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Keywords:

  • peripheral T cell lymphoma;
  • CD4;
  • angioimmunoblastic;
  • anaplastic;
  • zanolimumab

Summary

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. Author contributions
  8. Disclosures
  9. References

The efficacy and safety of zanolimumab (HuMax-CD4) in patients with relapsed or refractory peripheral T Cell lymphoma (PTCL) was evaluated. Twenty-one adult patients with relapsed or refractory CD4+ PTCL of non-cutaneous type (angioimmunoblastic T cell lymphoma (AITL) n = 9, PTCL-not otherwise specified (NOS) n = 7, anaplastic large cell lymphoma (ALCL) n = 4 and enteropathy type T cell lymphoma n = 1) were treated in a single-arm multi-centre study, with weekly intravenous infusions of zanolimumab 980 mg for 12 weeks. Median age was 69 years (range 26–85). Seventeen of the patients had advanced stage disease (Ann Arbor stages III–IV). Objective tumour responses were obtained in 24% of the patients with two complete responses unconfirmed (CRu) and three partial responses (PR). One of the CRus lasted more than 252 d. Responses were obtained in different PTCL entities: AITL (n = 3), ALCL (n = 1) and PTCL-NOS (n = 1). In general, the trial drug was well tolerated with no major toxicity. Zanolimumab at a dose of 980 mg weekly demonstrated clinical activity and an acceptable safety profile in this poor-prognosis patient population, suggesting that the potential benefit combining zanolimumab with standard chemotherapy in the treatment of PTCL should be investigated.

Systemic peripheral T cell lymphoma (PTCL) of non-cutaneous type is a heterogeneous group of mature non-Hodgkin lymphomas (NHLs) with diverse histological, molecular and clinical characteristics (Armitage et al, 2008). In western countries, PTCL accounts for 7–10% of all NHLs and approximately 20% of the aggressive lymphomas (Morton et al, 2006; Anderson et al, 1998; Rüdiger et al, 2002). Within the group of aggressive lymphomas the T cell phenotype itself is associated with a poor prognosis and a 5-year overall survival of 30–35% using standard chemotherapy (Coiffier et al, 1990; Melnyk et al, 1997; Zaja et al, 1997; Gisselbrecht et al, 1998; Lopez-Guillermo et al, 1998; Gallamini et al, 2004; Morabito et al, 2004). Because of these disappointing results, novel therapies are needed for PTCL.

Specific immunotherapy with an anti-CD20 antibody added to standard chemotherapy has markedly improved the prognosis for aggressive B-cell lymphomas (Coiffier et al, 2002; Feugier et al, 2005; Habermann et al, 2006; Pfreundschuh et al, 2006). A similar approach, with addition of specific immunotherapy to standard therapy, in T cell lymphoma could potentially improve the prognosis of affected patients. The CD4 molecule is expressed on the malignant cells in the majority of cases of PTCL-not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma (ALCL) and angioimmunoblastic T cell lymphoma (AITL), and is therefore a relevant target for immunotherapy.

Zanolimumab (HuMax-CD4) is a human monoclonal antibody specific for the CD4 antigen, which is expressed on a subset of T cells (Fishwild et al, 1996). Zanolimumab inhibits CD4+ T cells by combining signalling inhibition with potent induction of Fc-mediated effector functions. T cell activation is inhibited by a fast dual mechanism in which the antibody abrogates signalling via the T cell receptor (TCR) and, in addition, down regulates T cell activation by transmission of direct inhibitory signals. In addition, zanolimumab induces killing of CD4+ T cells via antibody-dependent cellular cytotoxicity (ADCC) (Rider et al, 2007). A phase 2 trial exploring weekly doses of 280, 560 and 980 mg zanolimumab demonstrated good safety and efficacy in patients with relapsed or refractory cutaneous T cell lymphoma (CTCL) (Kim et al, 2007). The best results were obtained at the dose level 980 mg thus; a prospective multicentre clinical trial was designed to evaluate the efficacy and safety of zanolimumab given as single agent in patients with relapsed or refractory non-cutaneous CD4+ PTCL.

Patients and methods

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. Author contributions
  8. Disclosures
  9. References

Study design

This phase 2 trial was conducted as a single-arm multi-centre trial in patients with refractory or relapsed CD4+ PTCL of non-cutaneous type. Patients were enrolled from October 2004 until January 2007 from 11 medical oncology and haematology departments in Denmark (two sites), Sweden (three sites), United Kingdom (one site), Germany (three sites) and France (two sites). Ethical approval was obtained from the independent ethics committees and by the national clinical trial agencies. The trial was performed in accordance with the Declaration of Helsinki. ClinicalTrial.gov no. NCT00877656.

The trial period was 18 weeks including a treatment period of 12 weekly zanolimumab infusions followed by a 6-week efficacy assessment period. The trial period included a follow-up period of up to 24 months to evaluate time to progression and safety.

All patients received the same dose level, 980 mg weekly. Zanolimumab was administered as an intravenous infusion over approximately 80 min for the first infusion and over approximately 60 min for subsequent infusions if no infusion-related reactions occurred. To minimize the risk of infusion-related adverse events (AEs), patients were pretreated with acetaminophen or a similar anti-pyretic agent prior to start of first treatment. The patients did not receive anti-histamines or steroids as premedication. Prophylactic antibiotics and granulocyte colony-stimulating factor (G-CSF) could be given at the discretion of the treating physician.

During the trial period, the use of other anti-neoplastic therapies or systemic steroids was prohibited.

Patient cohort

Patients (≥18 years) with a histological diagnosis of systemic non-cutaneous CD4+ PTCL relapsed after or refractory to at least one prior systemic lymphoma regimen were included in the trial. Twelve out of 21 patients had received more than one prior line of treatment. The remaining patients were either allocated to experimental treatment after a dose-dense intensive first-line therapy or because the responsible physician did not consider them eligible for further treatment intensification. No patients eligible for curative treatment were enrolled. Histological diagnosis according to the World Health Organization (WHO) classification of lymphoid neoplasms was established (Jaffe et al, 2001) and CD4 expression by immunohistochemistry was assessed on tumour specimens obtained at any time before enrollment. A computerized tomography (CT) scan was required to show at least two demarcated lesions with a diameter ≥1·5 cm or at least one lesion ≥2·0 cm.

Patients were excluded from the trial if they had received prior treatment with anti-CD4 monoclonal antibodies or had received alemtuzumab within the last year.

Before inclusion in the trial all patients gave written informed consent.

Study end points

The objective of the trial was to explore efficacy and safety of zanolimumab in relapsed or refractory patients with CD4+ PTCL of non-cutaneous type. Overall response rate (ORR) was the primary endpoint (threshold for continuation of the study at 20%) and the secondary assessments included frequency and severity of AEs, response duration, time to response, time to progression, human anti-human antibodies (HAHA) and serum concentration of zanolimumab.

Efficacy assessment

A pre-therapeutic CT scan (neck, thorax, abdomen and pelvis) was performed before start of treatment for diagnostic and staging purposes, and to ensure compliance with eligibility criteria.

Responses were assessed according to the international Workshop on NHL response criteria (Cheson et al, 1999).

Evaluation of objective response was based upon CT scan data assessed by the local radiologist, bone marrow biopsy (if pre-therapeutically involved), physical lymph node and organ examination assessed by the investigator and biochemistry. Evaluation of the objective response was based upon these assessments and performed by the investigator.

Response assessment was done at weeks 6, 12 and 18 and subsequently every 8 weeks until progression or until the end of the follow-up period.

Safety assessment

Safety assessments included AEs, physical examination, vital signs, standard laboratory parameters (flow cytometry, haematology and clinical chemistry) and host immune response.

Occurrence of AEs were recorded throughout the trial period and also during the follow-up period if the patient was followed for low CD4 count. The AE reporting period continued until progressive disease (PD) or until a maximum follow-up of 24 months. Serious adverse events (SAEs) were reported on an ongoing basis throughout the trial period and the post-trial follow-up period.

AEs were categorized and graded according to the National Cancer Institute Common Criteria for AEs, version 3.0 and coded according to the Medical Dictionary for Regulatory Activities (MedDRA) version 6.0.

Safety was monitored by an independent data monitoring committee.

Host immune response to zanolimumab was evaluated by determining the presence of HAHA in serum. This was done by a zanolimumab-coated enzyme-linked immunosorbent assay (ELISA) performed before treatment and at the last visit in the treatment period, i.e. week 18. The serum concentration of zanolimumab was determined by ELISA (limit of quantification: 0·015 μg/ml) at each visit from week 0 until week 18. All laboratory samples were analysed, including flow cytometry, by the Bio analytical research corporation (BARC), Ghent, Belgium.

Statistical methods

All patients who received the study drug, irrespective of their compliance to the planned course of treatment (intention-to-treat population), were included in the efficacy and safety analysis. Endpoints are presented as descriptive statistics or graphically.

Results

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. Author contributions
  8. Disclosures
  9. References

Patient cohort

Patient characteristics are summarized in Table I. In addition, Table II shows an overview of the therapy received by each patient prior to inclusion in the study. Twenty-one patients (11 male and 10 female) were enrolled in the trial. Median age was 69 years (range 26–85) and median time from primary diagnosis to trial-entry was 1·2 years (range 0·4–10·6). All but four patients showed advanced disease (stages III-IV according to Ann Arbor staging). Nineteen out of 21 patients had previously received and failed 1–2 lines of cytoreductive treatment (see Table II).

Table I.   Patient baseline characteristics.
Total number of patients21
  1. *Three alk-negative and one with unknown alk-status.

Male/Female11/10
Age (years), median (range)69 (26–85)
Weight (kg), median (range)76 (40–98)
Time since first diagnosis (years), median (range) 1·2 (0·4–10·6)
Diagnosis
 Angioimmunoblastic T cell lymphoma9
 Peripheral T cell lymphoma-not otherwise specified7
 Anaplastic large cell lymphoma 4*
 Enteropathy type T cell lymphoma1
Clinical stage (Ann Arbor)
 Localized disease (B symptoms)
  II4 (1)
 Disseminated disease (B symptoms)
  III7 (3)
  IV10 (5)
International prognostic index
 Low/low-intermediate6
 Intermediate-high/high15
Table II.   Prior therapy data.
PatientTherapyStatus at study entry
  1. PD, progressive disease; Cy, cyklophosphamide; MTX, methotrexate; AraC, cytosine arabinoside; Chl, chlorambucil; IF-RT, involved-field radiotherapy; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CHOEP, CHOP+etoposide; IVAM, iphosphamide, etoposide, doxorubicin, methotrexate; BEAM/-C, BCNU, etoposide, cytosine arabinoside (AraC), melphalan/-cyclophosphamide; ESHAP, etoposide, steroid, high-dose AraC, cisplatin; VAD, vincristine, adriamycin, dexamethasone; ACVBP, doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone; VAPAC, vincristine, cytosine arabinoside, prednisone, doxorubicin, cyclophosphamide; VAPAC-B, VAPAC+bleomycin (Bleo); ICE, iphosphamide, carboplatin, etoposide.

01CHOPPD + frail patient
02CHOP x6, BEAM, Radiation, Cy+MTX+AraC+steroid3rd relapse
03CHOP, IF-RT (nasal cavity)1st relapse + frail patient
04CHOP, BEAM, Radiation3rd relapse
05CHOP, Radiation2nd relapse
06CHOEP, Cisplatin+AraC+steroidPD after 2nd line therapy
07CHOPPD + frail patient
08CHOP, Ara-C, Cy+MTX+Etoposide, Radiation3rd relapse
09ACVBP, IVAM, BEAM, ESHAP3rd relapse
10CHOP-like1st relapse
11CHOP x 6, Fludarabin, Chl, VAD, Ara-CPD after 3rd relapse
12VAPAC - B x 7, ACx32nd relapse
13CHOP, vindesin+steroid, steroidPD after 2nd line therapy
14ACVBP, MTX1st relapse + frail patient
15Mitoxantrone + Cy, VAPAC-B1st relapse + frail patient
16CHOP1st relapse
17CHOEP, BEAC2nd relapse
18CHOP+MTX1st relapse
19CHOP, ICEPD after 2nd line therapy
20CHOP1st relapse
21CHOP-Bleo1st relapse

All patients received at least one infusion of zanolimumab. Out of 21 patients, 8 (38%) received all 12 infusions, 8 (38%) received 6–9 infusions and 5 (24%) received 1–3 infusions. Reasons for early discontinuation of treatment were: Disease progression (n = 10), AEs (n = 2) and administrative reasons (n = 1).

Efficacy

Objective tumour responses were obtained in five out of 21 patients [ORR 24%; 95% confidence interval (CI): 8–47%; Table III]. A partial response (PR) was obtained by three patients (Patients 002, 012, 013) and two patients (Patients 006, 015) achieved an unconfirmed complete response (CRu). Responses were seen in localized and advanced stage disease, and throughout histological subgroups, i.e. AITL (three patients), ALCL (one patient) and PTCL-NOS (one patient).

Table III.   Characteristics of responding patients.
PatientNo. of prior treatment regimensAge (years)SexHisto-logical DiagnosisNo. of infu-sionsObjective responseResponse duration (d)Ann Arbor StageLDH at baseline
  1. CRu, complete response unconfirmed; PD, progressive disease; PR, partial response; PTCL, peripheral T cell lymphoma, ALCL, anaplastic large cell lymphoma, AITL, angioimmunoblastic T cell lymphoma, NOS, not otherwise specified, LDH, lactate dehydrogenase.

  2. *ALK-protein status unknown.

  3. †See efficacy section for details.

  4. ‡Response documented at last efficacy assessment and no relapse has been documented.

002226MaleALCL*12PR43IIBNormal
006161MalePTCL-NOS12CRu46IVAElevated
012272FemaleAITL12PR51†IVBElevated
013274FemaleAITL12PR>1‡IVBNormal
015274FemaleAITL 9CRu>252IVANormal

Of the objective responses, four were observed 6 weeks after start of treatment and one was observed in the follow-up period (182 d after start of treatment).

Response duration was 43 and 46 d in the two patients (Patients 002 and 006, respectively) who experienced disease progression. In a third responder (Patient 012 who had a PR at week 6 (see Fig 1), one lymph node had increased in size at week 12, while all other lesions had decreased and was therefore assessed as having PD and a response duration of 51 d. At the following visits, including follow-up visits no evidence of disease was detected. No relapse/progression had been documented in Patients 013 and 015 at the time of reporting.

image

Figure 1.  Abdominal CT scans from a patient with AITL showing a marked reduction in lymph node diameter (partial remission) after six infusions of i.v. zanolimumab 980 mg given as monotherapy.

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Pharmacokinetics and pharmacodynamics

Zanolimumab trough concentrations increased over time after weekly repeated infusions in the majority of patients (Fig 2). The highest maximum trough zanolimumab serum concentrations were obtained in the patients who received the highest number of doses. Up to week 6, 10 patients obtained trough Cmax concentrations above 160 μg/ml, including all those who obtained an objective tumour response either at week 6 (four patients) or later, i.e. week 26 (one patient). A decrease in the concentration of blood CD3+CD4+ T cells was demonstrated in all patients by flow cytometry after zanolimumab administration regardless of their response. All four patients who obtained a response in the trial period had rapid, profound and sustained CD3+CD4+ T cell depletion throughout this period. The relationship between the trough concentrations of zanolimumab and CD3+CD4+ T cell concentrations showed that all patients who obtained an objective tumour response at week 6 had zanolimumab concentrations above 160 μg/ml, which coincided with markedly reduced blood CD3+CD4+ T cell counts. The patient who obtained a late objective response had a transient zanolimumab concentration that exceeded 160 μg/ml, but the CD3+CD4+ T cell concentration was not markedly suppressed at this time point.

image

Figure 2.  Zanolimumab serum concentration from baseline to week 14 in 21 patients. The serum samples were obtained before administration of Zanolimumab (serum trough values).

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Anti-zanolimumab antibodies were not detected in any of the patients, including the five who reached visit 15 at the scheduled time point (week 18). Although not systematically analysed in relapsed/progressing cases, the tumours were still CD4-positive in those cases where biopsies were performed after zanolimumab treatment.

Safety

During the trial, 108 AEs were reported. One death (PD) occurred during the trial period and seven deaths were reported during the follow-up period (until December 3rd, 2007). All deaths were evaluated as unrelated to the trial drug.

Furthermore, 18 SAEs in 11 patients were reported during the trial period. Among these, four SAEs in four patients occurred as infusion-related events and were considered related to the trial drug by the investigator (see below).

Ten AEs were reported as non-serious grade 3 AEs; five were related and five were non-related to the trial drug. The related events were decreased lymphocyte count (two events), arthralgia (one event) and two infusion-related events (see below).

The most frequently reported AEs were rash (five events) and pyrexia (five events).

Infusion-related

Four SAEs (thrombocytopenia- grade 4, hyperpyrexia with hypotension- both grade 1, face oedema and pyrexia- both grade 2, and cytokine-release syndrome- grade 3) in four patients were infusion-related and considered to be related to the trial drug by the investigator. In the patient with thrombocytopenia the platelet count had normalized 8 h later without intervention. The event occurred the day after the first infusion, whereas the remaining related SAEs occurred on the first infusion day. All four patients recovered.

Two related non-serious grade 3 AEs (one event of bronchospasm and one event of infusion-related allergic reaction) occurred on the first infusion day. Both patients recovered.

Fifty AEs reported for 16 patients had onset on infusion days. Of these infusion-related AEs, 23 (46%) were reported on the first and 3 (6%) on the second infusion day. The most frequently related AEs on the day of first infusion were pyrexia (three events in three patients), rigours (three events in three patients) and hypotension (two events in two patients).

Infections

During the trial, seven infectious episodes were reported in six patients. Five of these seven events were graded as SAEs. Among the latter, two episodes of viraemia occurred in the same patient and required hospitalization. During the first event the patient developed chills and fever but recovered after 3 days with intravenous antibiotics. A polymerase chain reaction (PCR)-based analysis for Epstein-Barr virus (EBV) DNA was positive. A corresponding analysis for cytomegalovirus (CMV) DNA was negative. During the second event the patient had diarrhoea, vomiting, abdominal pain, fever, increased C-reactive protein and again a positive EBV DNA PCR. PCR for CMV DNA was still negative. The patient recovered after 1 week of treatment with intravenous antibiotics, immunoglobulin and acyclovir. The patient subsequently continued zanolimumab treatment. The additional infectious SAEs were a bacterial septicaemia, a febrile neutropenia and one episode of bronchitis.

Safety laboratory parameters

A decrease in the concentration of blood CD3+CD4+ T cells was demonstrated in all patients by flow cytometry after zanolimumab administration. At the start of the follow-up period, CD3+CD4+ T cell levels were normal in only a few patients (Fig 3). CD3+CD8+ T cells and neutrophils were not depleted.

image

Figure 3.  Concentration of CD3+CD4+ peripheral blood T cells from pre-therapeutic screening to end of follow-up (21 patients).

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All other abnormal laboratory values either reflected the underlying disease and/or pre-trial chemotherapy treatments.

Discussion

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. Author contributions
  8. Disclosures
  9. References

Zanolimumab is a biologically active drug that targets the CD4 antigen present on a subset of T cells. Among T cell lymphomas, CD4 expression has been demonstrated in CTCL (Ralfkiaer, 1991), PTCL-NOS (Matutes et al, 1996; Went et al, 2006), AITL (Chen et al, 2006; Went et al, 2006) and ALCL (Krenacs et al, 1997; Felgar et al, 1999; Juco et al, 2003).

Two phase 2 clinical trials have demonstrated the efficacy of zanolimumab monotherapy in refractory CD4+ CTCL (Kim et al, 2007). In the present open-label clinical exploratory trial, 21 patients with relapsed or refractory CD4+ non-cutaneous PTCL were treated with weekly intravenous zanolimumab at a dose of 980 mg for 12 weeks. Five out of the 21 patients (24%) obtained an objective tumour response, with one case acheiving long lasting CRu (>252 d).

Serum trough levels of zanolimumab in the majority of patients showed a gradual accumulation over time depending on the number of doses received. All patients who obtained an objective tumour response during the trial period, had serum zanolimumab concentrations above 160 μg/ml along with a marked depletion of CD3+CD4+ T cells at the time when the response was detected. The patient who first obtained response in the follow-up period also had a transient zanolimumab concentration above 160 μg/ml. For this patient, however, the concentration of CD3+CD4+ T cells was not markedly suppressed. No objective tumour response was observed in patients that did not, at any time during the treatment or follow-up period, reach a serum trough level of at least 160 μg/ml. This observation and the fact that all patients were not completely depleted of CD3+CD4+ T cells indicates that the optimal dose of zanolimumab for patients with systemic PTCL may be higher than 980 mg weekly. Other factors may influence the optimal therapeutic level of the drug, such as tumour cell burden and administration schedule.

In all patients, zanolimumab caused depletion of CD3+CD4+ T cells in the peripheral blood. The mechanisms responsible for zanolimumab-induced T cell depletion are inhibition of TCR signalling and ADCC. Inhibition of TCR signalling is caused by a dual mechanism leading to impaired cell proliferation and survival (Rider et al, 2007). Concentrations of neutrophils and CD3+CD8+ T cells were unaffected by zanolimumab treatment.

In the five patients who reached week 18, the HAHA test was negative and coincided with undetectable levels of zanolimumab in the patient serum. Significant concentration levels of the drug are therefore not likely to have interfered with HAHA detection. This is in accordance with the results from zanolimumab-treated CTCL patients, where no development of HAHA was detected (Kim et al, 2007).

Overall, zanolimumab demonstrated a favourable safety profile. All infusion-related SAEs, except one case of transient grade 4 thrombocytopenia, occurred on infusion days, were mild to severe in intensity and resolved within a range of 8 h to 4 d from the onset of the event.

The most frequently reported AE was rash (either infusion related or non-infusion related) which is consistent with the findings recorded in zanolimumab-treated CTCL patients (Kim et al, 2007). The non-infusion related rash events could be explained by the depletion of CD4+ T regulatory cells normally engaged in down regulating immune responses.

Interestingly, despite profound depletion of CD3+CD4+ T cells, the frequency of severe infections was rather low. A case of bacterial septicaemia, one of neutropenic fever and one of promptly recovering bronchitis were recorded. Perhaps more interestingly, a clinically significant and recidivating EBV viraemia was reported in a patient with AILT pre-therapeutically positive for EBV. A possible relationship between this episode and an antibody-induced CD4-depletion cannot be excluded. A larger clinical experience is needed in order to assess the frequency of these events, particularly if the antibody is to be used in combination with other potentially immunosuppressive anti-neoplastic drugs. At the investigators discretion, six patients (29%) received prophylactic treatment with trimethoprim/sulphamethoxazole, fluconazole, aciclovir or valaciclovir alone or in combination. No cases of CMV reactivation were reported.

Alemtuzumab, a humanized anti-CD52 IgG1, is effective in T cell malignancies (i.e. T cell prolymphocytic leukemia and CTCL) (Dearden et al, 2002). In addition, a response rate of 36% in 14 patients with relapsed or refractory PTCL treated with alemtuzumab as monotherapy was demonstrated in a Nordic trial (Enblad et al, 2004). However, despite trimethoprim/sulphamethoxazole and valaciclovir prophylaxis administered to all patients, the treatment resulted in a high rate of opportunistic infections, with five patients dying of infectious complications leading to a premature closure of the trial (Enblad et al, 2004). Even with mandatory prophylaxis, alemtuzumab is associated with infectious complications also when used in the first-line setting (Gallamini et al, 2007; Kluin-Nelemans et al, 2008; Weisel et al, 2008).

Other monoclonal antibodies have been tested, primarily as monotherapy, in phase 1–2 trials. Treatment with anti-CD30 in relapsed ALCL of primary cutaneous or systemic type showed a response rate of 28% and an acceptable safety profile (Ansell et al, 2007). Anti-CD25 (interleukin-2 receptor) antibody treatment has shown clinical effect in anecdotal cases. Other drugs targeting the CD25 receptor, such as diphtheria toxin-linked to human IL-2, have been used in the treatment of CTCL (Olsen et al, 2001) and in relapsed systemic PTCL, where an overall response rate of 48% in 27 patients was reported (Talpur et al, 2002; Dang et al, 2007). Anti-CD2 treatment has been used in a mixed group of T cell malignancies where objective tumour responses were observed. However, a marked decline in CD4+ and CD8+ T cells and in natural killer (NK) cells resulted in CMV reactivation and development of EBV-related B-cell lymphoproliferative disease (Morris et al, 2008). Within the field of lymphoma, immunotherapy with anti-CD4 antibodies, including zanolimumab, has previously only been tested in CTCL (Knox et al, 1991, 1996; Kim et al, 2007). The present study has provided the first data on systemic PTCL. We obtained a response rate of 24% with zanolimumab monotherapy in relapsed/refractory systemic PTCL. Responses, some of which were long lasting, were observed throughout all the common subtypes of CD4+ PTCL. The safety profile of zanolimumab in this heavily pretreated patient population was favourable.

Recently, new non-antibody compounds, such as the histone-deacetylase inhibitor romidepsin (Woo et al, 2009) and the antifolate pralatrexate (O’Connor et al, 2009), were shown to have clinical activity as monotherapy in relapsed/refractory cutaneous and systemic PTCL.

In the light of the therapeutic refractoriness of systemic PTCL, even in the first line setting, the present result is encouraging and supports a role for anti-CD4 immunotherapy within the well-defined limits of this indication. Additional PTCL trials with zanolimumab exploring the pharmacokinetics, efficacy and safety of higher doses of the antibody given as monotherapy and/or in combination with other PTCL-active compounds are warranted.

Acknowledgements

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. Author contributions
  8. Disclosures
  9. References

The authors thank Genmab A/S for supplying trial material, including zanolimumab; contributing to the design and conduct of the trial; collecting, managing, analysing and interpreting the data; and contributing to the preparation of the manuscript. The authors also thank Dorthe Grønnegaard Hansen, Genmab A/S, for editorial assistance.

This work was supported by clinical research funding from Genmab A/S (F. d`Amore, J.A.R., T.R., H.T., A.Ö., F.M., M.G., M.D., H.H.).

Author contributions

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. Author contributions
  8. Disclosures
  9. References

F. d`Amore, in collaboration with Genmab A/S designed the trial. All the authors performed the research, collected the data, interpreted the data and contributed to the manuscript in collaboration with Dorthe Grønnegaard Hansen.

Disclosures

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. Author contributions
  8. Disclosures
  9. References

This trial was sponsored by Genmab A/S, and subsequently licensed in its entirety when exclusive worldwide rights to zanolimumab were acquired by TenX Biopharma, Inc. B. Bang was formerly employed by Genmab A/S, whose investigational drug zanolimumab was studied in the present work. F. d’Amore: Participation in three advisory board meetings on zanolimumab. H. Hagberg: Involved in data monitoring committee work concerning Humax-CD20. All other authors: No relevant conflicts of interest to disclose.

References

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. Author contributions
  8. Disclosures
  9. References
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