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Clinical Lymphoma & Myeloma Nov 2006Denileukin diftitox, a fusion protein consisting of peptide sequences for the enzymatically active and membrane translocation domains of diphtheria toxin and human... (Clinical Trial)
Clinical Trial
BACKGROUND
Denileukin diftitox, a fusion protein consisting of peptide sequences for the enzymatically active and membrane translocation domains of diphtheria toxin and human interleukin, resulted in a response rate of 30% in the phase III registration trial in patients with recurrent or persistent cutaneous T-cell lymphoma (CTCL). Little is known with regard to the biologic correlates of response or the impact of denileukin diftitox on disease progression and survival.
PATIENTS AND METHODS
In our single-center series of 37 patients with early- and advanced-stage disease with CTCL treated with denileukin diftitox at a dose of 9 microg/kg or 18 microg/kg per day, we observed an overall response rate of 51%.
RESULTS
In 8 patients with early-stage (< IIA) CTCL, there were 5 responses (62.5%), and the median survival has not been reached, with 70% of patients still alive at 46 months. In 29 patients with advanced-stage (>/= IIB) disease, there were 14 responses (49.3%), and the median survival was 31 months. Changes in the number of CD4+ CD25+ T-cell populations were observed in 7 of 19 responders, with no overall changes in the absolute lymphocyte counts during the course of therapy. Decrease in lactate dehydrogenase was strongly correlated with clinical response (P < 0.05).
CONCLUSION
Denilekin diftitox was a well-tolerated treatment in early- and advanced-stage CTCL and was not associated with detrimental immunologic efects on lymphocyte populations.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; CD4-Positive T-Lymphocytes; Clinical Trials as Topic; Diphtheria Toxin; Female; Humans; Interleukin-2; Interleukin-2 Receptor alpha Subunit; Lymphoma, T-Cell, Cutaneous; Male; Middle Aged; Mycosis Fungoides; Receptors, Interleukin-2; Recombinant Fusion Proteins; Skin Neoplasms; Treatment Outcome
PubMed: 17229335
DOI: 10.3816/CLM.2006.n.059 -
Methods and Findings in Experimental... Jun 2002Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from... (Review)
Review
Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies knowledge area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: Abacavir sulfate, abarelix, abciximab, alicaforsen sodium, almotriptan, alteplase, amlodipine, amoxicillin trihydrate, amprenavir, argatroban monohydrate, aspirin, atorvastatin calcium, azathioprine; Baclofen, benidipine hydrochloride, benserazide, BMS-214662, bosentan, botulinum toxin type B; Candesartan cilexetil, carbamazepine, carbidopa, carboplatin, ceftriaxone sodium, celecoxib, cetirizine hydrochloride, clarithromycin, clavulanate potassium, clopidogrel hydrogensulfate, clozapine, CPI-1189, cyclophosphamide, cytarabine; Darbepoetin alfa, denileukin diftitox, dexamethasone, dipyridamole, droperidol, DW-166HC; Ebastine, efalizumab, efavirenz, eletriptan, enalapril maleate, enfuvirtide, enoxaparin sodium, enrasentan, entacapone, epoetin, eprosartan mesilate, etanercept, etoricoxib; Fenofibratefexofenadine hydrochloride, filgrastim, fludarabine phosphate, fluoxetine hydrochloride fluvoxamine maleate, frovatriptan, furosemide; Gabapentin, galantamine hydrobromide, gatifloxacin, gefitinib, ghrelin (human), glatiramer acetate; Haloperidol; Ibuprofen, ibuprofen, guaiacol ester, idarubicin hydrochloride, imipramine hydrochloride, imiquimod, interferon beta, interferon beta-1a, interferon beta-1b, interferon omega, irbesartan, itraconazole; Ketorolac, ketorolac tromethamine; Lamifiban, lamotrigine, lanoteplase, lansoprazole, leflunomide, leuprorelin acetate, levetiracetam, levocetirizine, levodopa, lisinopril, loratadine; Manidipine, methylprednisolone, metronidazole, mirtazapine, mizolastine, modafinil, morphine sulfate; Naproxen sodium, naratriptan hydrochloride, nifedipine, NSC-683864; Ofloxacin, olanzapine, omalizumab, omapatrilat, ondansetron hydrochloride, oxcarbazepine; Paclitaxel, parecoxib sodium, paroxetine hydrochloride, phenytoin sodium, pimecrolimus, pramipexole hydrochloride, pravastatin, prednisone, pregabalin; Quetiapine fumarate; Ranitidine hydrochloride, rasburicase, ritonavir, rivastigmine tartrate, rizatriptan benzoate, rofecoxib; Saquinavir mesilate, sertraline, sildenafil citrate, simvastatin, sumatriptan succinate; Tacrolimus, tiagabine hydrochloride, ticlopidine hydrochloride, tirofiban hydrochloride, tolvaptan, topiramate, tretinoin; Valproic acid, valsartan, venlafaxine hydrochloride, verapamil; Warfarin sodium; Ximelagatran; Zanamivir, ziconotide, zolmitriptan, zonisamide.
Topics: Drug Therapy; Humans; Randomized Controlled Trials as Topic
PubMed: 12168506
DOI: No ID Found -
Oncology (Williston Park, N.Y.) Oct 2003Mycosis fungoides is a low-grade lymphoproliferative disorder of skin-homing CD4+ lymphocytes that may produce patches, plaques, tumors, erythroderma, and, ultimately,... (Review)
Review
Mycosis fungoides is a low-grade lymphoproliferative disorder of skin-homing CD4+ lymphocytes that may produce patches, plaques, tumors, erythroderma, and, ultimately, systemic dissemination. Treatment selection is generally guided by institutional experience, patient preference, and toxicity profile, as data from phase III clinical trials are limited. Effective topical treatments currently include mechlorethamine (Mustargen), carmustine (BCNU, BiCNU), corticosteroids, bexarotene (Targretin, a novel rexinoid), psoralen plus ultraviolet A, ultraviolet B, and total-skin electron-beam radiotherapy. Effective systemic treatments include interferon, retinoids, bexarotene, denileukin diftitox (Ontak), extracorporeal photopheresis, chemotherapy, and high-dose chemotherapy with allogeneic bone marrow transplant. Each of these treatments is discussed in detail, followed by specific recommendations for each stage of mycosis fungoides.
Topics: Administration, Topical; Adrenal Cortex Hormones; Antineoplastic Agents; Bone Marrow Transplantation; Clinical Trials as Topic; Humans; Mycosis Fungoides; Phototherapy
PubMed: 14606365
DOI: No ID Found -
Clinical Lymphoma & Myeloma Jul 2007Human T-lymphotrophic virus-1-associated adult T-cell leukemia/lymphoma (ATLL) is a rare and often fatal disease. Initial treatment often includes zidovudine/interferon...
Human T-lymphotrophic virus-1-associated adult T-cell leukemia/lymphoma (ATLL) is a rare and often fatal disease. Initial treatment often includes zidovudine/interferon (IFN)-based therapy, although disease remission is typically not complete or durable. This study reports on a 55-year-old man with relapsed/refractory leukemic-phase ATLL including significant central nervous system (CNS) disease with resistance to previous zidovudine/IFN and arsenic trioxide/IFN treatment. The patient experienced a rapid hematologic and CNS clinical response with single-agent denileukin diftitox therapy (18 microg/kg per day for 5 days). He tolerated 8 cycles of denileukin diftitox therapy well and experienced a sustained complete hematologic and CNS remission. The patient subsequently underwent matched sibling reduced-intensity allogeneic transplantation and remains disease free. Further study examining denileukin diftitox in patients with relapsed/refractory ATLL is warranted.
Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Bone Marrow Transplantation; Central Nervous System Neoplasms; Diphtheria Toxin; Drug Resistance, Neoplasm; Hematologic Neoplasms; Humans; Interferons; Interleukin-2; Leukemia-Lymphoma, Adult T-Cell; Male; Middle Aged; Oxides; Recombinant Fusion Proteins; Recurrence; Remission Induction; Transplantation, Homologous; Zidovudine
PubMed: 17875237
DOI: 10.3816/clm.2007.n.030 -
Cancer Treatment Reviews Oct 2014Peripheral T-cell lymphoma (PTCL) represents a relatively rare group of heterogeneous non-Hodgkin lymphomas with a very poor prognosis. Current therapies, based on... (Review)
Review
Peripheral T-cell lymphoma (PTCL) represents a relatively rare group of heterogeneous non-Hodgkin lymphomas with a very poor prognosis. Current therapies, based on historical regimens for aggressive B-cell lymphomas, have resulted in insufficient patient outcomes. The majority of patients relapse rapidly, and current 5-year overall survival rates are only 10-30%. It is evident that new approaches to treat patients with PTCL are required. In recent years, prospective studies in PTCL have been initiated, mainly in patients with relapsed/refractory disease. In some of these, selected histologic subtypes have been evaluated in detail. As a consequence, numerous new therapies have been developed and shown activity in PTCL, including: agents targeting the immune system (e.g. brentuximab vedotin, alemtuzumab, lenalidomide); histone deacetylase inhibitors (romidepsin, belinostat); antifolates (pralatrexate); fusion proteins (denileukin diftitox); nucleoside analogs (pentostatin, gemcitabine); and other agents (e.g. alisertib, plitidepsin, bendamustine, bortezomib). A variety of interesting novel combinations is also emerging. It is hoped that these innovative approaches, coupled with a greater understanding of the clinicopathologic features, pathogenesis, molecular biology, and natural history of PTCL will advance the field and improve outcomes in this challenging group of diseases. This review summarizes the currently available clinical evidence on the various approaches to treating relapsed/refractory PTCL, including the role of stem cell transplantation, with an emphasis on potential new drug therapies.
Topics: Alemtuzumab; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brentuximab Vedotin; Cyclophosphamide; Depsipeptides; Diphtheria Toxin; Doxorubicin; Folic Acid Antagonists; Histone Deacetylase Inhibitors; Humans; Immunoconjugates; Interleukin-2; Lenalidomide; Lymphoma, T-Cell, Peripheral; Neoplasm Recurrence, Local; Peptides, Cyclic; Prednisolone; Recombinant Fusion Proteins; Stem Cell Transplantation; Thalidomide; Topoisomerase Inhibitors; Vincristine
PubMed: 25199959
DOI: 10.1016/j.ctrv.2014.08.001 -
Journal For Immunotherapy of Cancer 2013An effective anti-tumor immune response requires the coordinated action of the innate and adaptive phases of the immune system. Critical processes include the activation... (Review)
Review
An effective anti-tumor immune response requires the coordinated action of the innate and adaptive phases of the immune system. Critical processes include the activation of dendritic cells to present antigens, produce cytokines including type I interferons, and express multiple costimulatory ligands; induction of a productive T cell response within lymph nodes; migration of activated T cells to the tumor microenvironment in response to chemokines and homing receptor expression; and having effector T cells gain access to antigen-expressing tumor cells and maintain sufficient functionality to destroy them. However, tumors can become adept at escaping the immune response, developing multiple mechanisms to disrupt key processes. In general, tumors can be assigned into two different, major groups depending on whether the tumor there is an 'inflamed' or 'non-inflamed' tumor microenvironment. Improvements in our understanding of the interactions between the immune system and cancer have resulted in the development of various strategies to improve the immune-mediated control of tumors in both sub-groups. Categories of major immunotherapeutic intervention include methods to increase the frequency of tumor antigen-specific effector T cells in the circulation, strategies to block or uncouple a range of immune suppressive mechanisms within the tumor microenvironment, and tactics to induce de novo immune inflammation within the tumor microenvironment. The latter may be particularly important for eliciting immune recognition of non-inflamed tumor phenotypes. The premise put forth in this review is that synergistic therapeutic effects in vivo may be derived from combination therapies taken from distinct "bins" based on these mechanisms of action. Early data in both preclinical and some clinical studies provide support for this model. We also suggest that optimal application of these combinations may be aided by appropriate patient selection based on predictive biomarkers.
PubMed: 24829752
DOI: 10.1186/2051-1426-1-16 -
Current Pharmaceutical Design 2009Recombinant immunotoxins are proteins composed of fragments of monoclonal antibodies fused to truncated protein toxins. No agents of this class are approved yet for... (Review)
Review
Recombinant immunotoxins are proteins composed of fragments of monoclonal antibodies fused to truncated protein toxins. No agents of this class are approved yet for medical use, although a related molecule, denileukin diftitox, composed of interleukin-2 fused to truncated diphtheria toxin, is approved for relapsed/refractory cutaneous T-cell lymphoma. Recombinant immunotoxins which have been tested in patients with chemotherapy-pretreated hematologic malignancies include LMB-2 (anti-CD25), BL22 (CAT-3888, anti-CD22) and HA22 (CAT-8015, anti-CD22), each containing an Fv fragment fused to truncated Pseudomonas exotoxin. Major responses were observed with LMB-2 in adult T-cell leukemia, chronic lymphocytic leukemia (CLL), cutaneous T-cell lymphoma, Hodgkin's disease, and hairy cell leukemia (HCL). BL22 resulted in a high complete remission rate in patients with HCL, particularly those without excessive tumor burden. HA22, an improved version of BL22 with higher affinity to CD22, is now undergoing phase I testing in HCL, CLL, non-Hodgkin's lymphoma, and pediatric acute lymphoblastic leukemia.
Topics: Clinical Trials as Topic; Diphtheria Toxin; Drug Discovery; Drug Resistance, Neoplasm; Hematologic Neoplasms; Humans; Immunotoxins; Leukocidins; Models, Biological; Recombinant Proteins; Toxins, Biological
PubMed: 19689336
DOI: 10.2174/138161209788923949 -
Frontiers in Immunology 2023Regulatory T cell (Treg)-targeting cancer immunotherapy aims to transiently deplete Treg cells in the tumor microenvironment, without affecting effector T cells (Teff),...
INTRODUCTION
Regulatory T cell (Treg)-targeting cancer immunotherapy aims to transiently deplete Treg cells in the tumor microenvironment, without affecting effector T cells (Teff), thus both enhancing anti-tumor activity and avoiding autoimmunity. This study evaluated whether adding E7777 (a new formulation of denileukin diftitox [DD]) improved the efficacy of anti-PD-1 antibody therapy. DD is a recombinant protein containing the hydrophobic and catalytic portions of diphtheria toxin fused to full-length human IL-2. E7777 has the same amino acid sequence and brief circulatory half-life as DD, but with greater purity and potency.
METHODS
Subcutaneous syngeneic murine solid tumor models (colon cancer CT-26 and liver cancer H22) were used to evaluate safety, efficacy, and overall survival with E7777 and anti-PD-1 antibodies, each administered as monotherapy or in concurrent or sequential combination. In Experiment 1, treatments were compared to assess anti-tumor activity at various time points, with tumors excised and dissociated and tumor leukocytes characterized. In Experiment 2, tumor growth, response, and overall survival were characterized for 100 days following a 3-week treatment.
RESULTS
E7777 administered in combination with anti-PD-1 led to significantly increased anti-tumor activity and durable, extended overall survival compared to either treatment alone. In both tumor models, the Treg cell infiltration induced by anti-PD-1 treatment was counterbalanced by co-treatment with E7777, suggesting potential synergistic activity. Combination therapy showed the most favorable results. Treatment with E7777 was safe and well-tolerated.
DISCUSSION
Combined E7777 and anti-PD-1 therapy was well tolerated and more effective than monotherapy with either drug.
Topics: Mice; Humans; Animals; T-Lymphocytes, Regulatory; Immunotoxins; CD8-Positive T-Lymphocytes; Diphtheria Toxin; Colonic Neoplasms; Tumor Microenvironment
PubMed: 38022532
DOI: 10.3389/fimmu.2023.1268979 -
Blood Aug 2002Rexinoids binding to both the retinoic acid receptor (RAR) and retinoid X receptor (RXR) families of rexinoid receptors have demonstrated clinical activity in...
Rexinoids binding to both the retinoic acid receptor (RAR) and retinoid X receptor (RXR) families of rexinoid receptors have demonstrated clinical activity in hematologic malignancies and have been shown to mediate genes associated with both growth and differentiation. RXR rexinoids have demonstrated efficacy in the treatment of cutaneous T-cell lymphomas, but the mechanism of action is unclear. We explored the immunomodulatory effects of RAR and RXR rexinoids in human T- and B-cell leukemia cells and demonstrated that RXR rexinoids are capable of up-regulating high-affinity interleukin-2 receptor (IL-2R) expression. Exposure to 10(-6) to 10(-10) M bexarotene or Panretin for 48 hours was associated with increased expression of both the p55 and p75 subunits of the IL-2R in T-cell leukemias and p75 in B-cell leukemias. Furthermore, rexinoid exposure enhanced susceptibility of the cells to denileukin diftitox fusion toxin-targeting and -intoxicating cells expressing high-affinity IL-2R. These results suggest a rationale for combining rexinoids with IL-2R-targeted therapies in lymphoid malignancies as well as possibly in autoimmune diseases.
Topics: Adjuvants, Immunologic; Alitretinoin; Antineoplastic Agents; B-Lymphocytes; Bexarotene; Diphtheria Toxin; Gene Expression Regulation; Humans; Interleukin-2; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia-Lymphoma, Adult T-Cell; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Receptors, Interleukin-2; Receptors, Retinoic Acid; Recombinant Fusion Proteins; Retinoid X Receptors; Retinoids; T-Lymphocytes; Tetrahydronaphthalenes; Transcription Factors; Tretinoin; Tumor Cells, Cultured
PubMed: 12149223
DOI: 10.1182/blood-2002-01-0300 -
Clinical Lymphoma & Myeloma Feb 2008Cutaneous gamma/delta T-cell lymphoma (CGD-TCL) is a rare and usually fatal lymphoma that is generally resistant to chemotherapy and radiation. It has recently been...
Cutaneous gamma/delta T-cell lymphoma (CGD-TCL) is a rare and usually fatal lymphoma that is generally resistant to chemotherapy and radiation. It has recently been included as a provisional entity in the combined 2005 World Health Organization-European Organization for Research and Treatment of Cancer consensus classification. Subcutaneous panniculitic T-cell lymphomas with a gamma/delta T-cell receptor phenotype are now distinguished from the less aggressive alpha/beta panniculitic T-cell lymphoma. We describe a patient with deep ulcers initially diagnosed as pyoderma gangrenosum, which was reclassified as CGD-TCL. Local radiation followed by weekly infusions of denileukin diftitox put the patient into remission.
Topics: Antineoplastic Agents; Combined Modality Therapy; Diphtheria Toxin; Hepatitis C; Humans; Interleukin-2; Interleukin-2 Receptor alpha Subunit; Lymphoma, T-Cell, Cutaneous; Male; Middle Aged; Receptors, Antigen, T-Cell, gamma-delta; Recombinant Fusion Proteins; Skin Neoplasms
PubMed: 18501089
DOI: 10.3816/clm.2008.n.005