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Denileukin diftitox: a biotherapeutic paradigm shift in the treatment of lymphoid-derived disorders.Expert Review of Anticancer Therapy Jan 2007Denileukin diftitox (Ontak) represents an example of a fused molecule that targets cells bearing high affinity interleukin-2 receptors internalized via receptor-mediated... (Review)
Review
Denileukin diftitox (Ontak) represents an example of a fused molecule that targets cells bearing high affinity interleukin-2 receptors internalized via receptor-mediated endocytosis in an acidified vesicle. Denileukin diftitox is proteolytically cleaved within the endosome liberating the enzymatically active portion of the diphtheria toxin, the A fragment. Diphtheria toxin fragment A is released into the cytosol inhibiting the protein synthesis through the ADP-ribosylation of the elongation factor-2, and leading to cell death. This review focuses on the clinical trials that led to the FDA approval of the drug for cutaneous T cell lymphoma in the US, and investigational studies demonstrating drug-activity against B and T-cell non-Hodgkin's lymphoma, chronic lymphocytic lymphoma and acute graft versus disease within allogeneic hematopoietic stem cell transplant.
Topics: Antineoplastic Agents; Clinical Trials as Topic; Diphtheria Toxin; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Interleukin-2; Leukemia, Lymphocytic, Chronic, B-Cell; Recombinant Fusion Proteins; Safety; United States; United States Food and Drug Administration
PubMed: 17187516
DOI: 10.1586/14737140.7.1.11 -
Clinical Journal of Oncology Nursing Oct 2012Cutaneous T-cell lymphoma (CTCL) is a rare non-Hodgkin lymphoma with predominant skin manifestations and a relatively indolent course at early stages, but it can be... (Review)
Review
Cutaneous T-cell lymphoma (CTCL) is a rare non-Hodgkin lymphoma with predominant skin manifestations and a relatively indolent course at early stages, but it can be fatal in advanced settings. In the absence of cure, the goal of therapy for CTCL is to induce long-term remissions without further compromising a patient's immune system or quality of life. Denileukin diftitox (DD) is a fusion protein chemotherapeutic agent used for the treatment of persistent or recurrent CTCL. It binds selectively to the high- and intermediate-affinity interleukin-2 receptor (CD25+) on lymphocytes and is internalized by these cells. Inside the cells, the diphtheria toxin portion of fusion protein is cleaved by proteolytic enzymes, causing cell death. DD produces durable responses and may forestall disease progression. This article reviews DD phase III clinical trial data and summarizes one institution's clinical experience in the management of the most frequent and clinically significant adverse effects of DD (e.g., acute infusion reactions, capillary leak syndrome, hypoalbuminemia, visual changes, constitutional symptoms, rash, hepatobiliary disorders). Many DD-associated adverse effects can be managed effectively without dose reduction or interruption of treatment with prudent use of supportive care measures.
Topics: Antineoplastic Agents; Clinical Trials, Phase III as Topic; Diphtheria Toxin; Humans; Interleukin-2; Lymphoma, T-Cell; Recombinant Fusion Proteins; Skin Neoplasms
PubMed: 23022942
DOI: 10.1188/12.CJON.E164-E172 -
Leukemia May 2012Follicular lymphoma exhibits intratumoral infiltration by non-malignant T lymphocytes, including CD4+CD25+ regulatory T (T(reg)) cells. We combined denileukin diftitox... (Clinical Trial)
Clinical Trial
Follicular lymphoma exhibits intratumoral infiltration by non-malignant T lymphocytes, including CD4+CD25+ regulatory T (T(reg)) cells. We combined denileukin diftitox with rituximab in previously untreated, advanced-stage follicular lymphoma patients anticipating that denileukin diftitox would deplete CD25+ T(reg) cells while rituximab would deplete malignant B cells. Patients received rituximab 375 mg/m(2) weekly for 4 weeks and denileukin diftitox 18 mcg/kg/day for 5 days every 3 weeks for 4 cycles; neither agent was given as maintenance therapy. Between August 2008 and March 2010, 24 patients were enrolled. One patient died before treatment was given and was not included in the analysis. Eleven of 23 patients (48%; 95% confidence interval (CI): 27-69%) responded; 2 (9%) had complete responses and 9 (39%) had partial responses. The progression-free rate at 2 years was 55% (95%CI: 37-82%). Thirteen patients (57%) experienced grade ≥3 adverse events and one patient (4%) died. In correlative studies, soluble CD25 and the number of CD25+ T cells decreased after treatment; however, there was a compensatory increase in IL-15 and IP-10. We conclude that although the addition of denileukin diftitox to rituximab decreased the number of CD25+ T cells, denileukin diftitox contributed to the toxicity of the combination without an improvement in response rate or time to progression.
Topics: Adult; Aged; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Diphtheria Toxin; Female; Humans; Interleukin-2; Interleukin-2 Receptor alpha Subunit; Lymphoma, B-Cell; Lymphoma, Follicular; Male; Middle Aged; Recombinant Fusion Proteins; Rituximab; T-Lymphocytes
PubMed: 22015775
DOI: 10.1038/leu.2011.297 -
Biology of Blood and Marrow... Sep 2006Denileukin diftitox (Ontak) was evaluated in combination with methotrexate (MTX) for preventing acute graft-versus-host disease (GVHD) in dogs given 9.2 Gy of total body...
Denileukin diftitox (Ontak) was evaluated in combination with methotrexate (MTX) for preventing acute graft-versus-host disease (GVHD) in dogs given 9.2 Gy of total body irradiation and DLA-nonidentical hematopoietic cell grafts. Six dogs were given denileukin diftitox 9 ,microg/kg/day intravenously (IV) on days 2, 4, 5, 7, 8, and 10, in combination with MTX 0.4 mg/kg/day IV on days 1, 3, 6, and 11 after transplantation. Median survival of the dogs given MTX in combination with denileukin diftitox was 16 days (range, 13-18 days), similar to that of 35 historical controls given MTX alone (median survival, 20 days). Five of the 6 denileukin diftitox-treated dogs had clinical and pathological evidence of 3-system GVHD; 1 dog died of canine herpes virus infection without evidence of GVHD. In conclusion, denileukin diftitox did not prevent, mitigate, or delay acute GVHD in this stringent and predictive (with respect to outcomes in human patients) hematopoietic cell transplantation model.
Topics: Animals; Antineoplastic Agents; Diphtheria Toxin; Dogs; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Herpesviridae Infections; Immunosuppressive Agents; Interleukin-2; Methotrexate; Models, Animal; Recombinant Fusion Proteins; Time Factors; Whole-Body Irradiation
PubMed: 16920555
DOI: 10.1016/j.bbmt.2006.05.005 -
Clinical Journal of Oncology Nursing 2000Primary cutaneous T-cell lymphomas (CTCLs) encompass a wide variety of lymphomas that are characterized by the localization of the malignant lymphocytes to the skin at...
Primary cutaneous T-cell lymphomas (CTCLs) encompass a wide variety of lymphomas that are characterized by the localization of the malignant lymphocytes to the skin at presentation. They are slow-growing and rare, occurring in fewer than 1,000 people annually. Patients may go for months to years with skin abnormalities before being diagnosed. Mycosis fungoides and Sezary syndrome are the most common forms of CTCL and are considered to be indolent diseases. Patients with T1 disease have a normal life expectancy, whereas patients who undergo transformation to large cell lymphoma (8%-23% of patients) have a poor prognosis, with mean survival ranging from 2-19 months.
Topics: Antineoplastic Agents; Diphtheria Toxin; Humans; Interleukin-2; Lymphoma, T-Cell, Cutaneous; Recombinant Fusion Proteins; Skin Neoplasms
PubMed: 11899329
DOI: No ID Found -
Biology of Blood and Marrow... Mar 2005Acute graft-versus-host disease (aGVHD) is partly mediated through activated T cells, and these cells are known to express the high-affinity receptor for interleukin 2... (Clinical Trial)
Clinical Trial
Acute graft-versus-host disease (aGVHD) is partly mediated through activated T cells, and these cells are known to express the high-affinity receptor for interleukin 2 (IL-2R). Denileukin diftitox is composed of human IL-2 and diphtheria toxin that is cytotoxic to activated lymphocytes expressing the high-affinity IL-2R. We describe the results of a phase II study of denileukin diftitox in 22 patients with steroid-resistant aGVHD. Twenty patients were treated at dose level 1 (4.5 microg/kg daily on days 1-5 and then weekly on study days 8, 15, 22, and 29), and 2 patients were treated at dose level 2 (9.0 microg/kg delivered on the same schedule). Dose level 2 was associated with grade 3/4 renal and hepatic toxicity and vascular leak syndrome, and no further patients were treated at this level. Dose level 1 was generally well tolerated. The response of aGVHD was assessed at study days 36 and 100. Nine patients (41%) responded, all with a complete response at study day 36, and 6 patients (27%) responded at study day 100 (4 complete responses and 2 partial responses). Denileukin diftitox has promising activity in steroid-resistant aGVHD, and further study is warranted.
Topics: Acute Disease; Capillary Leak Syndrome; Chemical and Drug Induced Liver Injury; Diphtheria Toxin; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Interleukin-2; Recombinant Fusion Proteins; Remission Induction; Steroids
PubMed: 15744237
DOI: 10.1016/j.bbmt.2004.11.022 -
Journal For Immunotherapy of Cancer 2016Depletion of CD25(+) Tregs improves anti-tumor immunity in preclinical models. Denileukin diftitox is a recombinant fusion protein of human IL-2 and diptheria toxin...
Single dose denileukin diftitox does not enhance vaccine-induced T cell responses or effectively deplete Tregs in advanced melanoma: immune monitoring and clinical results of a randomized phase II trial.
BACKGROUND
Depletion of CD25(+) Tregs improves anti-tumor immunity in preclinical models. Denileukin diftitox is a recombinant fusion protein of human IL-2 and diptheria toxin fragment that also can kill CD25(+) T cells. Prior clinical trials of denileukin diftitox suggested reduction of FoxP3(+) Tregs and some clinical responses.
METHOD
To investigate the immunologic effects of denileukin difitox on vaccine-specific immune responses in melanoma, a randomized clinical trial of single dose denileukin diftitox prior to vaccination versus vaccination alone in subjects with HLA-A2(+) metastatic melanoma was performed. Treatment included randomization to a 4-peptide vaccine (Melan-A, gp100, MAGE3 and NA17 with GM-CSF emulsified in Montanide) alone or after single dose of denileukin diftitox (18 mcg/kg). Vaccine was given every 2 weeks for 3 doses and, absent clinical progression, continued every 2 weeks. Blood and tumor biopsies were obtained pretreatment and after 3 vaccinations for immunologic assessments.
RESULTS
In 17 treated subjects there were no drug-related G3-4 adverse events. One partial response and 8 stable disease were observed in 9 subjects (4 DD: 5 vaccine only) with no impact of denileukin diftitox on time to progression. Total peripheral Tregs were not significantly altered, and in 1 patient biopsy intra-tumoral FoxP3 transcripts were not reduced following denileukin diftitox. ELISA for IL2R-α demonstrated no impact on outcomes by soluble CD25 level. Immune monitoring suggested the development of modest vaccine-specific CD8(+) T cell responses in the control group, however immunization efficacy was actually reduced in the denileukin diftitox group.
CONCLUSION
Our results indicate that denileukin diftitox did not effectively deplete Tregs, augment T cell responses, or improve clinical activity in melanoma. Clinicaltrials.gov ID: NCT00515528; Registered August 9, 2007.
PubMed: 27330808
DOI: 10.1186/s40425-016-0140-2 -
Clinical Lymphoma Nov 2000DAB(389)IL-2 (denileukin diftitox, ONTAK) is an interleukin-2 receptor (IL-2R)-specific ligand fusion protein that may potentially be selective for IL-2R-expressing... (Review)
Review
DAB(389)IL-2 (denileukin diftitox, ONTAK) is an interleukin-2 receptor (IL-2R)-specific ligand fusion protein that may potentially be selective for IL-2R-expressing malignancies. The activity of DAB(389)IL-2 in the treatment of cutaneous T-cell lymphoma has established the feasibility of utilizing such a targeted therapeutic in disseminated disease with acceptable toxicity. Data from the phase I trial suggest that the definition of activity in other cancer types, including other non-Hodgkin's lymphomas (NHL), is warranted. Three NHL patients in this study responded, two of whom had follicular lymphomas, with the third having a primary intermediate-grade B-cell NHL that was refractory to chemotherapy and stem cell transplant. This patient has remained in complete remission over 3 years after treatment with DAB(389)IL-2. Patients treated to date have had IL-2R-positive tumors, but this remains a very complex clinical issue. The need for a threshold level of receptor expression, the difficulty in obtaining representative tissue, the lack of an assay that accurately reflects high-affinity receptor, and the potential difficulty of observer variability in evaluating the assays should point us toward examining response rates in cancer patients where IL-2R cannot be detected or is unknown. The potential to target the high-affinity IL-2R supports the development of this agent in transplantation and in autoimmune diseases. Targeting IL-2R-expressing lymphocytes may be an effective strategy for the prevention of graft rejection and to treat or prevent graft-versus-host disease. DAB(389)IL-2 has been examined in clinical trials of psoriasis and rheumatoid arthritis and has shown promising results. The potential utility in other autoimmune disorders is unknown, but diseases such as systemic lupus, scleroderma, and vasculitis also may be effective candidates for such ligand fusion therapy.
Topics: Arthritis, Rheumatoid; Autoimmune Diseases; Clinical Trials as Topic; Diphtheria Toxin; Humans; Immunosuppressive Agents; Immunotoxins; Interleukin-2; Lymphoma, Non-Hodgkin; Lymphoma, T-Cell, Cutaneous; Psoriasis; Recombinant Fusion Proteins; Skin Neoplasms
PubMed: 11707862
DOI: No ID Found -
Clinical Lymphoma Nov 2000Mycosis fungoides (MF), CD4(+) epidermotropic cutaneous T-cell lymphoma (CTCL), often arises as indolent, inflammatory, chronic, persistent patches and plaques.... (Review)
Review
Mycosis fungoides (MF), CD4(+) epidermotropic cutaneous T-cell lymphoma (CTCL), often arises as indolent, inflammatory, chronic, persistent patches and plaques. Conservative and sequential topical therapy patients have the same survival as patients treated with aggressive chemotherapy. Hence, until curative therapy is found, therapies that keep MF in check and prevent progression to more advanced lymphoma may be desirable alternatives and may preserve quality of life. Stage IA patients with stable disease have a very favorable prognosis and often initially receive psoriasis-type therapy. Bexarotene gel, a new topical retinoid X receptor retinoid will resolve MF lesions, reducing dermal T-cell infiltrates when used as a single agent. However, it may be even more effective when combined with topical steroids, with phototherapy (ultraviolet B and psoralen-ultraviolet A), or even with oral bexarotene. The gel may also provide a safe adjunctive therapy for individual lesions that are refractory to other agents, including keratodermas. When more than 10% of the body is involved with CTCL or when adenopathy is present (> stage IB), systemic therapy is indicated. Bexarotene capsules have the advantage of easy oral administration and are extremely effective both for early-stage patients with long-standing extensive plaques and for late-stage patients with Sézary syndrome or large-cell transformation. Monitoring of white blood cell count, lipids, and thyroid function is required. Bexarotene should be tested in combination with interferon-alfa or other therapies such as photopheresis, psoralen-ultraviolet A, and methotrexate and for maintenance after total body skin electron beam. DAB(389)IL-2 is targeted to CD25(+), the interleukin-2 receptor on activated T cells as measured by the expression of CD25. DAB(389)IL-2 has given complete or partial remission in 30% of highly refractory patients with extensive plaques and disfiguring tumors. Because it is effective in killing T cells that surround dermal vessels, cytokine release may occur and result in capillary leak syndrome. Hence, it will be reserved for more advanced and refractory patients and will require intravenous administration and monitoring. The use of oral bexarotene first to reduce dermal infiltrates prior to DAB(389)IL-2 administration might reduce subsequent side effects imparted by this therapy. With three new highly effective agents in the armamentarium for the treatment of CTCL, new combination treatment algorithms can be tested to achieve maximal benefit and quality of life for these patients.
Topics: Algorithms; Anticarcinogenic Agents; Bexarotene; Diphtheria Toxin; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Immunotoxins; Interleukin-2; Lymphoma, T-Cell, Cutaneous; Recombinant Fusion Proteins; Skin Neoplasms; Tetrahydronaphthalenes
PubMed: 11707865
DOI: 10.3816/clm.2000.s.010 -
Journal of Pharmacological and... 2023Denileukin Diftitox (DD), comprising fragments of diphtheria toxin (DT) and interleukin-2 (IL2), was developed for the treatment of lymphoma and has been approved for...
Denileukin Diftitox (DD), comprising fragments of diphtheria toxin (DT) and interleukin-2 (IL2), was developed for the treatment of lymphoma and has been approved for marketing in Japan. Toxicological evaluation including pharmacokinetics and immunogenicity in preclinical animals is important for drug development and thus the assays of DD and anti-drug antibody (ADA) were developed by electrochemiluminescence (ECL) detection. For the DD assay, ruthenium-labeled anti-DT Ab and biotinylated anti-IL2 Ab were mixed with serum samples and the mixture was captured by streptavidin-coated wells for ECL detection. For the ADA assay, signals of immuno-complex of biotinylated DD, ruthenium-labeled DD, and ADA, bound to streptavidin plate were determined. DD was quantifiable from 10 ng/mL. Accuracy and precision of quality control samples were within ±20% and 20%, respectively, and stability of DD in rat serum was successfully assessed. Precision of positive control samples of ADA was within the acceptance criteria and cut point values for ADA detection in the screening and confirmatory assay were determined by statistical analysis. Drug-induced ADA was detected by screening assay followed by confirmatory assay. The developed method was successfully applied to assess pharmacokinetics and immunogenicity to support toxicity studies in rats.
Topics: Rats; Animals; Streptavidin; Ruthenium; Antibodies; Diphtheria Toxin
PubMed: 36526166
DOI: 10.1016/j.vascn.2022.107239