In 2018, it is estimated that 8500 new cases of classic Hodgkin lymphoma (cHL) will be diagnosed in the United States.1 While this represents only 10% of all lymphoma diagnoses annually because of the bimodal distribution of cHL cases, most of patients are younger adults in their late teenage years or early 20s. With the advent of combination chemotherapy,2,3 systemic therapy often in combination with radiotherapy is able to cure approximately 80% of these patients.4 Upon relapse, the goal of treatment remains cure, and eligible patients are commonly managed with high-dose chemotherapy and autologous stem cell transplant. Some patients, however, become chemotherapy refractory and have relapse requiring additional treatment. It has therefore become vitally important to identify additional therapeutic targets rather than simply administering further chemotherapy. New treatment strategies that mobilize the patient's immune system have proven highly effective, and targeting pathways that restrict immune function has proven to be a proven new approach to treating patients with cHL.
Classic HL appears particularly susceptible to immunological therapy in that the tumor has a unique composition. Only 1% to 2% of the cell infiltrate in cHL biopsies is due to malignant cells, the so-called Hodgkin-Reed-Sternberg (HRS) cells, with the vast majority of infiltrating cells due to a mixture of normal immune and stromal cells including T lymphocytes, natural killer cells, monocytes, macrophages, and dendritic cells.5 Despite this extensive immune response within the tumor microenvironment, the HRS cells are able to effectively evade the immune system. In fact, HRS cells appear to promote and use this immune infiltrate to their advantage, resulting in increased HRS cell survival and proliferation. Recognizing this has led investigators to explore the mechanisms that lead to the immune evasion and then modulate these mechanisms to allow the immune system to effectively target the tumor cells.
IMMUNE CHECKPOINT SIGNALING
Cytotoxic T cells are typically responsible for malignant cell killing, and T-cell activation is a carefully regulated process. It requires recognition of a foreign antigen by the T-cell receptor in the context of the major histocompatibility complex (MHC) and then requires a costimulatory signal. This costimulatory signal typically involves engagement between CD28 on the T-cell surface and B7 molecules, including B7-1 (CD80) or B7-2 (CD86), on antigen-presenting cells (APCs) or tumor cells resulting in activation, differentiation, and expansion of the effector T cells.6 The absence of an appropriate costimulatory signal results in T-cell anergy.
To prevent indiscriminant cytotoxicity, T-cell homeostasis is tightly regulated. Once the antigenic stimulation has been eliminated, the positive stimulatory signals are rapidly inhibited by immune checkpoint signaling to avoid damage from activated, unregulated T cells.7 T-cell activation leads to expression of inhibitory molecules, such as cytotoxic T-lymphocyte antigen 4 (CTLA4) and programmed death 1 (PD-1), on the surface effector T cells. These negative inhibitory signals suppress effector T-cell function, but signaling through these pathways is often the reason for an ineffective immune response in lymphoma.
Cytotoxic T-lymphocyte antigen 4 (CD152) is exclusively expressed on T cells, and signaling through this receptor provides an inhibitory signal in the early stages of T-cell activation. Cytotoxic T-lymphocyte antigen 4 has high affinity for B7 molecules and binds to CD80 and CD86 more avidly than CD28, thereby preventing CD28 binding to B7, thereby limiting T-cell activation and inducing T-cell cycle arrest.6,8 Mice deficient in CLTA4 have significant T-cell activation and succumb to a devastating polyclonal lymphoproliferative process with skewed expansion of CD4+ T cells.9 The hypothesis is therefore that CTLA4 blockade will lead to persistently activated effector T cells within the tumor microenvironment with enhanced antitumor immune responses. Also, preclinical studies have found that CTLA4 down-regulates CD4+ helper T cells and induces regulatory T cells, resulting in immunosuppression.10,11 These findings make blockade of CTLA4 signaling an appealing target to promote the function of activated effector T cells.
Similarly, PD-1 (CD279) signaling regulates effector T-cell function peripherally within tissue. Programmed death 1 is expressed on APCs and on activated T cells and binds to 2 ligands: PD-L1 (CD274) and PD-L2 (CD273). While PD-L2 expression is ubiquitous, PD-L1 expression is limited to immune cells, particularly APCs, natural killer cells, and activated T cells.12 Programmed death 1 ligand and PD-2 ligand binding to PD-1 leads to inhibition of downstream kinase signaling via the PI3K pathway and suppression of T-cell function. While these effects are similar to those seen with CTLA4 signaling, knockout mice deficient in PD-1 have a less disabling phenotype than mice deficient in CTLA4, consistent with the milder adverse effects observed in clinical trials with PD-1 versus CTLA4 blockade.13 The PD-1 ligands, PD-L1 and PD-L2, are commonly overexpressed in cHL and account in part for the ineffective antitumor immune response seen in this disease. Genetic alterations of chromosome 9p24.1 in cHL have been recognized as a frequent chromosomal abnormality leading to PD-L1/2 overexpression in HRS cells.14 Furthermore, in cHLs with diploid 9p24.1, Epstein-Barr virus infection, which is commonly present in cHL, leads to up-regulation of JAK/STAT signaling and overexpression of PD-L1 and PD-L2, allowing the tumor cells to escape immune surveillance.15
THE TUMOR MICROENVIRONMENT IN HODGKIN LYMPHOMA
As mentioned previously, the tumor microenvironment in cHL is composed of a small number of malignant HRS cells within an extensive immune-cell infiltrate.16 The exact composition of the tumor microenvironment differs by HL subtype17 and is determined by cytokines secreted by the HRS cells. The HRS cells have the ability to not only modulate the immune infiltrate but are relatively invisible to the immune system due to loss of MHC expression and have also co-opted the immune checkpoint pathways by overexpressing PD-1 ligands on the cell surface.
Several mechanisms result in increased expression of PD-L1 and PD-L2. Amplification or copy number gain of chromosome 9p24.1, where the loci for the PD-ligands and JAK2 are located, has been described in nodular sclerosis HL. Programmed death 1 ligand and PD-L2 genetic alterations are a defining feature of cHL and are associated with an increase in PD-L1 and PD-L2 expression by immunohistochemistry.18 Analysis of biopsy samples from patients with both newly diagnosed and refractory or relapsed cHL showed copy gain or amplification of PD-1 ligand genes in almost all tested samples, ranging from low-level polysomy to uniform amplification.19,20 However, higher copy numbers were found in patients with advanced-stage disease as opposed to early-stage disease,19 and the genetic alterations at this locus may activate the JAK/STAT pathway, resulting in further increases in PD-L1/2 expression.18 Of significant importance, 9p24.1 amplifications have associated with a poorer progression-free survival (PFS) in patients with newly diagnosed cHL.19
Aside from inhibition of effector T-cell function by increased PD-1 signaling, an additional mechanism that HRS cells exploit to evade the host's immune mechanisms is loss of expression of MHC-I molecules on the tumor cells because of inactivating mutations in β2-microglobulin. Major histocompatibility complex I expression on the surface of nucleated cells is responsible for antigen presentation to cytotoxic CD8+ T cells and requires β2-microglobulin expression. The loss of MHC-I expression on HRS cells results in impaired recognition of these cells by cytotoxic T cells, thereby limiting the antitumor immune response. The β2-microglobulin gene is commonly mutated in cHL,21 and lack of MHC expression on HRS cells is an independent negative prognostic factor in cHL.22,23
In addition, an immunosuppressive tumor microenvironment appears to play an important role in the survival and growth of HRS cells because of the presence of exhausted T cells24 and increased numbers of regulatory T cells and tumor-associated macrophages.24,25 Indeed, T cells in the tumor microenvironment and periphery of patients with cHL express high levels of PD-1, suggesting an anergic and exhausted T-cell phenotype,26 and increased PD-1 expression has been associated with a poor prognosis.27 Characterization of the tumor microenvironment has suggested that it is mainly composed of activated and tumor-specific TH1 rather than senescent TH2 cells.28 Recent data using mass cytometry have defined a more terminally differentiated CD4+ predominant and TH1-polarized immunosuppressive microenvironment in cHL and identified CD4+ exhausted T-effector cells as a potential target of therapeutic intervention.24 Furthermore, a unique topology has been described in cHL in which PD-L1+ tumor-associated macrophages surround HRS cells and would be expected to inhibit activation of PD-1–expressing cells.25 Thus, the expression of PD-L1/2 on HRS cells and PD-1 on intratumoral immune cells suggests the presence of an inhibited or exhausted T-cell population in the tumor microenvironment and provides the rationale for targeting the PD-1 pathway in order to reactivate T cells and promote antitumor immunity.
PD-1 BLOCKADE IN HODGKIN LYMPHOMA
The unique tumor microenvironment in cHL, as well as the central role of immune checkpoints in the host response to the malignancy, provides a therapeutic opportunity for the use of immune checkpoint blockade in this disease. Agents that block the PD-1:PD-L1/L2 axis have now been tested in early-phase clinical trials in HL. Most are monoclonal antibodies that disrupt the PD-1 pathway by blocking signaling via the PD-1 receptor. More recently, monoclonal antibodies that bind to PD-L1 have been tested. Overall, antibodies that inhibit the PD-1 pathway have been found to be safe when administered to patients with relapsed and refractory cHL. Now with longer follow-up, the efficacy signal with antibodies targeting PD-1 or PD-L1 seems consistent and durable, establishing immune checkpoint inhibition as a clear therapeutic target in HL.
Nivolumab is a fully human IgG4 monoclonal antibody targeting PD-1 and was tested in a multicenter phase I trial in patients with relapsed and refractory cHL.20 In this study, 23 heavily pretreated patients with cHL received nivolumab 3 mg/kg every 2 weeks until progression or completion of 2 years of therapy. Most of the patients (65%) had received 4 or more lines of prior therapy, had undergone an autologous stem cell transplant (78%), or received treatment with brentuximab vedotin (BV) (78%). Treatment with nivolumab was well tolerated, and no drug-related grade 4 or 5 events were reported. Five patients (22%) experienced drug-related grade 3 events including pancreatitis, pneumonitis, colitis, thrombocytopenia, and leukopenia. An objective response rate of 87% was seen with complete responses (CRs) in 4 patients and partial responses (PRs) in 16 patients. Three additional patients had stable disease, and no progressions were observed for the reported duration of the trial. At the time of the initial publication, responses were durable with a PFS at 24 weeks of 86% and the median overall survival (OS) not yet reached.
A subsequent phase II trial (CheckMate 205) was performed to confirm these results.29,30 This multicenter, single-arm, phase II study enrolled patients with relapsed or refractory cHL who had failed an autologous stem cell transplant into 1 of 3 cohorts: patients who were BV-naive (cohort A, n = 63), patients who received BV after an autologous transplant (cohort B, n = 80), or patients who received BV before and/or after an autologous transplant (cohort C, n = 100). Initially, the results of cohort B were reported.29 Among the 80 treated patients in this cohort, at a median follow-up of 8·9 months, 53 (66·3%) had an objective response to nivolumab. Subsequently, with more extended follow-up, the safety and efficacy of all 3 cohorts were reported.30 After a median follow-up of 18 months, the overall objective response rate for all patients was 69%, with 16% of the patients achieving a CR and 53% achieving a PR. The overall response rates in cohorts A, B, and C were 65%, 68%, and 73%, with a CR in 29%, 13%, and 12% of patients, respectively. The median duration of response was 16.6 months for all patients. The median PFS was 14.7 months overall and 18.3, 14.7, and 11.9 months in cohorts A, B, and C, respectively. The median PFS was similar for patients who received BV after (11.9 months) or only before (11.5 months) their autologous transplant. The median OS was not reached in any cohort, and the 1-year OS rate was 92% overall, 93% in cohort A, 95% in cohort B, and 90% in cohort C. The conclusion of the trial was that responses to nivolumab were frequent and durable. Based on these results, nivolumab was approved for patients with relapsed and refractory cHL.
Similarly, pembrolizumab, a humanized IgG4 monoclonal antibody targeting PD-1, has also been evaluated in a phase I trial of patients with hematologic malignancies (KEYNOTE-013).31 Patients in the cohort with classic HL showed high response rates similar to those seen with nivolumab. Thirty-one patients were enrolled, 55% of whom had more than 4 lines of prior therapy, and 71% had relapsed after a prior autologous stem cell transplant. The overall response rate was 65%, with a CR rate of 16%. With a median follow-up of 17 months, most of the responses (70%) were durable, lasting longer than 24 weeks. The PFS rate was 69% at 6 months and 46% at 1 year. Biomarker analyses demonstrated a high expression of PD-L1 and PD-L2 in all specimens tested, treatment-induced expansion of T cells and natural killer cells, and up-regulation of immune-related signaling pathways. These biomarkers, however, did not clearly correlate with responses to pembrolizumab.
The high response rate seen with pembrolizumab therapy in the phase I study was then confirmed in a phase II trial (KEYNOTE-087).32 Pembrolizumab was again tested in 3 cohorts of patients with relapsed and refractory cHL. Patients had progressed either after an autologous stem cell transplant and subsequent BV or salvage chemotherapy and BV in patients ineligible for stem cell transplantation due to chemoresistant disease, or after a stem cell transplant but without having received BV. All patients received pembrolizumab 200 mg once every 3 weeks, and response was assessed every 12 weeks. A total of 210 patients were enrolled (69 in cohort 1, 81 in cohort 2, and 60 in cohort 3). The overall response rate for all patients was 69%, and the CR rate was 22%, with 31 patients having a response that lasted more than 6 months. The overall response rate was 74% for cohort 1, 64% for cohort 2, and 70% for cohort 3. Overall, pembrolizumab was associated with high response rates and an acceptable safety profile in patients with relapsed and refractory cHL. These results led to the approval of pembrolizumab for this disease and confirmed that PD-1 blockade offered a new treatment paradigm for cHL.
Many patients with relapsed cHL undergo an allogeneic transplant as management for their disease. The use of anti–PD-1 antibodies in these patients raises the concern for exacerbation of graft-versus-host disease (GVHD) when cytotoxic T cells are activated by these agents. Studies have evaluated PD-1 both before and after allogeneic transplantation. In an international series of 39 patients, the 1-year cumulative incidences of grades 2 to 4 and grades 3 to 4 acute GVHD were 44% and 23%, respectively, and the 1-year incidence of chronic GVHD was 41%.33 There were 4 treatment-related deaths including 1 from hepatic sinusoidal obstruction syndrome and 3 from early acute GVHD. It was concluded that allogeneic transplant after PD-1 blockade is feasible with a low rate of relapse, but there may be an increased risk of early immune toxicity. Similarly, in patients with relapsed cHL receiving PD-1 blockade for progressive disease after allogeneic transplant, PD-1 blockade appeared to be highly efficacious but was frequently complicated severe and treatment-refractory GVHD. In a series of 31 cHL patients, the overall response rate to PD-1 blockade was 77%; however, there were 8 deaths related to GVHD after anti–PD-1 therapy.34 Seventeen patients (55%) developed treatment-emergent GVHD after initiation of anti–PD-1 therapy (6 acute, 4 overlap, and 7 chronic GVHD).
OTHER IMMUNE CHECKPOINT INHIBITORS IN HODGKIN LYMPHOMA
Blockade of the PD-1 receptor ligands (PD-L1 or PD-L2) may be an additional therapeutic opportunity but could possibly yield different results in cHL when compared with direct inhibition of the PD-1 receptor, as signaling induced by the alternate ligand will not be inhibited. Both PD-L1 and PD-L2 are overexpressed on HRS cells, and there is therefore concern that blockade of only 1 ligand may not sufficiently protect exhausted PD-1+ cells from being inhibited. Avelumab is a fully human IgG1 monoclonal antibody that selectively binds to PD-L1, leaving the PD-1/PD-L2 interaction intact, thereby enabling assessment of the contribution of PD-L2 signaling. In the phase I JAVELIN Hodgkin study, 31 patients with cHL were required to have disease progression following either autologous or allogeneic stem cell transplant or to be ineligible for a stem cell transplant.35 Patients were then randomized to various avelumab dosing regimens. The overall response rate for all 31 patients was 55% with 2 CRs and 15 PRs. Responses were observed in all dosing groups. The overall response rate in the 5 autologous transplant patients was 20% with 1 PR, whereas the overall response rate in the 8 allogeneic transplant patients was 75% with 1 CR and 5 PRs. Two patients who had received a prior allogeneic transplant developed grade 3 liver GVHD that resolved with immunosuppressive therapy and discontinuation of avelumab. The overall response rate in this study appeared similar to the results observed with anti–PD-1 antibodies, indicating that targeting PD-L2 may not be necessary for the clinical effect seen with PD-1 blockade in cHL. Clinical trials using other antibodies targeting PD-L1 (including durvalumab and atezolizumab) are in progress.
As mentioned previously, CTLA4 is expressed on T cells and when engaged provides an inhibitory signal that suppresses T-cell activation. Ipilimumab is a fully human IgG1 monoclonal antibody targeting CTLA-4, and this antibody has been tested in a small phase I trial of patients with advanced hematologic malignancies who had progressed after an allogeneic stem cell transplant.36 Twenty-nine patients, 14 of whom had cHL, were treated with ipilimumab in escalating doses (0.1–3.0 mg/kg). Ipilimumab was reasonably well tolerated, and no severe GVHD or exacerbation of previous low-grade GVHD was observed. Three patients achieved an objective response including 2 CRs in patients with cHL. Two additional patients with cHL achieved stable disease for 3 and 6 months while receiving therapy with ipilimumab.
COMBINATION APPROACHES IN HODGKIN LYMPHOMA THAT INCORPORATE IMMUNE CHECKPOINT BLOCKADE
Immune checkpoint inhibitors have been used together or with antibody drug conjugates or chemotherapy in patients with cHL. Similar to strategies that have been tested in other malignancies, nivolumab has been combined with ipilimumab in patients with hematologic malignancies (n = 65), including 31 patients with cHL.37 In this study, nivolumab and ipilimumab were given at 3 and 1 mg/kg intravenously, respectively, every 3 weeks for 4 doses, followed by nivolumab monotherapy (3 mg/kg) every 2 weeks for up to 2 years. With a median follow-up of 11.4 months, 23 (74%) of the patients with cHL responded: 6 patients with a CR (19%) and 17 (55%) with a PR.
Nivolumab was been combined with BV as initial salvage therapy in patients with relapsed or refractory cHL.38 Patients received up to 4 cycles of combination treatment, and patients could then proceed to an autologous stem cell transplant. Sixty-two patients were enrolled, and the CR rate was 61%, with an overall objective response rate of 82%. Adverse events occurred in 98% of patients treated with the combination, most of which were grades 1 and 2. Notably, there was an increased incidence of infusion-related reactions that occurred in 44% of patients, and 5 patients (8%) required systemic steroids for immune-related adverse events. In a similar fashion, ECOG-ACRIN conducted a phase I study of the combination of BV and ipilimumab and nivolumab in patients with cHL. The first cohorts of patients were treated with BV 1.8 mg/kg and 2 escalating doses of ipilimumab (1 or 3 mg/kg), and the combination was shown to be safe and well tolerated.39 The overall response rate for the combination of BV plus ipilimumab was 67% with a CR rate of 42%. For the subsequent cohorts of patients receiving BV plus nivolumab, the overall safety profile showed that the regimen was also well tolerated.40 For the evaluable patients in these cohorts, the overall response rate for the combination of BV plus nivolumab was 100%, with a CR rate of 62.5%.
Based on the excellent results seen with immune checkpoint blockade in relapsed and refractory cHL patients, anti–PD-1 antibodies have now been added to frontline therapy.41 The safety and efficacy of nivolumab as a single-agent lead-in treatment followed by nivolumab in combination with chemotherapy for patients with previously untreated advanced-stage cHL have recently been tested. Cohort D of the CheckMate 205 trial enrolled untreated patients with advanced-stage, newly diagnosed cHL and treated them with 4 biweekly doses of nivolumab monotherapy followed by nivolumab plus chemotherapy (doxorubicin, vinblastine, dacarbazine) for 6 cycles. The combination was safe, and when assessed at the end of therapy, the overall response rate per investigator in the intent-to-treat population was 84%, with 80% of patients achieving a CR.
Immune checkpoint blockade in patients with cHL has shown remarkable results, and anti–PD-1 antibodies are now approved for cHL patients with relapsed and refractory disease. Combinations of these agents with chemotherapy or antibody drug conjugates have shown very promising results, and it is anticipated that in the future these combinations may constitute the standard of care. To confirm this, however, randomized clinical trials will be necessary to compare these promising combinations to standard treatment. Overall, the future for patients with Hodgkin lymphoma is very promising, and the hope is that more patients will be cured in the future with frontline treatment that incorporates immunological therapy.
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