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 Table of Contents  
REVIEW ARTICLE
Year : 2019  |  Volume : 32  |  Issue : 2  |  Page : 405-410

Immune checkpoint blockade in malignant lymphomas


1 Department of Clinical Oncology, Faculty of Medicine, Menoufia University, Shebin-El-Kom, Menoufia Governorate, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Shebin-El-Kom, Menoufia Governorate, Egypt

Date of Submission26-Feb-2018
Date of Acceptance10-Apr-2018
Date of Web Publication25-Jun-2019

Correspondence Address:
Dina El-Habashy
El-Thawra Street, Ashmoun 32511, Menoufia Governorate
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_90_18

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  Abstract 

Objective
The objective of this study was to identify the emerging role of immune checkpoint inhibitors in lymphomas.
Materials and methods
Medline databases (Google Scholar, PubMed, http://www.ekb.eg) and all materials available on the Internet from 2008 till 2015. The initial search presented 10 articles of which seven have met the inclusion criteria. These articles studied the emerging role of immune checkpoint inhibitors in lymphoma. Studies that did not fulfill were excluded. Study quality assessment included whether ethical approval was gained, eligibility criteria specified, appropriate controls, adequate information, and defined assessment measures have been undertaken. Comparisons were made by a structured review with the results tabulated.
Results
Antibodies blocking immune checkpoints (programmed death 1 ligand, programmed death 1, and cytotoxic T-lymphocyte-associated protein 4) have shown promising results in relapsed/refractory lymphoma. Formal approval of these drugs is being awaited, and the results of combination therapy of checkpoint inhibitors with other treatment modalities, including chemotherapy, small-molecule inhibitors, and other immune therapies.
Conclusion
Immune therapy with checkpoint inhibitors shows promising results against relapsed/refractory Hodgkin's lymphoma (HL) and non-HL. The efficacy of checkpoint inhibitors against HL is questionable compared with that against non-HL and other solid tumors. Despite these treatment modalities are effective in relapsed/refractory lymphoma, caution is needed due to serious immune-related adverse effects. Results from currently ongoing studies are awaited and will hopefully provide us with better understanding of treatment efficacy as well as increased information about biomarkers of response that will guide in patient selection.

Keywords: checkpoint inhibitors, cytotoxic T-lymphocyte, Hodgkin's lymphoma, immunotherapy, programmed death 1 ligand


How to cite this article:
Razek EA, El-Hassanin S, El-Desouky A, Fouad A, El-Habashy D. Immune checkpoint blockade in malignant lymphomas. Menoufia Med J 2019;32:405-10

How to cite this URL:
Razek EA, El-Hassanin S, El-Desouky A, Fouad A, El-Habashy D. Immune checkpoint blockade in malignant lymphomas. Menoufia Med J [serial online] 2019 [cited 2019 Jul 16];32:405-10. Available from: http://www.mmj.eg.net/text.asp?2019/32/2/405/260940




  Introduction Top


Cancer occurs because of a dysfunctional immune system. Evasion of host immune responses and tumor-induced immune suppression are important for oncogenesis[1].

Immune checkpoints are inhibitory pathways that suppress antitumoral T-cell responses. Immune checkpoint inhibitors (ICIs) prevent tumor-induced immunosuppression of T cells, and thereby stimulate antitumor immunity[2].

Blocking the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 ligand (PD-L1) pathways has emerged promisingly in melanoma, non-small-cell lung cancer, and renal cell carcinoma, with ongoing clinical trials in many other cancers, including hematologic malignancies.CTLA-4 is an inhibitory receptor presented in the cytoplasm of resting naive T cells. Upon antigen stimulation, it is transferred to the T-cell surface, incorporated into the immunologic synapse, and binds with its ligands, CD80 and CD86, causing the downregulation of T-cell activation[3].

Programmed death 1 (PD-1), another checkpoint molecule, is present on the surface of different immune cells, including activated T cells, B cells, and natural killer (NK) T cells. Upon T-cell activation, PD-1 expression on the cell surface is stimulated as the T-cell infiltrates the peripheral tissues[4].

To prevent excessive immune-mediated toxicity, there is a balancing system by which the PD-1 ligands (PD-L1, PD-L2) on antigen presenting cells binds to the PD-1 receptor on T-cells leading to the suppression of T cells[5].

Recent understanding of different malignancies has led to the introduction of monoclonal antibodies (mAbs) targeted against the receptors of ligands involved in the CTLA-4 and PD-1 pathways, making it possible to reverse the tumor-induced inhibition of T-cell function and to stimulate antitumor immune activity[6].

Lymphomas are a clinically and biologically heterogeneous group of malignancies that arise from mature T lymphocytes or B lymphocytes in secondary lymphoid organs. Hodgkin's lymphoma (HL) accounts for about 10% of all lymphomas and consists mainly of two major disease categories: classical Hodgkin's lymphoma (cHL), which represent the majority of the cases and nodular lymphocyte-predominant HLs. Non-Hodgkin's lymphoma (NHLs) are much more frequent diseases, representing the fifth most common cancer in the USA[7].

In lymphomas, malignant cells are arrested at different stages of differentiation; expand in lymph nodes, bone marrow, and often other tissues and organs. They often arise from genetic changes, such as chromosome translocations that stimulate oncogenesis. These genetic changes lead to the modification of the immune system by re-educating the cells in the microenvironment through cytokine and chemokine signaling as well as aberrant expression of checkpoint proteins such as PD-1 and its ligands[5].

Recent data show that the tumor microenvironment in lymphomas is highly immunosuppressive, with cells within the immune microenvironment expressing PD-L1 and many of the malignant T-cells expressing PD-1, making lymphoma an excellent target for immune checkpoint blockade and other immune therapies[8].

Moreover, the post-autologous hematopoietic stem cell transplantation (AHSCT) setting may be a good opportunity for PD-1 blockade, during which there is a remodeling of the immune system. Indeed, the majority of the circulating leukocytes in the first few months after AHSCT are NK cells, memory/effector cells, and monocytes, which are considered a target for PD-1 blockade and whose presence in lymphomas has been associated with a favorable prognosis[9].

In this study, we aim to declare the newly emerging role of checkpoint inhibitors and other immunotherapies in lymphomas.


  Materials and Methods Top


Search strategy

We reviewed papers on the role of ICIs in HLs and NHLs from Medline databases such as the PubMed, Google Scholar (http://www.ekb.eg). We used checkpoint inhibitors, immunotherapy, Hodgkin's lymphoma, non-Hodgkin's lymphoma as the search terms. The search was performed in the electronic databases from 2008 to 2015.

Study selection

All the studies were independently assessed for inclusion. They were included if they fulfilled the following criteria:

  1. Published in English language
  2. Published in peer-reviewed journals
  3. Focused on responses to ICIs in patients with relapsed or refractory (R/R) lymphoma
  4. Discussed the relation between tumor microenvironment in lymphoma and ICIs
  5. If a study had several publications on certain aspects we used the latest publication giving the most relevant data.


Data extraction

If the studies did not fulfill the above criteria, they were excluded such as studies not published in English language, report without peer review and studies discussing the role of checkpoint inhibitors in solid malignancies. The analyzed publications were evaluated according to evidence-based medicine criteria.

  1. Level I: Evidence obtained from at least one properly designed randomized-controlled trial
  2. Level II-1: Evidence obtained from well-designed controlled trials without randomization
  3. Level II-2: Evidence obtained from well-designed cohort or case–control analytic studies, preferably from more than one center or research group
  4. Level II-3: Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled trials might also be regarded as this type of evidence
  5. Level III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.


Quality assessment

The quality of all the studies was assessed. Important factors included the study design, attainment of ethical approval, evidence of power calculation, specified eligibility criteria, appropriate controls, adequate information, and specified assessment measures. It was expected that the confounding factors would be reported and controlled for and appropriate data analysis made in addition to an explanation of missing data.

Data synthesis

A structured, systematic review was performed with the results tabulated.


  Results Top


In total, 10 potentially relevant publications were identified; three articles were excluded as they did not meet our inclusion criteria. A total of seven studies were included in the review as they were considered eligible by fulfilling the inclusion criteria. Of these seven articles included in this review, two (28.5%) articles were about HLs, three (42.8%) about NHLs, and two (28.5%) about both HLs and NHLs. The majority of the studies detected the role of ICIs on malignant lymphomas. The studies were analyzed with respect to the study design using the classification of the US Preventive Services Task Force and UK National Health Service protocol for evidence-based medicine. The results are tabulated in [Table 1].
Table 1: Summary of clinical trials

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  1. Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies:


  2. It is a phase I study that included 17 patients with various hematologic malignancies, eight of whom had lymphoid malignancies (one with HL, four with NHL, and three with chronic lymphocytic leukemia). These patients were treated with a single dose of pidilizumab at five different dose levels (0.2, 0.6, 1.5, 3, and 6 mg/kg) after premedication with an antihistamine, pain relief medication, and corticosteroids; no dose-limiting toxicity was observed. Overall, six patients responded to treatment, including a complete response (CR) in a patient with follicular lymphoma (FL) and stable disease (SD) in two patients with chronic lymphocytic leukemia and one patient with HL[10].

  3. Disabling immune tolerance by PD-1 blockade with pidilizumab after AHSCT for diffuse large B-cell lymphomas (DLBCL):


  4. This international phase II study included patients with DLBCL, primary mediastinal B-cell lymphomas, or transformed indolent B-cell lymphomas after AHSCT. They were treated with intravenous pidilizumab at a dosage of 1.5 mg/kg every 42 days for three cycles, starting 30–90 days after AHSCT. Seventy-two patients received at least one dose of the drug, 66 of whom were evaluable. The most frequently reported grades 3–4 adverse events (AEs) were neutropenia (19%) and thrombocytopenia (8%). There was no evidence of significant autoimmune toxicity, infusion reactions, or treatment-related mortality. The 16-month progression-free survival (PFS) and overall survival of the 66 evaluable patients were 0.72 [90% confidence interval (CI): 0.60–0.82] and 0.85 (90% CI: 0.74–0.92), respectively[11].

  5. Safety and activity of PD-1 blockade by pidilizumab in combination with rituximab in patients with relapsed FL:


  6. Another phase II study evaluated pidilizumab in combination with rituximab in patients with relapsed, rituximab-sensitive FLs. Patients received pidilizumab 3 mg/kg every 4 weeks for four cycles; those with SD or better were given the option to receive up to a total of 12 cycles. Rituximab was given at 375 mg/m2 intravenously weekly for 4 weeks, starting 17 days after the first pidilizumab infusion. Thirty-two patients were enrolled, 29 of whom were evaluable for activity. The treatment was well tolerated, with no autoimmune or treatment-related AEs of grade 3 or 4. The most common grade 1 AEs were anemia (44%) and fatigue (41%); the most common grade 2 AE was respiratory infection (16%). CR was achieved in 15 (52%) patients and partial responses (PRs) in four (14%), leading to an objective response in 19 (66%). Median PFS for all patients was 18.8 months (95% CI: 14.7–not reached). No deaths occurred during the trial[12].

  7. Nivolumab in patients with R/R cHL: clinical outcomes from extended follow-up of a phase I study (CA209-039):


  8. In this study, a group of 23 patients with R/R cHL received nivolumab at a loading dosage of 1 mg/kg, escalated to 3 mg/kg; the results showed that nivolumab was well tolerated and yielded an overall response rate (ORR) of 87%. Drug-related AEs were reported in 18 (78%) patients, the most common of which were rash (22%) and thrombocytopenia (17%). Drug-related grade 3 AEs were reported in five (22%) patients; and included myelodysplastic syndrome, pancreatitis, pneumonitis, stomatitis, colitis, gastrointestinal inflammation, thrombocytopenia, increased lipase levels, decreased lymphocyte levels, and leukopenia. There were no drug-related grade 4/5 AEs. Three patients had one serious drug-related AEs: one grade 3 pancreatitis, one grade 3 myelodysplastic syndrome, and one grade 2 lymph node pain.

    A follow-up report recently was presented, with the median follow-up period extended to 101 weeks. The ORR remained at 87% (CR: 5, PR: 15, SD: 3 patients), with one patient previously with a PR improving to a CR. Among the responders, the time to CR after starting nivolumab ranged from 3 to 88 weeks. Overall survival was 91% at 1 year and 83% at 1.5 years. Among the 20 responding patients at the time of data cutoff, three were still receiving nivolumab treatment, with ongoing responses. Some of these patients exceeded the 2-year treatment mark; one patient who discontinued treatment after initial response and subsequently experienced disease progression was retreated with nivolumab and achieved a second response. This report declared not only a high response in cHL but also the safety, tolerability, and durable response with long-term treatment[13].

  9. Nivolumab in patients with R/R lymphoid malignancies and cHL: updated results of the CA209-039 study:


  10. Patients with R/R NHL were treated at the same dose escalation of 1–3 mg/kg of nivolumab every 2 weeks for up to 2 years. Among the 31 patients with B-NHL enrolled in the study, an ORR of 26% (CR: 10%, PR: 16%) was observed, with 52% of the patients achieving SD. Patients with more common disease subtypes were more likely to respond, with an ORR in DLBCL of 36% (CR: 18%, PR: 18%) and in FL of 40% (CR: 10%, PR: 30%). The median duration of response was 22 weeks in patients with DLBCL and was not reached in patients with FL. Responses were also seen in 23 patients with T-cell NHL, with superior response seen in patients with peripheral T-cell lymphoma (PTCL). The ORR for patients with T-NHL was 17% (all PRs). The ORR in patients with PTCL was 40% and was 15% in those with cutaneous T-cell lymphoma (CTCL). Sixty-nine percent of the patients with CTCL had SD; therefore, the median duration of response was not reached for both PTCL and CTCL[14].

  11. PD-1 blockade with the mAb pembrolizumab (MK-3475) in patients with cHL after brentuximab vedotin failure: preliminary results from a phase Ib study (KEYNOTE-013):


  12. Thirty-one patients received pembrolizumab 10 mg/kg intravenously every 2 weeks until tumor progression, excessive toxicity, or ending 2 years of therapy. Altogether, 68% of the patients presented with AEs of any grade; however, none had a grade 4 or fatal AE. AEs leading to treatment discontinuation were pneumonitis and nephritic syndrome. The ORR was 65% (CR: 16%; PR: 48%); 23% of patients achieved SD, with 90% exhibiting a reduction in target lesions. Seventy-one percent of the patients had a sustained response of more than 24 weeks. With a median follow-up of nearly 18 months for survivors, the PFS at 24 weeks was 69%[15].

  13. Phase I study of ipilimumab, an anti-CTLA-4 mAb, in patients with relapsed and refractory B-cell NHLs:


  14. In this phase I study, ipilimumab was administered in a single dose of 0.1–3.0 mg/kg to 29 patients, with relapsed hematologic malignancies after allogeneic stem cell transplantation. No dose-limiting toxicity was observed, and ipilimumab did not induce graft-versus-host disease or graft rejection. Three patients with lymphoid malignancy developed objective disease responses, including two patients with HL in CR and one patient with mantle cell lymphoma achieving a PR. An ongoing follow-up phase I/Ib is administering ipilimumab at 3 or 10 mg/kg intravenously every 3 weeks for four induction cycles, followed by maintenance dosing every 12 weeks up to 1 year. Preliminary results reported 13 patients treated, including three with NHL and four with cHL, with 36.4% of patients achieving a clinical benefit (one HL with PR, one HL, and one CTCL with SD)[16].



  Discussion Top


mAb therapy is now an emerging therapy for targeting immune checkpoints effectively. Hematologic malignancies, specially, are attractive targets for this type of treatment. This increases the possibility that patients' own immune systems can be used to eradicate those diseases, if the mechanisms that lead to immune tolerance of the tumor can be safely disabled[17].

HL is a B-cell lymphoma, and R/R HL has poor survival. In HL, the PD-1/PD-L1 pathway is amplified through three mechanisms. First, 9p24.1 amplification is a recurrent genetic abnormality and this region encodes for the PD-L1 and PD-L2, which subsequently becomes amplified. Second, 9p amplification that encodes the JAK/STAT pathway resulting in the overexpression of PD-L1. Third, HL has a high expression of EBV-related proteins which increases PD-1 expression[10].

On the other side, PD-L1 protein is expressed in different subtypes of NHL including primary mediastinal large B-cell lymphoma, T-cell/histiocyte-rich B-cell lymphoma, Epstein–Barr virus (EBV)-positive and EBV-negative post-transplant lymphoproliferative disorder, EBV-associated DLBCL, plasmablastic lymphoma, extranodal NK/T-cell lymphoma, nasopharyngeal carcinoma, and human herpes virus-8-associated primary effusion lymphoma[17].

Pidilizumab was the first PD-1 blocking antibody to be tested in patients with lymphoid malignancies. Data from phase I and II studies of pidilizumab in patients with DLBCL, and in combination with rituximab in patients with R/R FL, showed promising results[12].

Pidilizumab can also be given to patients with DLBCL after AHSCT. Treatment was associated with a significant CR rate of 34% and ORR of 51% among patients with measurable disease after transplant[11].

Nivolumab, a fully human IgG4 anti-PD-1mAb, has been studied in patients with lymphomas. Nivolumab was also tested in 29 patients with R/R NHLs at 3 mg/kg, every 2 weeks. The ORR was 36%, but differed according to the subtype: DLBCL, FL, and PTCL having an ORR of 36, 40, and 40%, respectively[18]. Similarly, nivolumab was studied in patients with R/R HL who have failed AHSCT and brentuximab vedotin at a dose of 3 mg/kg every 2 weeks. The ORR was 87%, 17% with a CR, 70% with a PR, and 13% had SD and the PFS at 6 months was 86%[13].

Pembrolizumab, is a humanized IgG4 antagonistic anti-PD-1 (mAb). Pembrolizumab was studied in the KEYNOTE-013 trial in R/R HL in patients who have failed AHSCT and brentuximab vedotin. The ORR was 65% with 16% achieving CR and the median duration of response was not yet reached[19].

Ipilimumab is a fully humanized IgG1 mAb targeting the CTLA-4 pathway. In a phase I study, ipilimumab was administered in a single dose of 0.1–3.0 mg/kg to 29 patients with relapsed lymphoma after allogeneic stem cell transplantation. Preliminary results reported 36.4% of patients achieving a clinical benefit[20].

Another phase I study was conducted to evaluate safety, immunologic activity, and potential clinical efficacy in patients with R/R lymphomas through the administration of ipilimumab at a dose of 3 mg/kg and then monthly at 1 mg/kg for 3 months, with subsequent escalation to 3 mg/kg monthly for 4 months. Among the 18 patients treated, two patients showed a clinical response, one patient with DLBCL had an ongoing CR for more than 31 months, and one patient with FL had a PR lasting 19 months[16].

Atezolizumab, a humanized engineered IgG1 mAb against PD-L1, is being developed for use in lymphomas. A global phase I/II study testing atezolizumab in combination with obinutuzumab in patients with R/R NHL (NCT02220842) is currently recruiting patients[21].


  Conclusion Top


Immune-therapy with checkpoint inhibitors shows a promising result against malignant lymphomas, although the efficacy of checkpoint inhibitors against HL is questionable compared with that against NHLs and other solid tumors. Although these treatment modalities are effective in R/R HL and NHL, caution is needed due to serious immune-related AEs. Results from the currently ongoing studies are awaited and will hopefully provide us with better understanding of treatment efficacy as well as increased information on biomarkers of response that will help in patient selection.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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12.
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13.
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14.
Ansell S, Armand P, Timmerman JM, Shipp MA, Bradley Garelik MB, Zhu L, et al. 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). Blood 2015; 126:583.  Back to cited text no. 14
    
15.
Timmerman J, Armand P, Lesokhin AM, Halwani A, Millenson MM, Schuster SJ, et al. Nivolumab in patients with relapsed or refractory lymphoid malignancies and classical Hodgkin lymphoma: updated results of a phase 1 study (CA209-039). Hematol Oncol 2015; 33:100–180.  Back to cited text no. 15
    
16.
Moskowitz CH, Ribrag V, Michot JM, Martinelli G, Zinzani PL, Gutierrez M, et al. PD-1 blockade with the monoclonal antibody pembrolizumab (MK-3475) in patients with classical Hodgkin lymphoma after brentuximab vedotin failure: preliminary results froma phase 1b study (KEYNOTE-013). Blood 2014; 124:290.  Back to cited text no. 16
    
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