Over the last several years of clinical MET targeting therapeutics development, mixed clinical trial studies results especially in the phase 3 study outcomes have resulted in disappointment and hurdles in the drug development. More recent advances in technological profiling platforms and their increasingly common implementation to inform therapeutics in cancer therapies have uncovered and validated novel MET alterations especially

juxtamembrane skipping alternative splicing variant, and MET chromosomal fusion products. These findings alongwith some emerging clinical tumor response in MET therapy targeting

in lung adenocarcinoma, soft tissue sarcoma and pulmonary sarcomatoid carcinoma have regenerated new enthusiasm in further exploring MET targeted therapy. It is also becoming clear in recent years that concurrent genomic, proteomics and immune surveillance milieu beyond the identifiable MET alterations could play important roles in determining the ultimate tumor response to MET targeted therapy. These bioinformatics data should be considered essential in modern omics era drug development and in the elucidation of predictive biomarkers. Emerging discoveries of MET chromosomal fusions provide additional promise as therapeutic genomic targets in MET cancer therapy and would need to be tested vigorously.

MET is a multifunctional receptor tyrosine kinase (RTK) that normally plays an important role in embryonic developmental signaling. In adulthood tissues and cellular environment, it is primarily activated during tissue injuries and wound healing, otherwise it remains mostly quiescent. Pathologically, MET signaling dysregulation leads to malignant cellular transformation, proliferation, survival, motility and migration, scattering, epithelial-mesenchymal transition (EMT), angiogenesis, invasion, and metastasis.

The MET protooncogene resides on the 7q31 locus of chromosome 7, consisting of 21 exons separated by 20 introns.

MET is composed of an a-chain (50 kDa) and a transmembrane b-chain (140 kDa) subunit linked by a covalent disulphide bond. The MET b-chain adopts a 7-blade b-propeller fold structural domain within the aminoterminal Semaphorin (or Sema) domain, which has homology with the plexin family of semaphorin receptors.

The Sema domain plays a key role in the ligand binding and receptor homodimerization of MET.

Following the Sema domain is the PSI domain (found in plexins, semaphorins, and integrins), then 4 IPT repeats (found in immunoglobulin, plexins, and transcription factors), and a single a-helix transmembrane domain. The cytoplasmic tyrosine kinase domain contains a number of key serine and tyrosine phosphorylation sites important in the recruitment of SRC-homology-2-domain (SH2) containing signaling transducers and intermediaries. The natural ligand for MET is hepatocyte growth factor (HGF), alternatively called scatter factor (SF), which can be found and is produced in the stromal and mesenchymal cells, acting in endocrine and/or paracrine fashion on the MET- expressing epithelial cells.

Besides, autocrine tumoral source of HGF can also mediate oncogenic signaling.

Upon ligand binding to HGF, MET is phosphorylated at multiple residues, with subsequent catalytic activation of cellular signaling transduction cascades.

Phosphorylation of the major autophosphorylation sites Y1230, Y1234, and Y1235, located within the activation loop of the tyrosine kinase domain, activates the intrinsic catalytic MET kinase activity. It leads then to further recruitment of intracellular adaptor molecules through the SH2 domains and other recognition motifs, such as GAB1 (key signaling adaptor coordinator of the cellular responses to MET). Downstream GRB2- mitogen-activated protein kinases (MAPK) signaling cascade, PI3K-mTOR pathway and the STAT signaling pathway are also eventually activated to effectuate various cellular functions.

MET/HGF signaling has been designated as one of the new generation &ldquo;Hallmarks of Cancer&rdquo;, as a key oncogenic pathway for &ldquo;activating invasion and metastasis.&rdquo;

Extensive past preclinical studies have documented the role of MET/HGF signaling in various processes in the development of human malignancies. The first evidence of clinical relevance of MET kinase mutations was reported in the germline and somatic mutations of MET in the kinase domain, homologous to those in the KIT and Ret Proto-Oncogene (RET) proto-oncogenes, in hereditary and sporadic papillary renal cell carcinoma.

Besides, multitudes of MET mutations including those within the kinase domain and also extracellular sema domain, and more recently within the juxtamembrane domain, have been reported in various human cancers.

Oncogenic MET and/or HGF over- expression have also been demonstrated in various human cancers, including both hematologic and solid malignancies (http://www.vai.org/met).

Phosphorylated MET was shown to be highly expressed in lung cancer tissues among other common solid cancers.

The crosstalk between MET and epidermal growth factor receptor (EGFR) family receptors,

as well as Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) signaling has been implicated in recent years.

MET/ HGF signaling can also crosstalk with other oncogenic pathways, such as EGFR, erb-B2 receptor tyrosine kinase 3 (ERBB3), AXL, macrophage stimulating 1 receptor (RON), CD44, a6b4-integrin and Hypoxia-inducible factor 1 (HIF)-1a.

Some of these &ldquo;bypass&rdquo; pathways have emerged as possible mechanisms contributing to acquired EGFR-tyrosine kinase inhibitor (TKI) resistance.

Basic and translational research studies on oncogenic MET/HGF signaling have ushered the therapeutic development of clinical MET targeted agents in recent years in cancer therapy.

MET/HGF signaling can be activated through genomic amplification or transcriptional upregulation, protein overexpression of the ligand and/or receptor itself, oncogenic mutations, or alternative splicing. MET oncogenic signaling can be induced via both HGF-ligand dependent or independent fashion. MET gene mutations and copy number variations have been reported in a wide variety of human tumor tissues.

MET mutations can be found clustered in the non-tyrosine kinase domain, namely in the juxtamembrane and Sema domains, in addition to the kinase domain. MET kinase domain mutations have been found to be somatically selected in the metastatic tissues, compared with the primary solid cancers.

Previous studies characterizing the juxtamembrane (JM) mutations (R988C, T1010I, and alternative spliced JM-skipping variant) demonstrated that these are activating oncogenic variants (FIG. 1A), with enhanced oncogenic signaling, tumorigenicity, cell motility, and migration.

Somatic and germline variants of MET were first reported in sporadic and hereditary papillary renal cell carcinoma, and later in a variety of other human cancers.

The relative significance and relevance of many specific reported mutations in cancer biology and progression remain to be better defined. By using quantitative real time polymerase chain reaction (QPCR) assay for MET amplification, multiple studies have reported primary MET amplification to be 2-21% in nonsmall-cell lung cancer (NSCLC) lung adenocarcinomas.

Based on the QPCR method using formalin-fixed paraffin embedded (FFPE) tumor tissues, MET gene copy number >4 in lung adenocarcinoma tissue samples has been associated with better prognosis (median survival 39 vs 16 months,

= .06).37 Using fluorescence in-situ hybridization (FISH) assay, the Lung Cancer Mutation Consortium (LCMC) reported 4.1% of adenocarcinoma with MET amplification >2.2 (MET/CEP7).

A TCGA lung adenocarcinoma study identified MET amplification to be 2.2%.43 Cappuzzo et al44 reported in a study of 447 NSCLC patients, a high MET gene copy number (greater than or equal to 5 copies/cell) was negatively associated with survival (hazard ratio [HR], 0.66,

Most recent attention has turned to the MET exon 14 alternative splicing variant (

) that generates an activating form of MET receptor skipping the juxtamembrane domain.

Genomic alterations involving exon 14 skipping alternative splicing of MET were first reported in lung cancer in 2003-200534,35. In the MET mutational analysis studies, 2

variants were identified in small cell lung cancer (SCLC) involving a 2 base-pair insertion in a splice acceptor site 5 of exon 14 and one in a non-small cell lung cancer (NSCLC) sample involving an in-frame skipping of exon 14.

MET JM domain activating mutations R988C and T1010I were also reported in lung cancer. Soon after, another series of somatic intronic mutations was reported in lung cancer cell lines and patient samples immediately flanking exon 14, and Y1003 residue that serves as the JM domain binding site for Cbl Proto-Oncogene (CBL), the E3-ubiquitin ligase to regulate MET receptor turnover.

In addition, a recent TCGA lung adenocarcinoma study reported the presence of mRNA transcripts expressing

skipping in 4.3% of samples as a result of somatic in-cis DNA exon 14 splice site mutation (ss mut), splice site deletion (ss del) or a Y1003* mutation45. The frequency of

skipping in lung adenocarcinoma was determined to be 4.3%. Another transcriptome meta-anal- ysis of lung cancer detected

skipping in 15 samples with 14 occurring in driver-unknown tumor samples (3.6%).46 Most recently, there have been several additional reports further validating the existence and, importantly, the clinical relevance of

in human cancers, including but not limiting to lung adenocarcinoma. Paik et al reported that mutations of RNA splice acceptor and donor sites involving MET exon 14 lead to exon skipping and in-frame deletion of the JM domain. Furthermore, clinical evidence of tumor response to MET targeted therapies using crizotinib or carbozantinib was reported.

In another article, Frampton et al identified through a Clinical Laboratory Improvement Amendments (CLIA)-certified clinical tumor genomic profiling platform from over 38,000 patient samples, recurrent and highly diverse genomic alterations in multiple tumor types, with overall frequency at 0.6% (221/38,028) of

. Among the positive cases, there were 126 distinct genomic sequence variants. Of note,

mutations were found most frequently in lung adenocarcinoima (3%), but also in other lung neoplasms (2.3%), brain glioma (0.4%), and tumors of unknown primary origin (0.4%).48 A small series of patients harboring

was identified that demonstrated tumor response toward MET inhibitors crizotinib and INC280. Moreover,

variants have most recently been reported to occur very frequently in pulmonary sarcomatoid carcinoma (PSC) at 22%,

with an example of remarkable tumor response to crizotinib observed in a chemo-refractory patient with PSC.

Recently, chromosomal translocations have emerged as a class of oncogenic aberrancy more important than previously recognized in solid cancers especially in prostate and lung cancers. Interestingly, novel chromosomal translocations involving MET have also been uncovered in a variety of human cancers.

In particular, at least 2 fusion variants (ie, KIF5BMET in lung adeno-carcinoma and TFG&ndash;MET in thyroid papillary carcinoma) evidently possess the predicted chimeric protein confirmed with the classic fusion activation paradigm, joining the dimerization motifs to an intact kinase domain.

These findings provide support for chromosomal MET translocation products to be a candidate as a

oncoprotein. Moreover, protein tyrosine phos- phatase, receptor type, Z polypeptide 1

fusion transcripts have been identified as a novel and recurrent alteration in grade III astrocytomas (7.7%) and in secondary glioblastomas (15%) through RNA-seq analysis.51 Recent studies also suggested that

enhanced expression and phosphorylation of the fusion-MET receptor.

Clinical Targeting of MET/HGF in Cancer Therapy

There are generally three main cancer therapeutic strategies in targeting the MET/HGF pathway: HGF antibodies, MET receptor antibodies, and MET receptor small molecule inhibitors (ATP-competitive and non-competitive). Many of them have undergone various phases of clinical trial studies in recent years, resulting in mixed study outcomes. To this date, there have not been an inhibitory agent against MET or HGF that have been FDA-approved primarily for targeting MET/ HGF in cancer therapy. The following section will review succinctly the rationale and updates for targeting various forms of MET genomic alterations in cancer therapy.

Up to date, there have been two mature phase III clinical trial studies targeting MET in cancer therapy, both followed successful positive phase II clinical study results. One involved an anti-MET, one-arm monoclonal antibody onartuzumab (MetMab) which was found to be efficacious in advanced NSCLC patients selected for high MET expression by protein IHC assay, leading to the development of the phase III METLung trial. The METLung study was a biomarker-selected clinical trial to investigate onartuzumab/erlotinib versus erlotinib/ placebo in previously treated stage IIIB-IV NSCLC with centrally confirmed MET-positive expression by IHC (MET-IHC 2+/3+ in &ge;50% tumor cells). While the phase II study results strongly supported the notion that MET expression status by IHC may predict clinical benefit from onartuzumab/erlotinib combination; the phase III METLung study was terminated early due to lack of clinically meaningful efficacy. Another phase III study involved the use of tivantinib (ARQ197) which is a non- ATPcompetitive small molecule MET inhibitor. A global randomized phase II trial ARQ197-209, comparing erlotinib/tivantinib (ET) versus erlotinib/placebo (EP) in unselected advanced NSCLC, revealed progression- free-survival (PFS) as the primary endpoint to be prolonged in the ET group. Biomarker analysis highlighted that among nonsquamous tumors, 75% were MET-positive by IHC(2+/3+), compared with only 12% among squamous subtype. Exploratory analysis demonstrated significant delay in time-to-development of new me- tastases among patients treated with ET (HR 0.49,

<0.01), most notable in the nonsquamous population. This study led to the activation of a global randomized phase III clinical trial, MARQUEE, focusing on patients with nonsquamous NSCLC histology, and patients enriched for MET-high expression, using overall survival (OS) as the primary endpoint.

The MARQUEE trial was again discontinued early after a planned interim analysis revealed study futility. Nonetheless, final analysis showed both PFS and overall response rates (ORR) were improved. The tivantinib treatment group did show significant OS improvement in the subgroup with MET-high expression, essentially recapitulating the phase II onartuzumab study results.

Although crizotinib was initially developed as a putative MET inhibitor, its anaplastic lymphoma kinase (ALK) activities were validated as being clinically relevant in inhibiting ALK(2p23) translocation-positive NSCLC leading to its FDA approval in 2011. Thereafter, MET genomic amplification associated with various tumor types has been reported to correlate with crizotinib treatment clinical response.

Hence, it was believed that MET amplification represents a predictive biomarker for a subgroup of tumors potentially addicted to MET-driven oncogenic pathways. A recent TCGA Research Network report on lung adenocarcinoma confirmed a frequency of 2.2% MET amplification, and provided evidence for it as &ldquo;driver&rdquo; alteration.

A report of crizotinib treatment in MET-amplified NSCLC from the original phase I study included 14 patients accrued to the NSCLC cohort, mostly adenocarcinoma and with positive smoking status.

This study observed objective response rates to be: 0% in the low-MET (MET/CEP7 ratio &ge;1.8-&le;2.2), 17% in the intermediate-MET (ratio >2.2-<5.0), and 67% in the high- MET (ratio &ge;5.0) group, hence supporting the notion of an improved efficacy correlating with an increasing MET amplification ratio.

Recently, clinical validation of precision therapy targeting the alternative splicing variants of MET receptors with the JM domain (encoded by exon 14) skipped, with the use of MET inhibitors, has been reported. The two recent reports by Paik et al47 and Frampton et al48 further enrich our understanding of MET as molecular target in precision cancer therapy. In the largest tumor genomic profiling cohort performed for MET alteration, Frampton et al reported 221 positive cases (0.6%) express

mutations out of 38,028 profiled tumors. Most interestingly,

alterations comprised a highly diverse 126 distinct sequence variants that were observed commonly but not exclusively in lung adenocarcinoma (3%).

alterations were identified also in other non-adenocarcinoma lung tumor types (2.3%), brain glioblastoma (0.4%), tumors of unknown primary (0.4%), and a number of other tumor types (0.06%) including renal cell carcinoma, soft tissue sarcoma, and hepatocellular carcinoma. Both reports highlighted

conferring sensitivity towards MET-targeting inhibitors with clinical response either by tumor measurement or metabolic positron-emission tomography (PET) response, further raising the specter of

collectively as &ldquo;actionable&rdquo; genomic alterations and cancer predictive biomarkers. Since the JM domain is a key negative regulatory region for the intracellular kinase domain in the human kinome, its disruption through splicing skipping in MET likely can transition the closed kinase conformation to a more open and thus active conformation, akin to the effects of oncogenic fms-related tyrosine kinase 3

(internal tandem repeat) in acute myeloid leukemia.

variants also stabilize the altered MET receptor through decreased CBL-mediated MET-ubiquitination.

Short interfering RNA silencing of MET and MET inhibition with crizotinib displayed marked effectiveness on cell viability and in downstream Protein kinase B (AKT) and MAPK survival-proliferative signaling inhibition in the gastric cancer cell line that harbors

as driver alteration alone, Hs746T. Moreover,

variants have most recently been reported to occur very frequently in pulmonary sacomatoid carcinoma at 22%.

The study also highlighted a patient within the study who had

and concurrent MET amplification, and was chemotherapy-refractory, but found to demonstrate remarkable response to crizotinib. Nonetheless, it is of note that often con- current genomic mutations could modulate tumor response to precision therapies against a driver-alterations as in the case of H596 adenosquamous cell line which expresses not only the

mutation. H596 cells were found to be insensitive to MET inhibitor crizotinib alone but had synergistic sensitivity to combined MET/PI3K in- hibitors treatment in preclinical models.

The identification of novel MET fusion transcripts of Kinesin Family Member 5B (KIF5B)MET, TRK-Fused Gene (TFG)&ndash;MET, and

50-52 in various cancers recently raises the question of whether chromosomal MET translocations would indeed represent predictive genomic biomarkers that can respond to MET targeting inhibitors/antibodies. This notion is rather attractive although definitive clinical evidence thus far is currently lacking. That said, recent clinical tumor response in genomics-matched targeted therapies against various novel fusion onco-kinases involving RET,

in NSCLC, sarcoma, and other solid tumor types does offer promising notes to speculate perhaps similar clinical response might soon be observed in MET-fusion driven tumors.

Multitudes of MET mutations have been reported in various cancer tissues and also now more systemically compiled in TCGA database over the years [cBioPortal for Cancer Genomics database (http://www.cbioportal.org/index.do)]. While many of the specific mutations involving the kinase domain and the JM domain have been shown to play oncogenic roles and promote tumor cellular motility/migration, invasion, and metastasis, the specific oncogenic role of most of the identified somatic mutations nowadays remains less clear. Furthermore, specific mutations of MET kinase domain may constitute differing oncogenic signaling in a tissue-specific fashion.

Clinically, if MET mutations play a role as a critical signaling network to promote tumor invasion and metastasis, and not primarily in tumor cell proliferation or survival per se, targeting MET therapeutically might not result in remarkable tumor shrinkage response as seen in other classic oncogene-addicted tumor scenarios under genomics-matched precision inhibitor therapy.

MET as requirement in the recruitment of anti- tumoral neutrophils

Recent report on the novel role of MET as expressed on neutrophils within the tumor-associated stromal compartment and its requirement for neutrophil chemoattraction and cytotoxicity in response to HGF is provocative.

MET deletion in mouse neutrophils was found to upregulate tumor growth and metastasis, correlating with reduced tumor-infiltrating neutrophils both to primary and metastatic lesion sites. Most intriguingly, the authors showed that MET targeting inhibitor cancer in vivo treatment had confounding pro-tumoral effects stemming from the MET-blockade in neutrophils thereby counteracting the therapeutic anti-tumoral effects.

More work is needed to further understand if the model translates closely in the clinical setting of MET therapy in cancer patients. It would now be critically important to better comprehend the potential interplay between MET/HGF signaling pathway and the tumor-host immune surveillance network.

Targeting MET in Cancer Therapy - Current Challenges

Over the last several years of clinical MET targeting therapeutics development, it has become clear that the invasive MET/HGF signaling axis likely is not a simple molecular target. The signaling pathway plays multifaceted roles in tumorigenesis and in the process of tumor progression and metastasis. The case for MET alterations to represent an oncogenic addictive event whereby clinically targeting the aberrant MET receptor with specific inhibitors could bring about remarkable tumor shrinkage response has been an attractive goal in clinical therapeutic development. Nonetheless, genuine tumor addiction to MET for proliferation and survival may not be an exceedingly common occurrence in human tumors. Tumor dependence on activated MET pathway to promote EMT, invasion and metastasis, is also a key consideration in clinical MET targeting but might be difficult to measure in inhibitory efficacy. Furthermore, the multitudes of activating venues of MET/HGF signaling in human cancers, including genomic amplification and transcriptional upregulation, protein overexpression, somatic and possibly germline mutations,

JM domain skipping splicing alterations, and chromosomal fusions raise an important question of whether each of these alterations may have differential impact over oncogenic signaling and tumor biology. The biologic and clinical relevance of the genomic target alterations is key to successful clinical molecular targeting.

In recent years, with technological advances in vari- ous genomic and molecular profiling methodologies and platforms, it has become more feasible and routine to uncover various MET/HGF alterations in tumor tissues. Nonetheless, it cannot be over-emphasized in this new era of cancer genomics that understanding the impact of concurrent genomic alterations beyond the MET/HGF aberrancies is essential in refining and defining the role of MET/HGF alterations as predictive biomarkers for targeted therapies. It is important to implement broad and comprehensive molecular-genomic tumor profiling in MET targeting clinical studies and in clinical therapy. For instance, the finding of

skipping alterations with concurrent MET amplification warrants further definitive investigations.

Similarly, the coincident genomic events of genomic amplification of MDM2 and CDK4 with

also require further studies to address their underlying clinical implications.

Interestingly, a recent study also highlighted the occurrence of molecular heterogeneity and receptor co-amplification in driving tumor resistance against targeted therapy in MET-amplified esophagogastric carcinomas.

Window-of-opportunities in MET targeting therapies now include also

, MET-fusions, and MET amplification. More thoughtful clinical outcomes measurement would need to be developed to implement in clinical trial studies of MET/HGF therapeutics to increase the chance of success. To this end, novel emerging genomic biomarkers assays in genomics and proteomics as well as circulating tumor DNA (ctDNA) liquid biopsy platforms to detect and monitor genomic MET alterations undoubtedly would facilitate our abil- ity to better understand the impact of MET inhibition and to further define clinically relevant predictive biomarkers in MET cancer therapy. Lastly, the potential for other interacting and counteracting pathways in MET therapy, especially in tumor-host immune surveillance pathways would deserve in-depth investigations to help arrive at rational and optimal combinational MET targeting cancer therapeutic regimens.

Patrick C. Ma, MD, MSC, is supported by WVU Cancer Institute - Mary Babb Randolph Cancer Center, WVU Medicine, West Virginia University, and also West Virginia Clinical and Translational Science Institute (WVCTSI), by the National Institute Of General Medical Sciences of the National Institutes of Health under Award Number U54GM104942 (IDeA CTR). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Xiaoliang Wu, MD,. is supported by a scholarship to study overseas by the Sun Yat-sen University Cancer Center, China.

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Articles

Clinical Articles

Emerging discoveries of MET chromosomal fusions provide additional promise as therapeutic genomic targets in MET cancer therapy and would need to be tested vigorously.

Current Role of MET Inhibitors in Cancer Therapy

Checkpoint inhibitors have drawn considerable attention in the field of oncology and hold promise to significantly impact the treatment of lymphomas. The two main targets for immune checkpoint inhibitors in lymphoma are Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). CTLA-4 downregulates T-cell activity and leads to a decrease in the antitumor immune response. Hence, blocking CTLA-4 promotes the persistence and activation of intratumoral T cells. PD-1 binds to its ligands PD-L1 and PD-L2, resulting in apoptosis of activated T-cells. Tumor cells are associated with persistently high PD-1 expression leading to T-cell exhaustion and hence, blockade of this pathway is an attractive therapeutic strategy. Various antibodies targeting these pathways are currently being studied in lymphoma. Nivolumab, an anti- PD-1 antibody, has been granted Breakthrough Therapy Designation by the US FDA for the treatment of patients with Hodgkin lymphoma (HL) after failure of autologous stem cell transplant and brentuximab. The clinical development of other checkpoint inhibitors in lymphoma is ongoing. In this article, we summarize the current clinical development of these novel agents in lymphoid malignancies.

Lymphoma is the most common hematologic malignancy in the United States with an estimated 81,000 new cases of Hodgkin (HL) and non-Hodgkin lymphoma (NHL) combined and 21,000 deaths in 2015.

NHL is the sixth most common type of cancer in both males and females, accounting for 5% and 4% of new cancer cases, respectively.

Survival rates for both HL and NHL have improved significantly over the past several decades; however, outcomes continue to be poor in patients with relapsed/refractory disease.

Recently, the introduction of novel targeted agents has ushered in a new era in management of lymphomas, especially in the relapsed/refractory setting and in frail, elderly patients with multiple comorbid conditions who are unable to tolerate cytotoxic combination chemotherapy and presents an interesting field for further research.

The immune system plays a key role in the surveillance, detection, and elimination of cancer cells. The curative role of immune therapy has long been recognized in patients with hematologic malignancies, with a prime example being allogeneic stem-cell transplantation. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance. In addition, they modulate the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage.

Checkpoint inhibitors act by &ldquo;releasing-the-brakes&rdquo; on the patient&rsquo;s immune system rather than targeting the tumor directly, and have demonstrated clinically meaningful results in various solid malignancies (ie, melanoma, renal cell carcinoma, lung cancer). This therapeutic strategy emerged from the recognition that tumors can evade the host immune system by usurping immune checkpoint pathways such as the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed-death 1 (PD-1) pathways. In this review, we discuss the mechanism of action and clinical development of various checkpoint inhibitors in lymphoma.

Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA-4)

CTLA-4, the first immune checkpoint receptor to be clinically targeted, is expressed exclusively on T cells and primarily regulates the amplitude of the early stages of T cell activation.

CTLA-4 downregulates T cell activity and leads to a decrease in the antitumor immune response.

The significance of CTLA-4 in maintaining normal immunologi- cal homeostasis was confirmed by the findings that CLTA-4 deficient mice die from fatal lymphoproliferative disorders.

Blocking CTLA-4 therefore promotes the persistence and activation of intratumoral T cells.

Primarily, CTLA-4 counteracts the activity of the T-cell co-stimulatory receptor CD28. CD28 and CTLA-4 share identical ligands: CD80 (also known as B7-1) and CD86 (also known as B7-2). CD28 does not affect T-cell activation unless the T cell receptor (TCR) is first engaged by a cognate antigen. Once antigen recognition occurs, CD28 signaling strongly amplifies TCR signaling to activate T cells.

Since CTLA-4 has a much higher overall affinity for both ligands, its expression on the surface of T cells dampens the activation of T cells by outcompeting CD28 in binding CD80 and CD86, as well as actively delivering inhibitory signals to the T cells.

CTLA-4 also confers &ldquo;signaling-independent&rdquo; T- cell inhibition through the sequestration of CD80 and CD86 from CD28 engagement, as well as active removal of CD80 and CD86 from the antigen-presenting cell (APC) surface.

Programmed-death (PD-1, CD 279) is a member of the B7 receptor family, expressed by activated T cells, activated B cells, natural killer cells (NK), and myeloid cells. PD-1 expression is induced when T cells become activated.3 It plays a major role in regulation of immune responses by interacting with 2 ligands, programmed death ligand 1 (PD-L1) (B7-H1 or CD274) and programmed death ligand 2 (PD-L2) (B7-DC or CD273).

PD-L1 is expressed by B and T cells and macrophages, mediating a generalized anti-inflammatory effect; whereas PD-L2 is expressed by APC10 and regulates T-cell priming.

These ligands are upregulated by the inflammatory environment and inhibit function of PD-1-bearing lymphocytes. When engaged by one of its ligands, PD-1 inhibits kinases that are involved in T-cell activation through the phosphatase SHP2. In a healthy host, PD-1/PD-L1 signaling regulates effector T-cell responses and protects bystander tissues from immune-mediated damage. This pathway is harnessed by many tumors to evade immune surveillance and forms a major resistance mechanism within the tumor microenvironment.

Mice deficient in PD-1 have an immune phenotype distinct from mice deficient in CTLA-4, as CTLA-4 is believed to primarily regulate early T-cell activation and PD-1 is be- lieved to inhibit T-cell effector activity in the effector phase.12 The inhibition of T-cell activity by PD-1 engagement ap- pears stronger than by CTLA-4 engagement, although the phenotype of PD-1 knockout mice is less severe than that of CTLA-4 knockout.

The expression of PD-1 is also observed on other immune subsets including T-regulatory (Treg) cells, B cells, and NK cells; Treg cells heavily infiltrate many tumors and suppress effector immune responses, thus PD-1 blockage may also increase antitumor cytotoxicity through increased NK-cell killing and reduction in Treg cell number and function.

PD-1 binds to its ligands PD-L1 and PD-L2 and the interaction results in downstream inhibitory signals resulting in apoptosis of activated T cells.

Chronic antigen exposure, such as in chronic viral infection or cancer, can lead to persistently high PD-1 expression, which is associated with T-cell exhaustion; blockade of the PD-1/ PD-ligand pathway augmented or restored the function of viral-infection specific and tumor-specific CD4+ and CD8+ T cells in mouse and human studies.

Expression of PD-1 and Its Ligands in Lymphomas

Lymphomas variably express PD-1 and its ligands.

PD-1 expression is common among tumor cells in chronic lymphocytic leukemia (CLL) and angioimmunoblastic T-cell lymphoma (AITL) but rare in other NHL subtypes.

PD-1+ T cells are frequently demonstrated in rosettes surrounding Reed-Sternberg (RS) cells in both classical Hodgkin lymphoma (cHL) and nodular lymphocyte subtypes.

PD- L1 expression is common in tumor cells in HL and primary mediastinal B-cell lymphoma (PMBL) where it appears to be associated with amplification in chromosome 9p24.1

A large proportion of cHL tumors have increased surface expression of PD-L1,

strongly suggesting that HL may have a genetic dependence on the PD-1 pathway for survival. HL is characterized by the presence of few RS cells surrounded by an extensive, but ineffective immune infiltrate. Amplification of 9p24.1 is a recurrent genetic abnormality in HL and mediates PD-L1 and PD-L2 expression.

PD-1 ligand expression is also increased through the JAK2/STAT pathway, as the extended 9p24.1 amplification region also includes the JAK2 locus.

In addition, EBV infection, seen commonly in HL also increases PD-1 ligand expression.

PD-L1 is also expressed on diffuse large B-cell lymphoma (DLBCL) cells and tumor-infiltrating non-malignant cells, primarily macrophages.

Andorsky and colleagues studied PD-L1 expression and functional activity in cell lines and lymphoma specimens.

PD-L1 was expressed uniformly in anaplastic large cell lymphoma (ALCL) cell lines, but rarely in B-cell NHL. PDL-1 expression in B-cell lymphoma was observed in activated B-cell (ABC) DLBCL. Anti-PD-L1 blocking antibody boosted proliferation and IFN-&gamma; secretion by allogeneic T cells responding to ALCL and DLBCL cells.

The prognostic implication of PD-1 and its ligand expression on tumor cells in lymphoma is conflicting. In 2 studies, a high proportion of follicular lymphoma (FL) cells expressing PD-1 correlated with a favorable overall survival (OS).

In other reports, the prognostic impact of PD-1 expression was negligible or adverse.

PD-1 is expressed on tumor-infiltrating lymphocytes (TILs) in DLBCL, and the presence of a large number of PD-1+ TILs is associated with favorable OS in patients with DLBCL.

In a prospective cohort of DLBCL patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R+CHOP), elevated soluble PD-L1 was adversely prognostic for OS.

In a recent study describing the clinicopathological impact of PD-L1+ DLBCL, Kiyasu et al defined a new sub-entity termed microenvironmental PD-L1+ (mPD-L11) DLBCL (ie, PD-L1DLBCL in which PD-L1+ nonmalignant cells are abundant in the tumor microenvironment).

The prevalence rates of PD-L1+ and mPD-L1+ DLBCL were 11% and 15.3%, respectively. Both PD-L1+ and mPD-L1+ DLBCL were significantly associated with non-germinal center B-cell (GCB) type and Epstein-Barr virus positivity. Patients with PD-L1+ DLBCL had inferior OS compared with patients with PD-L1 DLBCL. In contrast, there was no significant difference in OS between mPD-L1+ and mPD- L1&ndash;DLBCL.

In summary, level of expression of PD-1 and its ligands may be used to guide early development of checkpoint inhibitors in various lymphoma subtypes; however, it is not ready for primetime as either a predictor of response or prognosis.

Monoclonal Antibodies Targeting the CTLA-4 Axis in Lymphoma

Ipilimumab is a recombinant human IgG1 monoclonal antibody that binds to CTLA-4 and enhances T-cell activation and proliferation. It has significant clinical benefit in solid tumors such as melanoma, and it is approved as frontline therapy in metastatic melanoma.

A phase I study of ipilimumab was performed in patients with relapsed and refractory B-cell NHL.

Eighteen patients [14 follicular lymphoma (FL), 3 DLBCL, 1 mantle cell lymphoma (MCL)] were treated with ipilimumab at 2 dose levels with an 11% (2/18) overall response rate (ORR). One DLBCL patient achieved a complete response (CR) and 1 FL patient achieved a partial response (PR). Despite low rates of response, the responses were durable for both patients lasting 31 months for the DLBCL patient and 19 months for the FL patient. Ipilimumab was well tolerated, with common adverse events being diarrhea, headache, abdominal pain, anorexia, fatigue, neutropenia, and thrombocytopenia. Correlative studies confirmed that T-cell proliferation to recall antigens was increased in a significant proportion of patients, suggesting that the immune response was activated and enhanced.

Ipilimumab was also studied in the post-allogeneic stem cell transplant (alloSCT) setting in hematological malignancies.28 Twenty-nine patients with hematological malignancies that were recurrent or progressive after al-loSCT received a single infusion of ipilimumab; responses were predominantly seen in patients with lymphoma. There were 2 CR in patients with HL and a PR in a patient with MCL. Interestingly, ipilimumab did not induce or exacerbate clinical graft versus host disease or graft rejection in this study. There is currently a phase I trial in- vestigating the combination of ipilimumab and rituximab in patients with relapsed or refractory B-cell lymphoma (NCT01729806).

Monoclonal Antibodies Targeting the PD-1 Axis in Lymphoma

Nivolumab is a fully human IgG4 monoclonal antibody that inhibits PD-1 activity by binding to the PD-1 receptor and blocking its interaction with its ligands PD-L1 and PD-L2. It has shown promising results in the treatment of solid tumors and is currently approved by the FDA for treatment of advanced/metastatic melanoma and metastatic non small-cell lung cancer. A phase I study of nivolumab in patients with relapsed/refractory hematologic malignancies (NCT01592370) including classical HL, B-NHL, T-NHL, and multiple myeloma is currently underway. Results for the 23 patients with HL were published earlier this year.

The HL study consisted of a high risk population with a median of 4 to 5 lines of prior systemic therapy with 78% of patients relapsing post brentuximab vedotin and 78% of patients relapsing post-autologous stem cell transplant (ASCT). Patients received nivolumab 3 mg/kg every 2 weeks until CR, tumor progression, or intolerable toxicity. ORR was 87% (20/23) with 17% CR and 70% PR rate. The remaining 3 patients had stable disease. The rate of progression-free survival (PFS) at 24 weeks was 86%. Many of the responses appeared durable with some patients in continued remission for over a year, though the follow-up time of this study was short. Nivolumab was well tolerated in the study population. Drug-related adverse events of any grade and of grade 3 occurred in 78% and 22% of patients, respectively. No grade 4 or 5 events were reported. The most common adverse events were rash (22%) and decreased platelet count (17%). Drug-related grade 3 events reported in 5 patients consisted of myelodysplastic syndrome, pancreatitis, pneumonitis, stomatitis, increased lipase levels, decreased lymphocyte count, and leucopenia.

Nivolumab was granted FDA &ldquo;Breakthrough Therapy&rdquo; designation for HL. A phase II study of nivolumab in patients with classical HL who have relapsed post-ASCT has recently completed enrollment (NCT02181738). There is considerable interest in introducing nivolumab in the frontline setting in HL; however, to our knowledge, no such clinical trials have been initiated.

Results for the remaining lymphoid malignancies have been reported in an abstract form.

Twenty-nine patients with B-NHL, 2 patients with PMBL, and 23 patients with T-NHL were enrolled. These patients were heavily pretreated with more than two-thirds of patients receiving &ge; 3 prior therapies. The most common drug-related serious adverse event was pneumonitis (7%). The ORR for patients with B-NHL was 28% (7% CR) with an ORR of 36% in patients with DLBCL, and 40% in patients with FL. The ORR was 17% in patients with T-cell NHL (no CR) with an ORR of 40% in the 5 patients with peripheral T-cell lymphoma. These results have led to 2 additional phase II clinical trials investigating the efficacy of nivolumab in relapsed or refractory FL (NCT02038946) and relapsed or refractory DLBCL (NCT02038933), which are ongoing.

Pembrolizumab is a humanized IgG4 anti-PD-1 monoclonal antibody that also blocks binding of PD-1 to its ligands PD-L1 and PD-L2. Since IgG4 cannot engage the Fc receptor and cause antibody-dependent cellular cytotoxicity (ADCC) of PD-1+ cells, enhancement of antitumor immune response is the primary mechanism of action. Pembrolizumab was approved by the FDA for treatment of advanced/metastatic melanoma and nonsmall-cell lung cancer.

The KEYNOTE-013 trial is a phase Ib study investigating the safety and efficacy in patients with relapsed or refrac- tory hematologic malignancies (NCT01953692). Results of the classical HL cohort of this study were presented at the American Society of Hematology (ASH) 2014 conference in an abstract form.

Twenty-nine patients with relapsed/ refractory HL received pembrolizumab 10 mg/kg every 2 weeks. More than half the patients had received at least 5 prior lines of therapy; all had received brentuximab vedotin and two-thirds had undergone ASCT. ORR was 66% (all PRs) in the whole cohort, 75% in patients relapsing post-ASCT, and 44% in patients who did not receive ASCT. Median duration of response was not reached. The most common drug-related adverse events were grade 12 respiratory events (20%) and thyroid disorders (20%). Grade 3 or higher treatment-related adverse events were rare and included axillary pain, hypoxia, joint swelling, and pneumonitis in 1 patient each. There were no grade 4 events or treatment-related deaths. The trial is still in progress with final results including data from the B-NHL arm still pending. A phase II study of pembrolizumab in relapsed/refractory classical HL is currently recruiting (KEYNOTE-087, NCT02453594).

Pembrolizumab is currently under intensive investigation in a variety of settings in lymphoma. Studies are also investigating the efficacy of pem- brolizumab as consolidation therapy post ASCT in DLBCL and HL (NCT02362997), in combination with rituximab in relapsed FL (NCT02446457), and in combination with chemotherapy for advanced lymphoma (NCT02408042).

Pidilizumab is an anti-PD-1 humanized IgG1 monoclonal antibody that blocks PD-1 activity, leading to stimulation of NK-cell activity and extended effector/memory T-cell sur- vival. These changes are associated with the enhancement of antitumor immune responses and the generation of tumor- specific memory cells.

The first in-human study was a phase I trial conducted by Berger et al. Seventeen patients with advanced hematologic malignancies (CLL-3, DLBCL-2, HL-1, FL-1) were treated with a single dose of pidilizumab at 5 dose levels ranging from 0.2 to 6 mg/kg.32 The treatment was well tolerated and no dose-limiting toxicity was observed. Six patients (35%, including 1 FL, 2 CLL and 1 HL) had clinical benefit, with 1 CR in a patient with FL that lasted over a year. Based on this encouraging efficacy signal, pidilizumab has been moved into phase II trials in lymphoid malignancies.

Armand et al conducted an international phase II study of pidilizumab in patients with DLBCL or PMBL after ASCT.33 The rationale for selecting this population was the expression of PD-L1 in a subset of patients, low tumor burden post-ASCT, and remodeling of the immune system in the post-transplant setting. There was a preponderance of NK cells, monocytes, and CD45RO+ memory/effector cells among the circulating lymphocytes post ASCT, which comprise pidilizumab target populations and portend a favorable prognosis. Sixty-six patients were treated with 3 doses of pidilizumab 1.5 mg/kg beginning 1 to 3 months after ASCT. The 16-month PFS was 72%. Of note, the 18-month PFS was 70% among the 24 patients who had a positive positron emission tomography scan after pre-ASCT salvage therapy. These results compared favorably to the 52% PFS in an otherwise similarly high-risk historical control population. Among 35 patients with measurable disease post-ASCT, CR and ORR were 34% and 51%, respectively. The safety profile was favorable with no apparent autoimmune toxicity, treatment-related deaths, or infusion reactions. The main non-hematologic adverse events were fatigue, upper respiratory tract infection, diarrhea, cough, and hyperglycemia. Grade 3-4 neutropenia and thrombocytopenia occurred in 14 (20%) and 6 (8%) patients, respectively. Treatment with pidilizumab was asso- ciated with an increase in PD-L1-bearing activated helper T cells and PD-1 ligand bearing monocytes, suggesting an on-target in vivo effect of pidilizumab.

Westin et al performed a single center phase II study of pidilizumab with rituximab in patients with relapsed follicular lymphoma.

Thirty-two patients with rituximab- sensitive FL relapsing after 1 to 4 previous therapies were treated with 4 doses of pidilizumab 3 mg/kg every 4 weeks, with an option to receive up to an additional 8 doses for a total of 12 infusions. Rituximab was given 375 mg/m2 weekly for 4 doses commencing 17 days after the first dose of pidilizumab. Median follow-up was 15.4 months. In the 29 response-evaluable patients, ORR was 66% with 52% CR and median PFS of 18.8 months. The combination was well tolerated with no grade 3-4 adverse events. The most common grade 1 events were anemia and fatigue, with respiratory infection being the most common grade 2 adverse event. Responders expressed higher levels of PD-L1 on peripheral blood T cells and monocytes at baseline compared to non-responders. The in vivo on-target effect of pidilizumab was demonstrated by increased expression of activation-associated genes by T cells and NK cells in day 14 samples compared to baseline.

A phase II study of pidilizumab in patients with stage III-IV DLBCL following first remission is currently recruiting participants (NCT02530125).

In summary, anti-PD-1 antibodies have shown variable response in lymphomas ranging from an impressive 87% ORR in HL to 17% in T-cell lymphomas (for nivolumab). This underlines the inherent immunologic heterogeneity of lymphomas with the immunogenic tumors such as cHL responding much more briskly than other lymphoma subtypes. The safety profiles of nivolumab, pembrolizumab, and pidilizumab have been favorable. Most patients experienced mild drug-related adverse events with no treatment-related deaths. The frequencies of immune-related adverse events (irAEs) commonly noted with anti-PD-1 therapy were lower compared to previously reported trials in solid tumors [nivolumab29: rash-22%, grade 3/4  none; diarrhea-13%, grade 3/4 &ndash; none; hypothyroidism &ndash; 9%, grade 3/4 &ndash; none; pancreatitis grade 3/4 &ndash; 4%; pembrolizumab 31: grade 1-2 respiratory events &ndash; 20%; grade 1-2 thyroid disorders &ndash; 20%, grade 3/4 irAEs &ndash; none; pidilizumab 33,34: serious irAEs &ndash; none], however, since most lymphoma trials are phase I, data are immature, with most results being available in only abstract form, and the patient numbers are inadequate to comment on this issue conclusively.

In this article, Shipra Gandhi, MD, Pallawi Torka, MD, and Francisco J. Hernandez Ilizaliturri, MD summarize the current clinical development of these novel agents in lymphoid malignancies.

December 2015 | The Journal of Targeted Therapies in Cancer

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