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The Journal of Investigative Dermatology Mar 2006Denileukin diftitox (Ontak), a recombinant fusion protein of diphtheria toxin and ligand, IL-2, binds to the IL-2 receptor, is internalized, and causes cell death....
Denileukin diftitox (Ontak), a recombinant fusion protein of diphtheria toxin and ligand, IL-2, binds to the IL-2 receptor, is internalized, and causes cell death. Denileukin diftitox was approved for the treatment of cutaneous T-cell lymphomas (CTCLs) with CD25+ expression. We prospectively stained lesional skin biopsy specimens from 113 mycosis fungoides and Sézary Syndrome patients for activation markers CD25 and CD30 to correlate expression with clinical tumor-node metastasis (TNM) stage, histologic grade, and response to denileukin diftitox. High expression was defined as positivity of > or =20% of lesional T-cells using immunohistochemistry (IHC). CD25 and CD30 expression was more common in lesions from advanced patients (P = 0.04 and 0.002, respectively). Advanced TNM (T3 or T4) was significantly associated with intermediate-grade (P = 0.002) and large-cell transformation histology (P = 0.04). Of interest, clinical responses were observed in 78.5% of patients with high CD25 expression versus 20% with low to undetectable CD25 expression (P = 0.01) among 24 patients receiving standard 5-day infusions of denileukin diftitox at 18 microg/kg/day. These data suggest that high CD25 expression by IHC is associated with advanced CTCL and with clinical response to denileukin diftitox therapy.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Bexarotene; Diphtheria Toxin; Female; Humans; Interleukin-2; Ki-1 Antigen; L-Lactate Dehydrogenase; Lymphoma, T-Cell, Cutaneous; Male; Middle Aged; Receptors, Interleukin-2; Recombinant Fusion Proteins; Skin; Skin Neoplasms; Tetrahydronaphthalenes
PubMed: 16410787
DOI: 10.1038/sj.jid.5700122 -
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 -
Blood Aug 2004Denileukin diftitox (Ontak), a recombinant protein composed of human interleukin 2 (IL-2) fused to diphtheria toxin, has selective cytotoxicity against activated... (Clinical Trial)
Clinical Trial
Denileukin diftitox (Ontak), a recombinant protein composed of human interleukin 2 (IL-2) fused to diphtheria toxin, has selective cytotoxicity against activated lymphocytes expressing the high-affinity IL-2 receptor. We conducted a phase 1 study of denileukin diftitox in 30 patients with steroid refractory acute graft-versus-host disease (GVHD). Seven patients received 9 microg/kg intravenously on days 1 and 15; 18 received 9 microg/kg intravenously on days 1, 3, 5, 15, 17, and 19; and 5 received 9 microg/kg intravenously on days 1 to 5 and 15 to 19. Hepatic transaminase elevation was the dose-limiting toxicity (DLT), and dose level 2 was the maximum tolerated dose (MTD). Overall, 71% of patients responded with complete resolution (12 of 24; 50%) or partial resolution (5 of 24; 21%) of GVHD. Eight of 24 patients (33%) are alive at 6.3 to 24.6 months (median, 7.2 months). Denileukin diftitox is tolerable and has promising activity in steroid-refractory acute GVHD.
Topics: Acute Disease; Adult; Aged; Diphtheria Toxin; Dose-Response Relationship, Drug; Drug Resistance; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Interleukin-2; Lymphocyte Activation; Lymphocyte Depletion; Male; Middle Aged; Recombinant Fusion Proteins; Salvage Therapy; Steroids; T-Lymphocytes; Transplantation, Homologous; Treatment Outcome
PubMed: 15113758
DOI: 10.1182/blood-2004-01-0028 -
The Journal of Infectious Diseases Jun 2017Host-directed therapies that augment host immune effector mechanisms may serve as important adjunctive therapies for tuberculosis treatment. We evaluated the activity of...
Host-directed therapies that augment host immune effector mechanisms may serve as important adjunctive therapies for tuberculosis treatment. We evaluated the activity of denileukin diftitox in an acute mouse model of tuberculosis (TB) infection and analyzed the cellular composition and bacterial burden in lungs and spleens. These in vivo studies show that denileukin diftitox potentiates standard TB treatment in the mouse model, an effect which may be due to depletion of T-regulatory and myeloid-derived suppressor cells during TB infection. Our results indicate that denileukin diftitox and other suppressor cell-depleting therapies may be useful adjunctive, host-directed therapies for TB.
Topics: Animals; Diphtheria Toxin; Disease Models, Animal; Humans; Immunotherapy; Interleukin-2; Lung; Mice; Mice, Inbred C57BL; Mycobacterium tuberculosis; Myeloid-Derived Suppressor Cells; Recombinant Fusion Proteins; Recombinant Proteins; Spleen; T-Lymphocytes, Regulatory; Tuberculosis
PubMed: 28863467
DOI: 10.1093/infdis/jix208 -
Case Reports in Dermatology Jan 2011Advanced-stage primary cutaneous T-cell lymphoma has an unfavorable prognosis and low survival rates. Aggressive treatment with chemotherapy is not curative and causes...
Advanced-stage primary cutaneous T-cell lymphoma has an unfavorable prognosis and low survival rates. Aggressive treatment with chemotherapy is not curative and causes considerable side effects. The combination of bexarotene and denileukin diftitox is associated with an acceptable safety profile and a likely synergistic effect because bexarotene is capable of modulating expression of IL-2 receptor and enhance the susceptibility of T-cell leukemia cells to denileukin diftitox. In the case reported here, the response to this combined treatment was satisfactory and well tolerated. The patient showed a complete regression of pruritus, restlessness, and insomnia. Skin lesions improved partially, and lymphadenopathy was reduced and finally disappeared completely.
PubMed: 21931572
DOI: 10.1159/000324185 -
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 -
Immunotherapy Sep 2019T regulatory cells (Tregs) are an important T cell population for immune tolerance, prevention of autoimmune diseases and inhibition of antitumor immunity. The... (Review)
Review
T regulatory cells (Tregs) are an important T cell population for immune tolerance, prevention of autoimmune diseases and inhibition of antitumor immunity. The tumor-promoting role played by Tregs in cancer has prompted numerous approaches to develop immunotherapeutics targeting Tregs. One approach to depletion of Treg cells is retargeting the highly potent cytotoxic activity of bacterial toxins. These agents capitalize on the well-characterized bacterial toxins, diphtheria toxin and exotoxin A-both of which harbor membrane translocation domains and enzymatic domains that catalytically halt protein synthesis within intoxicated eukaryotic cells and act at picomolar or subpicomolar concentrations. In this review, we summarize the preclinical and clinical development of several Treg-depleting cancer immunotherapies based on these two bacterial toxins.
Topics: ADP Ribose Transferases; Animals; Bacterial Toxins; Clinical Trials as Topic; Diphtheria Toxin; Drug Evaluation, Preclinical; Exotoxins; Humans; Immunity, Cellular; Immunotherapy; Lymphocyte Depletion; Neoplasms; T-Lymphocytes, Regulatory; Tumor Microenvironment; Virulence Factors; Pseudomonas aeruginosa Exotoxin A
PubMed: 31361167
DOI: 10.2217/imt-2019-0060 -
FEBS Open Bio Jul 2023Cutaneous T-cell lymphoma (CTCL) encompasses two main subtypes: mycosis fungoides and Sezary syndrome. Global response rates for the systemic treatment of mycosis...
Cutaneous T-cell lymphoma (CTCL) encompasses two main subtypes: mycosis fungoides and Sezary syndrome. Global response rates for the systemic treatment of mycosis fungoides and Sezary syndrome are approximately 30%, and none of these treatments are thought to be curative. C-C chemokine receptor type 4 (CCR4) and CD25 are encouraging targets for the treatment of CTCL and are individually targeted by mogamulizumab and denileukin diftitox, respectively. We developed a novel CCR4-IL2 bispecific immunotoxin (CCR4-IL2 IT) targeting both CCR4 and CD25. CCR4-IL2 IT demonstrated superior efficacy against CCR4 CD25 CD30 CTCL in an immunodeficient NSG mouse tumor model. Investigative New Drug-enabling studies of CCR4-IL2 IT are ongoing, including Good Manufacturing Practice production and toxicology studies. In this study, we compared the in vivo efficacy of CCR4-IL2 IT versus the US Food and Drug Administration-approved drug, brentuximab, using an immunodeficient mouse CTCL model. We demonstrated that CCR4-IL2 IT was significantly more effective in prolonging survival than brentuximab, and combination treatment of CCR4-IL2 IT and brentuximab was more effective than brentuximab or CCR4-IL2 IT alone in an immunodeficient NSG mouse CTCL model. Thus, CCR4-IL2 IT is a promising novel therapeutic drug candidate for CTCL treatment.
Topics: United States; Animals; Mice; Immunotoxins; Sezary Syndrome; Interleukin-2; Skin Neoplasms; Lymphoma, T-Cell, Cutaneous; Antineoplastic Agents; Mycosis Fungoides; Antibodies, Monoclonal
PubMed: 37157185
DOI: 10.1002/2211-5463.13625 -
British Journal of Haematology Feb 2007This phase II study evaluated the safety and efficacy of denileukin diftitox, an interleukin-2-diphtheria toxin fusion protein, in relapsed/refractory T-cell non-Hodgkin...
This phase II study evaluated the safety and efficacy of denileukin diftitox, an interleukin-2-diphtheria toxin fusion protein, in relapsed/refractory T-cell non-Hodgkin lymphoma (T-NHL), excluding cutaneous T-cell lymphoma. Eligible patients received denileukin diftitox 18 microg/kg/d x 5 d every 3 weeks for up to eight cycles. Tumour staging was performed every two cycles and the primary endpoint was the objective response rate [complete response (CR) + partial response (PR)]. For 27 patients enrolled, median age: 55 years (range 26-80 years), 70.4% male, and mean prior therapies: 2.5 (range 1-6). Objective responses (six CRs, seven PRs) were achieved in 13 patients (48.1%), stable disease in eight (29.6%) and six (22.2%) had progressive disease. An objective response was achieved in eight of 13 patients (61.5%) with CD25(+) tumours (four CR/four PR) and five of 11 patients (45.5%) with CD25(-) tumours (two CR/three PR). Median progression-free survival was 6 months (range, 1-38+ months). Most adverse reactions were grade 1/2 and transient. No grade 4-5 toxicities were reported. Denileukin diftitox had significant activity and was well tolerated in relapsed/refractory T-NHL, with responses observed in both CD25(+) and CD25(-) tumours. Further studies of denileukin diftitox in combination with other agents are warranted in previously untreated and relapsed/refractory T-NHL.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Diphtheria Toxin; Disease-Free Survival; Drug Administration Schedule; Drug Resistance, Neoplasm; Fatigue; Female; Humans; Interleukin-2; Interleukin-2 Receptor alpha Subunit; Lymphoma, T-Cell; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Recombinant Fusion Proteins; Transaminases; Treatment Outcome
PubMed: 17233846
DOI: 10.1111/j.1365-2141.2006.06457.x -
CEN Case Reports Feb 2023Systemic capillary leak syndrome is a rare and life-threatening disorder, characterized by recurrent episodes of unexplained hypotension, hemoconcentration, and...
Systemic capillary leak syndrome is a rare and life-threatening disorder, characterized by recurrent episodes of unexplained hypotension, hemoconcentration, and hypoalbuminemia. This condition is caused by leakage of plasma and proteins into the extravascular space and can be classified as either idiopathic or secondary. Secondary systemic capillary leak syndrome can result from cancer, infections, medications, or surgery. Systemic capillary leak syndrome frequently develops as a side effect of denileukin diftitox treatment of refractory cutaneous T-cell lymphoma. However, the pathophysiology of this disease is not well understood. Herein, we report a case of denileukin diftitox-induced systemic capillary leak syndrome.
Topics: Humans; Capillary Leak Syndrome; Interleukin-2; Skin Neoplasms; Acute Kidney Injury
PubMed: 35870043
DOI: 10.1007/s13730-022-00720-3