wilson GA,
    9. Birkbak NJ,
    10. Hiley CT,
    11. et al.
    (2016) Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 351:1463–1469.
    OpenUrlAbstract/FREE Full Text
  50. ↵
    1. Mehta J and
    2. Singhal S
    (1998) Graft-versus-myeloma. Bone Marrow Transplant 22:835–843.
    OpenUrlCrossRefPubMed
  51. ↵
    1. Molldrem JJ,
    2. Lee PP,
    3. Wang C,
    4. Felio K,
    5. Kantarjian HM,
    6. Champlin RE, and
    7. Davis MM
    (2000) Evidence that specific T lymphocytes may participate in the elimination of chronic myelogenous leukemia. Nat Med 6:1018–1023.
    OpenUrlCrossRefPubMed
  52. ↵
    Moskowitz C, Ribrag V, Michot JM, Martinelli G, Zinzani PL, Gutierrez M, De Maeyer G, Jacob AG, Giallella K, Anderson JW, et al. (2014) 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), in American Society of Hematology Annual Meeting; 2014 December 6–9; San Francisco, CA. Abstract 290, American Society of Hematology, Washington, D.C.
  53. ↵
    1. Mumprecht S,
    2. Schürch C,
    3. Schwaller J,
    4. Solenthaler M, and
    5. Ochsenbein AF
    (2009) Programmed death 1 signaling on chronic myeloid leukemia-specific T cells results in T-cell exhaustion and disease progression. Blood 114:1528–1536.
    OpenUrlAbstract/FREE Full Text
  54. ↵
    1. Nishimura H,
    2. Nose M,
    3. Hiai H,
    4. Minato N, and
    5. Honjo T
    (1999) Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11:141–151.
    OpenUrlCrossRefPubMed
  55. ↵
    1. Nishimura H,
    2. Okazaki T,
    3. Tanaka Y,
    4. Nakatani K,
    5. Hara M,
    6. Matsumori A,
    7. Sasayama S,
    8. Mizoguchi A,
    9. Hiai H,
    10. Minato N,
    11. et al.
    (2001) Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 291:319–322.
    OpenUrlAbstract/FREE Full Text
  56. ↵
    1. Porter DL,
    2. Hwang WT,
    3. Frey NV,
    4. Lacey SF,
    5. Shaw PA,
    6. Loren AW,
    7. Bagg A,
    8. Marcucci KT,
    9. Shen A,
    10. Gonzalez V,
    11. et al.
    (2015) Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med 7:303ra139.
    OpenUrlAbstract/FREE Full Text
  57. ↵
    1. Porter DL,
    2. Levine BL,
    3. Kalos M,
    4. Bagg A, and
    5. June CH
    (2011) Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 365:725–733.
    OpenUrlCrossRefPubMed
  58. ↵
    1. Ray A,
    2. Das DS,
    3. Song Y,
    4. Richardson P,
    5. Munshi NC,
    6. Chauhan D, and
    7. Anderson KC
    (2015) Targeting PD1-PDL1 immune checkpoint in plasmacytoid dendritic cell interactions with T cells, natural killer cells and multiple myeloma cells. Leukemia 29:1441–1444.
    OpenUrlCrossRefPubMed
  59. ↵
    1. Re F,
    2. Arpinati M,
    3. Testoni N,
    4. Ricci P,
    5. Terragna C,
    6. Preda P,
    7. Ruggeri D,
    8. Senese B,
    9. Chirumbolo G,
    10. Martelli V,
    11. et al.
    (2002) Expression of CD86 in acute myelogenous leukemia is a marker of dendritic/monocytic lineage. Exp Hematol 30:126–134.
    OpenUrlCrossRefPubMed
  60. ↵
    1. Riley JL,
    2. Mao M,
    3. Kobayashi S,
    4. Biery M,
    5. Burchard J,
    6. Cavet G,
    7. Gregson BP,
    8. June CH, and
    9. Linsley PS
    (2002) Modulation of TCR-induced transcriptional profiles by ligation of CD28, ICOS, and CTLA-4 receptors. Proc Natl Acad Sci USA 99:11790–11795.
    OpenUrlAbstract/FREE Full Text
  61. ↵
    1. Rizvi NA,
    2. Hellmann MD,
    3. Snyder A,
    4. Kvistborg P,
    5. Makarov V,
    6. Havel JJ,
    7. Lee W,
    8. Yuan J,
    9. Wong P,
    10. Ho TS,
    11. et al.
    (2015) Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348:124–128.
    OpenUrlAbstract/FREE Full Text
  62. ↵
    1. Roddie C and
    2. Peggs KS
    (2011) Donor lymphocyte infusion following allogeneic hematopoietic stem cell transplantation. Expert Opin Biol Ther 11:473–487.
    OpenUrlCrossRefPubMed
  63. ↵
    1. Rudd CE,
    2. Taylor A, and
    3. Schneider H
    (2009) CD28 and CTLA-4 coreceptor expression and signal transduction. Immunol Rev 229:12–26.
    OpenUrlCrossRefPubMed
  64. ↵
    1. Saha A,
    2. Aoyama K,
    3. Taylor PA,
    4. Koehn BH,
    5. Veenstra RG,
    6. Panoskaltsis-Mortari A,
    7. Munn DH,
    8. Murphy WJ,
    9. Azuma M,
    10. Yagita H,
    11. et al.
    (2013) Host programmed death ligand 1 is dominant over programmed death ligand 2 expression in regulating graft-versus-host disease lethality. Blood 122:3062–3073.
    OpenUrlAbstract/FREE Full Text
  65. ↵
    San Miguel J, Mateos M, Shah JJ, Ocio EM, Rodriguez-Otero P, Reece D, Munshi NC, Avigan DE, Ge Y, Balakumaran A, et al. (2015) Pembrolizumab in combination with lenalidomide and low-dose dexamethasone for relapsed/refractory multiple myeloma (RRMM): Keynote-023, in American Society of Hematology Annual Meeting; 2015 December 5–8; Orlando, FL. Abstract 505, American Society of Hematology, Washington, D.C.
  66. ↵
    1. Schneider H,
    2. Downey J,
    3. Smith A,
    4. Zinselmeyer BH,
    5. Rush C,
    6. Brewer JM,
    7. Wei B,
    8. Hogg N,
    9. Garside P, and
    10. Rudd CE
    (2006) Reversal of the TCR stop signal by CTLA-4. Science 313:1972–1975.
    OpenUrlAbstract/FREE Full Text
  67. ↵
    1. Shin JH,
    2. Park HB,
    3. Oh YM,
    4. Lim DP,
    5. Lee JE,
    6. Seo HH,
    7. Lee SJ,
    8. Eom HS,
    9. Kim IH,
    10. Lee SH,
    11. et al.
    (2012) Positive conversion of negative signaling of CTLA4 potentiates antitumor efficacy of adoptive T-cell therapy in murine tumor models. Blood 119:5678–5687.
    OpenUrlAbstract/FREE Full Text
  68. ↵
    1. Snyder A,
    2. Makarov V,
    3. Merghoub T,
    4. Yuan J,
    5. Zaretsky JM,
    6. Desrichard A,
    7. Walsh LA,
    8. Postow MA,
    9. Wong P,
    10. Ho TS,
    11. et al.
    (2014) Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 371:2189–2199.
    OpenUrlCrossRefPubMed
  69. ↵
    1. Suen H,
    2. Brown R,
    3. Yang S,
    4. Ho PJ,
    5. Gibson J, and
    6. Joshua D
    (2015) The failure of immune checkpoint blockade in multiple myeloma with PD-1 inhibitors in a phase 1 study. Leukemia 29:1621–1622.
    OpenUrlCrossRefPubMed
  70. ↵
    1. Suen H,
    2. Joshua DE,
    3. Brown RD,
    4. Yang S,
    5. Barbaro PM,
    6. Ho PJ, and
    7. Gibson J
    (2014) Protective cytotoxic clonal T-cells in myeloma have the characteristics of telomere-independent senescence rather than an exhausted or anergic phenotype: Implications for immunotherapy, in American Society of Hematology Annual Meeting; 2014 December 6–9; San Francisco, CA. pp 3367, American Society of Hematology, Washington, D.C.
  71. ↵
    1. Taube JM,
    2. Klein A,
    3. Brahmer JR,
    4. Xu H,
    5. Pan X,
    6. Kim JH,
    7. Chen L,
    8. Pardoll DM,
    9. Topalian SL, and
    10. Anders RA
    (2014) Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res 20:5064–5074.
    OpenUrlAbstract/FREE Full Text
  72. ↵
    Tchekmedyian S, Glaspy J, Korman A, Keler T, Deo Y, and Davis T (2002) MDX-010 (human anti-CTLA4): a phase I trial in malignant melanoma, in Proceedings of the American Society of Clinical Oncology; 2002 May 18–21; Orlando, FL. Abstract 56, American Society of Clinical Oncology, Alexandria, VA.
  73. ↵
    1. Tsukada N,
    2. Aoki S,
    3. Maruyama S,
    4. Kishi K,
    5. Takahashi M, and
    6. Aizawa Y
    (1997) The heterogeneous expression of CD80, CD86 and other adhesion molecules on leukemia and lymphoma cells and their induction by interferon. J Exp Clin Cancer Res 16:171–176.
    OpenUrlPubMed
  74. ↵
    1. Tyler EM,
    2. Jungbluth AA,
    3. O’Reilly RJ, and
    4. Koehne G
    (2013) WT1-specific T-cell responses in high-risk multiple myeloma patients undergoing allogeneic T cell-depleted hematopoietic stem cell transplantation and donor lymphocyte infusions. Blood 121:308–317.
    OpenUrlAbstract/FREE Full Text
  75. ↵
    1. Van Allen EM,
    2. Miao D,
    3. Schilling B,
    4. Shukla SA,
    5. Blank C,
    6. Zimmer L,
    7. Sucker A,
    8. Hillen U,
    9. Geukes Foppen MH,
    10. Goldinger SM,
    11. et al.
    (2015) Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science 350:207–211.
    OpenUrlAbstract/FREE Full Text
  76. ↵
    1. Vollmer M,
    2. Li L,
    3. Schmitt A,
    4. Greiner J,
    5. Reinhardt P,
    6. Ringhoffer M,
    7. Wiesneth M,
    8. Döhner H, and
    9. Schmitt M
    (2003) Expression of human leucocyte antigens and co-stimulatory molecules on blasts of patients with acute myeloid leukaemia. Br J Haematol 120:1000–1008.
    OpenUrlCrossRefPubMed
  77. ↵
    1. Westin JR,
    2. Chu F,
    3. Zhang M,
    4. Fayad LE,
    5. Kwak LW,
    6. Fowler N,
    7. Romaguera J,
    8. Hagemeister F,
    9. Fanale M,
    10. Samaniego F,
    11. et al.
    (2014) 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 15:69–77.
    OpenUrlCrossRefPubMed
  78. ↵
    1. Whiteway A,
    2. Corbett T,
    3. Anderson R,
    4. Macdonald I, and
    5. Prentice HG
    (2003) Expression of co-stimulatory molecules on acute myeloid leukaemia blasts may effect duration of first remission. Br J Haematol 120:442–451.
    OpenUrlCrossRefPubMed
  79. ↵
    1. Wrangle J,
    2. Wang W,
    3. Koch A,
    4. Easwaran H,
    5. Mohammad HP,
    6. Vendetti F,
    7. Vancriekinge W,
    8. Demeyer T,
    9. Du Z,
    10. Parsana P,
    11. et al.
    (2013) Alterations of immune response of Non-Small Cell Lung Cancer with Azacytidine. Oncotarget 4:2067–2079.
    OpenUrlCrossRefPubMed
  80. ↵
    1. Yang H,
    2. Bueso-Ramos C,
    3. DiNardo C,
    4. Estecio MR,
    5. Davanlou M,
    6. Geng QR,
    7. Fang Z,
    8. Nguyen M,
    9. Pierce S,
    10. Wei Y,
    11. et al.
    (2014) Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. Leukemia 28:1280–1288.
    OpenUrlCrossRefPubMed
  81. ↵
    1. Yokosuka T,
    2. Takamatsu M,
    3. Kobayashi-Imanishi W,
    4. Hashimoto-Tane A,
    5. Azuma M, and
    6. Saito T
    (2012) Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. J Exp Med 209:1201–1217.
    OpenUrlAbstract/FREE Full Text
  82. ↵
    1. Zhang M,
    2. Xiao XQ,
    3. Jiang YF,
    4. Liang YS,
    5. Peng MY,
    6. Xu Y, and
    7. Gong GZ
    (2011) DNA demethylation in PD-1 gene promoter induced by 5-azacytidine activates PD-1 expression on Molt-4 cells. Cell Immunol 271:450–454.
    OpenUrlCrossRefPubMed
  83. ↵
    1. Zheng H,
    2. Matte-Martone C,
    3. Jain D,
    4. McNiff J, and
    5. Shlomchik WD
    (2009) Central memory CD8+ T cells induce graft-versus-host disease and mediate graft-versus-leukemia. J Immunol 182:5938–5948.
    OpenUrlAbstract/FREE Full Text
  84. ↵
    1. Zhou Q,
    2. Munger ME,
    3. Highfill SL,
    4. Tolar J,
    5. Weigel BJ,
    6. Riddle M,
    7. Sharpe AH,
    8. Vallera DA,
    9. Azuma M,
    10. Levine BL,
    11. et al.
    (2010) 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 116:2484–2493.
    OpenUrlAbstract/FREE Full Text
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Pharmacological Reviews: 68 (4)
Pharmacological Reviews
Vol. 68, Issue 4
1 Oct 2016
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Review ArticleReview Article

Checkpoint Blockade for Hematologic Malignancies

Gheath Alatrash, Naval Daver and Elizabeth A. Mittendorf
Pharmacological Reviews October 1, 2016, 68 (4) 1014-1025; DOI: https://doi.org/10.1124/pr.116.012682

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Review ArticleReview Article

Checkpoint Blockade for Hematologic Malignancies

Gheath Alatrash, Naval Daver and Elizabeth A. Mittendorf
Pharmacological Reviews October 1, 2016, 68 (4) 1014-1025; DOI: https://doi.org/10.1124/pr.116.012682
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  • Article
    • Abstract
    • I. Introduction
    • II. T Cell Inhibitory Pathways: Cytotoxic-T-lymphocyte Antigen 4, Programmed Death Protein 1, and Programmed Death Protein Ligand 1
    • III. Targeting Immune Checkpoint Molecules in Cancer
    • IV. Immune Checkpoint Inhibition in Hematologic Tumors
    • VI. Conclusion and Future Directions
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