Cancer Therapy: Clinical A Phase I Clinical Trial of CHT-25 a I-Labeled Chimeric Anti-CD25 Antibody Showing Efficacy in Patients with Refractory Lymphoma

Purpose: There is a need for new treatments for Hodgkin and T-cell lymphoma due to Auth Depa Dep Lond Radi Ham Unit Deve Rece Gran sored work Canc searc whic ww the development of drug resistance in a proportion of patients. This phase I study of radioimmunotherapy used CHT-25, a chimeric antibody to the α-chain of the interleukin-2 receptor, CD25, conjugated to iodine-131 (I) in patients with refractory CD25positive lymphomas. Experimental Design: Fifteen patients were treated (Hodgkin lymphoma, 12; angioimmunoblastic T-cell lymphoma, 1; adult T-cell leukemia/lymphoma, 2). Tumor was monitored by computed tomography and in all but two patients by F-fluorodeoxyglucose positron emission tomography. Results: There were no grade 3 or 4 infusion reactions. At the maximum tolerated dose of 1,200 MBq/m, the major side effect was delayed myelotoxicity with the nadir for platelets at 38 days and for neutrophils at 53 days. One patient treated with 2,960 MBq/m developed prolonged grade 4 neutropenia and thrombocytopenia and died of Pneumocystis jiroveci pneumonia. Nonhematologic toxicity was mild. Single photon emission computer tomography imaging showed tumor-specific uptake and retention of I and no excessive retention in normal organs. Of nine patients receiving ≥1,200 MBq/m, six responded (three complete response and three partial response); one of six patients with administered radioactivity of ≤740 MBq/m had a complete response. Conclusions: CHT-25 is well tolerated with 1,200 MBq/m administered radioactivity and shows clinical activity in patients who are refractory to conventional therapies. Phase II studies are justified to determine efficacy and toxicity in a broader range of clinical scenarios. (Clin Cancer Res 2009;15(24):7701–10) In spite of recent advances in therapy, there remains an acute need for improved treatments for Hodgkin lymphoma (HL) and other lymphomas. For instance, there is only a 50% prospect of long-term disease free survival for patients with relapsed HL responding to high-dose chemotherapy and autologous stem cell transplant (1, 2). The interleukin-2 (IL-2) receptor is selectively overexpressed in HL and other lymphomas and therefore is a potential target for new therapies. Radioimmuors' Affiliations: Cancer Research UK Targeting and Imaging Group, rtment of Oncology, University College London Cancer Institute and artment of Histopathology, University College London Hospitals, on, United Kingdom; Departments of Nuclear Medicine and ology, Immunology, and Hematology, Royal Free Hospital, pstead, United Kingdom; Cancer Research UK Medical Oncology , St Bartholomew's Hospital, London, United Kingdom; Drug lopment Office, Cancer Research UK, London, United Kingdom ived 6/3/09; revised 9/2/09; accepted 9/5/09; published online 12/15/09. t support: Cancer Research UK grant C34/A5149. The trial was sponby Cancer Research UK through the Drug Development Office. The was also supported by the University College London Experimental er Medicine Centre and University College London Cancer Institute Reh Trust. This work was undertaken at University College London h received a proportion of funding from the Department of Health's 7701 w.aacrjournals.org Resear on Ma clincancerres.aacrjournals.org Downloaded from notherapy (RIT) with CHT-25 [Iodine-131 (I)–labeled chimeric antibody to the IL-2 receptor (CD25)] has been developed for this purpose and a phase I study in relapsed HL and T-cell lymphoma is reported. CD25 is a 55-kDa protein with three transmembrane protein chains that is induced on T-cell activation but is not found on B or T lymphocytes or monocytes in the resting state (3, 4). Hodgkin/Reed-Sternberg cells frequently express CD25, and the NIHR Biomedical Research Centers funding scheme. We thank the Mark Fisher Trust and the James Baldwin Trust for additional support. Initial supply of the anti-CD25 antibody, basiliximab, was provided by Novartis. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Note: Preliminary clinical response and toxicity data were presented at the 49th annual meeting of the American Society of Hematology, Atlanta. The clinical trial and report is the original work of the authors. Requests for reprints: Richard Begent, Department of Oncology, University College London Cancer Institute, Paul O'Gorman Building, Huntley Street, London WC1E 6BT, United Kingdom. Phone: 44-20-7679-0706; Fax: 44-203108-2025; E-mail: [email protected]. F 2009 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-09-1421 Clin Cancer Res 2009;15(24) December 15, 2009 ch. y 3, 2017. © 2009 American Association for Cancer Translational Relevance A clinical trial is reported showing substantial therapeutic effects from radioimmunotherapy in Hodgkin and T-cell lymphomas using 131-Iodine–labeled CHT25 chimeric antibody against the interleukin-2 receptor. The chimeric mouse/human antibody did not generally generate an antiantibody response; as a result, it was possible to deliver repeated therapy. CHT25 cleared slowly from the circulation delivering therapy to tumor deposits over a sustained period. Effective therapy could thus be achieved without excessive toxicity at the maximum tolerated dose. Preliminary pharmacokinetic and pharmacodynamic information is reported on the conditions needed for safe and effective therapy. Potential advantages of chimeric antibodies in radioimmunotherapy have been identified, which may be applicable in common epithelial tumors as well as in lymphoma. Phase II clinical trials are being developed to determine efficacy of CHT25 in defined clinical situations either as a single agent or combined with chemotherapy. Cancer Therapy: Clinical well vascularized nature of lymphoma tissue makes it accessible to i.v. administered antibodies (5, 6). Although therapy with unlabeled antibody is effective for many B-cell lymphomas, (7, 8), it has shown limited activity 7702 Clin Cancer Res 2009;15(24) December 15, 2009 Researc on May clincancerres.aacrjournals.org Downloaded from in HL (9) and only short-term benefit in human T-cell lymphotrophic virus–associated lymphoma/leukemia where the IL-2 receptor is part of an important growth pathway (10). The problem of low potency can be addressed by conjugation of antibody to immunotoxins (11, 12) or by radiolabeling with a radionuclide such as I or Yttrium-90 (Y; ref. 13). Repeated treatment is often compromised with murine antibodies due to their immunogenicity(14, 15). We have addressed this by using a chimeric antibody with mouse variable regions (murine RFT5 cell antibody) and human constant regions with proven low immunogenicity (16–18). The antibody binds with an affinity approximating that of IL-2 itself (17) and in its unlabeled form is licensed for the prevention of acute cellular rejection in renal allografts (18). It is known to have a longer blood half-life than the murine antibodies directed against the same epitope (17) and differs in this respect from the murine antibodies ibritumomab and tositumomab also used in RIT (19–21). This article is believed to be the first to describe a clinical trial investigating the safety and efficacy of RIT with CHT-25 in refractory CD25-positive HL and other CD25-positive lymphomas. Patients and Methods The study was approved by the local Research Ethics Committee and the U.K. Medicines and Healthcare Products Regulatory Agency. All patients provided written informed consent. Patients with histologically confirmed lymphoma expressing CD25 on >50% of tumor cells (or the surrounding tumor milieu in HL) from a biopsy at diagnosis or relapse were eligible. Other inclusion criteria included the h. 3, 2017. © 2009 Fig. 1. A, escalation phase from 370 to 2,960 Mbq/m: includes the first nine patients treated only. B, MTD finding phase: the second phase of the study to refine the dose, includes patient 10 to 14 (patient 15 excluded). www.aacrjournals.org American Association for Cancer CHT25 in Refractory Lymphoma following: lymphoma refractory to prior therapy or relapsed after standard chemotherapy, age 18 y or older, measurable disease by computed tomography (CT), life expectancy of ≥3 mo, no serious comorbidities including HIV infection, WHO performance status of ≤2, bone marrow examination within 4 wk showing ≤25% involvement by tumor with adequate normal hematopoiesis, glomerular filtration rate of >50 mL/min, left ventricular ejection fraction on a multiple gated acquisition scan of >50%, absolute neutrophil count of ≥1.5 × 10/liter hemoglobin of ≥10 g/dl, platelet count of ≥100 × 10/liter, plasma creatinine mol/L, aspartate aminotransferase/alanine aminotransferase of ≤150 mol/L or EDTA clearance ≥50 mL/min, plasma bilirubin of ≤30 2× upper limit of normal, international normalized ratio of prothrombin time (INR) of ≤1.5, and normal thyroid function or stable on treatment. All patients were human anti-mouse antibody negative before therapy and any chemotherapy or radiotherapy was completed at least 4 wk before CHT-25 administration; corticosteroids were permitted as long as the dose was unchanged in the