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Case Reports in Oncology 2022Primary cutaneous anaplastic large cell lymphoma (PCALCL) is a rare variant of cutaneous T cell lymphoma (CTCL) characterized by CD30-expressing large atypical cells...
Primary cutaneous anaplastic large cell lymphoma (PCALCL) is a rare variant of cutaneous T cell lymphoma (CTCL) characterized by CD30-expressing large atypical cells with kidney-shaped nuclei called hallmark cells. Since PCALCL is a rare variant of CTCL, the treatment of PCALCL is still controversial. In this report, a case of PCALCL successfully treated with denileukin diftitox as second-line therapy is described. Interestingly, the administration of denileukin diftitox decreased CD8+ T cells, CD25+ cells, granulysin-bearing lymphocytes, and CD163+ macrophages. The present case suggests that denileukin diftitox might induce an anti-lymphoma effect as well as modulate the tumor microenvironment.
PubMed: 36157690
DOI: 10.1159/000526312 -
Cancer Biotherapy & Radiopharmaceuticals Feb 2011Cancer immunotherapy consists of approaches that modify the host immune system, and/or the utilization of components of the immune system, as cancer treatment. During... (Review)
Review
Cancer immunotherapy consists of approaches that modify the host immune system, and/or the utilization of components of the immune system, as cancer treatment. During the past 25 years, 17 immunologic products have received regulatory approval based on anticancer activity as single agents and/or in combination with chemotherapy. These include the nonspecific immune stimulants BCG and levamisole; the cytokines interferon-α and interleukin-2; the monoclonal antibodies rituximab, ofatumumab, alemtuzumab, trastuzumab, bevacizumab, cetuximab, and panitumumab; the radiolabeled antibodies Y-90 ibritumomab tiuxetan and I-131 tositumomab; the immunotoxins denileukin diftitox and gemtuzumab ozogamicin; nonmyeloablative allogeneic transplants with donor lymphocyte infusions; and the anti-prostate cancer cell-based therapy sipuleucel-T. All but two of these products are still regularly used to treat various B- and T-cell malignancies, and numerous solid tumors, including breast, lung, colorectal, prostate, melanoma, kidney, glioblastoma, bladder, and head and neck. Positive randomized trials have recently been reported for idiotype vaccines in lymphoma and a peptide vaccine in melanoma. The anti-CTLA-4 monoclonal antibody ipilumumab, which blocks regulatory T-cells, is expected to receive regulatory approval in the near future, based on a randomized trial in melanoma. As the fourth modality of cancer treatment, biotherapy/immunotherapy is an increasingly important component of the anticancer armamentarium.
Topics: Animals; Antineoplastic Agents; Humans; Immunotherapy; Neoplasms
PubMed: 21355777
DOI: 10.1089/cbr.2010.0902 -
Biologics : Targets & Therapy Dec 2008Cutaneous T-cell lymphoma/mycosis fungoides (CTCL/MF) is a rare lymphoproliferative disorder which can present as an indolent or as an aggressive process involving skin,...
Cutaneous T-cell lymphoma/mycosis fungoides (CTCL/MF) is a rare lymphoproliferative disorder which can present as an indolent or as an aggressive process involving skin, lymph nodes, and blood. In stages IA, IB and IIA, it is usually managed with topical medications and phototherapy. If there is progression despite application of these treatments, or if the patient presents with a higher stage of disease, systemic chemotherapy or retinoids, rexinoids, biologic response modifiers are often necessary. Consequently, patients are often treated with a sequence of modalities and drugs. Denileukin diftitox (DD, Ontak(R)) is a targeted immunotoxin which has biological activity against malignancies expressing the IL-2 receptor. In addition to its unique mechanism of action, DD has a toxicity profile which does not overlap with most commonly used chemotherapeutic agents. CTCL/MF has been found be particularly susceptible to treatment with this agent. This review will describe the development DD, its proposed mechanism of action, the clinical trials which identified its utility in the treatment of CTCL/MF, the common toxicities encountered with this agent, and the management of these toxicities. In addition the incorporation of DD in the sequential treatment of CTCL/MF and data suggesting potential combination therapies employing this novel agent will be discussed.
PubMed: 19707452
DOI: 10.2147/btt.s3084 -
Clinical Lymphoma Dec 2003We report a case of human T-cell lymphotropic virus 1 (HTLV-1)-associated adult T cell leukemia/lymphoma (ATL) in clinical remission > 1 year after therapy with...
We report a case of human T-cell lymphotropic virus 1 (HTLV-1)-associated adult T cell leukemia/lymphoma (ATL) in clinical remission > 1 year after therapy with denileukin diftitox and hyper-CVAD (hyperfractionated cyclophosphamide/doxorubicin/vincristine/decadron). The patient presented with leukocytosis, anemia, and thrombocytopenia, and bone marrow biopsy demonstrated extensive myelofibrosis and infiltration with leukemic T cells. Initial therapy with 4 cycles of denileukin diftitox resulted in restoration of normal hematopoiesis and a reduction in bone marrow myelofibrosis. After disease progression, 4 cycles of hyper-CVAD were administered and a complete clinical remission was achieved. The patient remains free of disease with normal hematopoiesis and has continued maintenance therapy with denileukin diftitox for 1 year. This case demonstrates clinical improvement of myelofibrosis and acute T-cell leukemia after denileukin diftitox administration, suggesting that denileukin diftitox may affect the paracrine secretion of HTLV-1-associated clinical manifestations of ATL.
Topics: Adult; Antineoplastic Agents; Biopsy; Bone Marrow; Bone Marrow Cells; Diphtheria Toxin; Female; Humans; Interleukin-2; Leukemia-Lymphoma, Adult T-Cell; Recombinant Fusion Proteins; Remission Induction; Time Factors; Treatment Outcome
PubMed: 14715100
DOI: 10.3816/clm.2003.n.027 -
The Journal of Clinical Endocrinology... Jun 2006Denileukin diftitox is a recombinant novel fusion protein of diphtheria toxin and the ligand-binding domain of human IL-2. Denileukin diftitox binds to the high-affinity...
CONTEXT
Denileukin diftitox is a recombinant novel fusion protein of diphtheria toxin and the ligand-binding domain of human IL-2. Denileukin diftitox binds to the high-affinity IL-2 receptor on the cell surface, and it is internalized by endocytosis and enzymatically cleaved. The cytotoxic A-fragment of the toxin inhibits protein synthesis and causes cell death.
OBJECTIVE
The objective of this study was to recognize thyrotoxicosis in association with denileukin diftitox therapy.
DESIGN
This study was a retrospective case series.
SETTING
The setting of this study was a comprehensive cancer center.
PATIENTS
Eight mycosis fungoides patients who were receiving 9 or 18 microg/kg.d iv denileukin diftitox for 5 d every 3 wk were identified with thyrotoxicosis.
INTERVENTION(S)
Thyroid testing was performed. Hypothyroidism after thyrotoxicosis was treated.
RESULTS
In eight mycosis fungoides patients who developed transient thyrotoxicosis during therapy, thyroid function tests were normal before onset of therapy. Clinical thyrotoxicosis developed within days of the first cycle of denileukin diftitox therapy in four patients and after the second cycle in the other four patients. Symptoms included tremors, nervousness, tachycardia, diarrhea, and weight loss. After cessation of denileukin diftitox, thyrotoxicosis resolved in all patients; two became euthyroid, and five became hypothyroid, requiring levothyroxine therapy. One patient was lost to follow-up.
CONCLUSIONS
Monitoring thyroid function before and during treatment with denileukin diftitox is recommended. Symptomatic thyrotoxicosis may be missed due to other acute reactions to the drug, and subsequent hypothyroidism may develop.
Topics: Aged; Antineoplastic Agents; Diphtheria Toxin; Female; Humans; Interleukin-2; Iodide Peroxidase; Male; Middle Aged; Mycosis Fungoides; Recombinant Fusion Proteins; Retrospective Studies; Skin Neoplasms; Thyrotoxicosis
PubMed: 16595600
DOI: 10.1210/jc.2005-2839 -
Clinical Cancer Research : An Official... Jul 2021Immunotherapy treats some cancers, but not ovarian cancer. Regulatory T cells (Tregs) impede anti-ovarian cancer immunity but effective human Treg-directed treatments...
PURPOSE
Immunotherapy treats some cancers, but not ovarian cancer. Regulatory T cells (Tregs) impede anti-ovarian cancer immunity but effective human Treg-directed treatments are lacking. We tested Treg depletion with denileukin diftitox (DD) ± IFNα as ovarian cancer immunotherapy.
PATIENTS AND METHODS
Mice with syngeneic ID8 ovarian cancer challenge were treated with DD, IFNα, or both. The phase 0/I trial tested one dose-escalated DD infusion for functional Treg reduction, safety, and tolerability. The phase II trial added IFNα2a to DD if DD alone failed clinically.
RESULTS
DD depleted Tregs, and improved antitumor immunity and survival in mice. IFNα significantly improved antitumor immunity and survival with DD. IFNα did not alter Treg numbers or function but boosted tumor-specific immunity and reduced tumor Treg function with DD by inducing dendritic cell IL6. DD alone was well tolerated, depleted functional blood Tregs and improved immunity in patients with various malignancies in phase 0/I. A patient with ovarian cancer in phase 0/I experienced partial clinical response prompting a phase II ovarian cancer trial, but DD alone failed phase II. Another phase II trial added pegylated IFNα2a to failed DD, producing immunologic and clinical benefit in two of two patients before a DD shortage halt. DD alone was well tolerated. Adding IFNα increased toxicities but was tolerable, and reduced human Treg numbers in blood, and function through dendritic cell-induced IL6 .
CONCLUSIONS
Treg depletion is clinically useful but unlikely alone to cure ovarian cancer. Rational treatment agent combinations can salvage clinical failure of Treg depletion alone, even when neither single agent provides meaningful clinical benefit.
Topics: Animals; Antineoplastic Agents; Diphtheria Toxin; Drug Therapy, Combination; Female; Humans; Interferon-alpha; Interleukin-2; Lymphocyte Depletion; Mice; Ovarian Neoplasms; Recombinant Fusion Proteins; T-Lymphocytes, Regulatory; Treatment Outcome; Tumor Cells, Cultured
PubMed: 33771857
DOI: 10.1158/1078-0432.CCR-20-4594 -
Leukemia Research Reports 2022Treatment of non-Hodgkin lymphoma (NHL) in general has improved over the years with the emergence of the monoclonal antibodies (MAB) therapy. NHL is divided into B cell...
Treatment of non-Hodgkin lymphoma (NHL) in general has improved over the years with the emergence of the monoclonal antibodies (MAB) therapy. NHL is divided into B cell NHL and T cell NHL. Treatment of NHL was based on the subtype of NHL and its staging. NHL is divided into aggressive and indolent NHL (iNHL). Subtypes of iNHL include: Follicular lymphoma (FL), Marginal zone lymphoma (MZL), Chronic lymphocytic leukemia/small-cell lymphocytic lymphoma (CLL/SLL), Gastric mucosa-associated lymphoid tissue (MALT) lymphoma, Lymphoplasmacytic lymphoma, Waldenström macroglobulinemia, Nodal marginal zone lymphoma (NMZL), Splenic marginal zone lymphoma (SMZL). Chemotherapy was the main stay treatment of iNHL until the emergence of Rituximab, anti-CD20 MAB targeting CD-20 surface cell antigens that are present on B-cells lymphoma and not on precursor cells, mainly efficacious in B cell iNHL, It became the mainstay treatment in follicular lymphoma (FL) as a single agent modality or in combination with chemotherapy. The anti-CD20 Rituximab played an important role in the development of the treatment of iNHL to become FDA approved in 1997. It was also proven effective in multiple other types of lymphoma. MAB through targeting the cell surface antigen leads to a direct or immune mediated cytotoxicity. This carries few side effects, including allergic reactions. Other than that, a resistance mechanism to rituximab emerged by inducing a failure in the apoptosis mechanism. Alternative mechanisms of resistance included the presence of soluble antigens that could act by binding to the antibody present before the drug itself can bind the lymphoma cell. Thus, the interest in immunotherapy grew further to explore the possibility of conjugating an immune mediated drug to a radio-sensitizing agent in order to enhance the selectivity of the drug. Here came the development of 90Y-ibritumomab tiuxetan and 131I-tositumomab. After it, humanized anti-CD20 emerged ofatumumab, IMMU106 (veltuzumab) in 2005, and ocrelizumab which are considered as second generation anti-CD20 and 3 generation anti-CD20 include AME-133v (ocaratuzumab), PRO131921 and GA101 (obinutuzumab). Also multiple other agents emerged targeting different surface cell antigens like CD52 (alemtuzumab), CD22 (unconjugated epratuzumab and calicheamicin conjugated CMC-544 [inotuzumab ozogamicin]), CD80 (galiximab), CD2 (MEDI-507 [siplizumab]), CD30 (SGN-30 and MDX-060 [iratumumab], Brentuximab vedotin), CD40 (SGN-40), and CD79b (Polatuzumab). Other agents include MAB targeting T-Cells like mogamulizumab, Denileukin Diftitox and BiTEs or bispecific T cell engagers like Mosunetuzumab, Glofitamab, and Epcoritamab. Moreover, further studies came up to evaluate the role of immunotherapy in combination chemotherapy as a pathway to evade the resistance mechanisms. Side effects of the treatment were mainly infusion related adverse reactions, myelosuppression in conjugated forms leading to immunosuppression and subsequently to infectious complications. Another important aspect in immunotherapy is the half-lives of the medication which is an important factor that can influence the evaluation of the response. The MAB treatment showed important benefit in the treatment of iNHL and it continuously shows how rapidly it can develop to provide optimum care and benefit to patients with iNHL.
PubMed: 35663281
DOI: 10.1016/j.lrr.2022.100325 -
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 -
The British Journal of Ophthalmology Aug 2006
Topics: Antineoplastic Agents; Diphtheria Toxin; Hematologic Neoplasms; Humans; Interleukin-2; Male; Middle Aged; Recombinant Fusion Proteins; Retinal Diseases; Vision Disorders
PubMed: 16854841
DOI: 10.1136/bjo.2006.091165 -
Nihon Yakurigaku Zasshi. Folia... 2022Denileukin Diftitox (DD) is a recombinant fusion protein of diphtheria toxin (DT) fragments and human interleukin-2 (IL-2). DD binds to IL-2 receptor (IL-2R) expressed...
Denileukin Diftitox (DD) is a recombinant fusion protein of diphtheria toxin (DT) fragments and human interleukin-2 (IL-2). DD binds to IL-2 receptor (IL-2R) expressed on tumor cells and is taken up into the cells. Subsequently, DT fragments with adenosine diphosphate ribosylation enzyme inhibit protein synthesis, then ultimately trigger cell death. DD binds to both high- and intermediate-affinity IL-2Rs via IL-2 domain and inhibits growth of human T-cell lymphomas cell lines. E7777, which contains DD as an active component, has improved purity and an increased percentage of active monomer compared with the approved drug E7272 (ONTAK in the US, not approved in Japan). In the phase I clinical study in Japanese patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL), the maximum tolerated dose and recommended dose of E7777 were 9 μg/kg/day (administered on Days 1-5 of each cycle) based on the evaluation of dose-limiting toxicity. In the phase II clinical study, the objective response rate was 36.1%, showing comparable efficacy to existing therapies. E7777 showed anti-tumor activity observed across the range of CD25 expression. Grade 3 or higher adverse events (AE) occurred in 94.6%, and serious AE such as capillary leak syndrome and rhabdomyolysis were reported. Therefore, safety monitoring activities have been continued along with alerting related events. Based on these results, E7777 obtained a new drug approval in Japan in March 2021 for the indication of relapsed or refractory PTCL/CTCL.
Topics: Antineoplastic Agents; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Diphtheria Toxin; Humans; Interleukin-2; Japan; Lymphoma, T-Cell; Lymphoma, T-Cell, Cutaneous; Receptors, Interleukin-2; Recombinant Fusion Proteins; Recombination, Genetic; Skin Neoplasms
PubMed: 36047157
DOI: 10.1254/fpj.22032