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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.
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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.