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BMC Cancer Dec 2011We previously found that administration of an interleukin 2/diphtheria toxin conjugate (DAB/IL2; Denileukin Diftitox; ONTAK) to stage IV melanoma patients depleted...
BACKGROUND
We previously found that administration of an interleukin 2/diphtheria toxin conjugate (DAB/IL2; Denileukin Diftitox; ONTAK) to stage IV melanoma patients depleted CD4(+)CD25(HI)Foxp3(+) regulatory T cells and expanded melanoma-specific CD8(+) T cells. The goal of this study was to assess the clinical efficacy of DAB/IL2 in an expanded cohort of stage IV melanoma patients.
METHODS
In a single-center, phase II trial, DAB/IL2 (12 μg/kg; 4 daily doses; 21 day cycles) was administered to 60 unresectable stage IV melanoma patients and response rates were assessed using a combination of 2-[(18)F]-fluoro-2-deoxy-glucose (FDG)-positron emission tomography (PET) and computed tomography (CT) imaging.
RESULTS
After DAB/IL2 administration, 16.7% of the 60 patients had partial responses, 5% stable disease and 15% mixed responses. Importantly, 45.5% of the chemo/immuno-naïve sub-population (11/60 patients) experienced partial responses. One year survival was markedly higher in partial responders (80 ± 11.9%) relative to patients with progressive disease (23.7 ± 6.5%; p value < 0.001) and 40 ± 6.2% of the total DAB/IL2-treated population were alive at 1 year.
CONCLUSIONS
These data support the development of multi-center, randomized trials of DAB/IL2 as a monotherapy and in combination with other immunotherapeutic agents for the treatment of stage IV melanoma.
TRIAL REGISTRATION
NCT00299689.
Topics: Aged; Antineoplastic Agents; Diphtheria Toxin; Female; Humans; Interleukin-2; Kentucky; Male; Melanoma; Middle Aged; Positron-Emission Tomography; Recombinant Fusion Proteins; Skin Neoplasms; Survival Analysis; T-Lymphocytes; Tomography, X-Ray Computed
PubMed: 22165955
DOI: 10.1186/1471-2407-11-515 -
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 -
Journal of the National Cancer Institute Nov 2011Unlike cytotoxic agents that indiscriminately affect rapidly dividing cells, newer antineoplastic agents such as targeted therapies and immunotherapies are associated... (Review)
Review
Unlike cytotoxic agents that indiscriminately affect rapidly dividing cells, newer antineoplastic agents such as targeted therapies and immunotherapies are associated with thyroid dysfunction. These include tyrosine kinase inhibitors, bexarotene, radioiodine-based cancer therapies, denileukin diftitox, alemtuzumab, interferon-α, interleukin-2, ipilimumab, tremelimumab, thalidomide, and lenalidomide. Primary hypothyroidism is the most common side effect, although thyrotoxicosis and effects on thyroid-stimulating hormone secretion and thyroid hormone metabolism have also been described. Most agents cause thyroid dysfunction in 20%-50% of patients, although some have even higher rates. Despite this, physicians may overlook drug-induced thyroid dysfunction because of the complexity of the clinical picture in the cancer patient. Symptoms of hypothyroidism, such as fatigue, weakness, depression, memory loss, cold intolerance, and cardiovascular effects, may be incorrectly attributed to the primary disease or to the antineoplastic agent. Underdiagnosis of thyroid dysfunction can have important consequences for cancer patient management. At a minimum, the symptoms will adversely affect the patient's quality of life. Alternatively, such symptoms can lead to dose reductions of potentially life-saving therapies. Hypothyroidism can also alter the kinetics and clearance of medications, which may lead to undesirable side effects. Thyrotoxicosis can be mistaken for sepsis or a nonendocrinologic drug side effect. In some patients, thyroid disease may indicate a higher likelihood of tumor response to the agent. Both hypothyroidism and thyrotoxicosis are easily diagnosed with inexpensive and specific tests. In many patients, particularly those with hypothyroidism, the treatment is straightforward. We therefore recommend routine testing for thyroid abnormalities in patients receiving these antineoplastic agents.
Topics: Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Anticarcinogenic Agents; Antineoplastic Agents; Bexarotene; Diphtheria Toxin; Humans; Hyperthyroidism; Hypopituitarism; Hypothyroidism; Interferon-alpha; Interleukin-2; Iodine Radioisotopes; Ipilimumab; Lenalidomide; Molecular Targeted Therapy; Neoplasms; Protein-Tyrosine Kinases; Quality of Life; Radioimmunotherapy; Recombinant Fusion Proteins; Recombinant Proteins; Tetrahydronaphthalenes; Thalidomide; Thyroid Function Tests; Thyroid Gland; Thyroid Hormones; Thyroiditis, Autoimmune
PubMed: 22010182
DOI: 10.1093/jnci/djr373 -
Clinical Lymphoma, Myeloma & Leukemia Feb 2012Subcutaneous panniculitis-like T-cell lymphoma (SPTL-AB) and cutaneous gamma/delta T-cell lymphoma (CGD-TCL) are rare T-cell lymphomas with varying clinical courses....
INTRODUCTION
Subcutaneous panniculitis-like T-cell lymphoma (SPTL-AB) and cutaneous gamma/delta T-cell lymphoma (CGD-TCL) are rare T-cell lymphomas with varying clinical courses. There is no standard treatment, although chemotherapy and hematopoietic stem cell transplantation are commonly used. We describe results using bexarotene for children and adults with these disorders.
METHODS
We identified 15 patients (12 adults, 3 children) who were treated with bexarotene between 2000 and 2010 from the Memorial Sloan-Kettering Cancer Center lymphoma database, the Stanford Cancer Center Registry, and the National Cancer Institute (NCI) pediatric lymphoma database. There were 8 females and 7 males, with a median age of 45 years (range, 3 years to 85 years). All patients had stage IV disease. Two of 15 and 4 of 15 patients had documented CGD-TCL and SPTL-AB, respectively; others were presumed to have SPTL-AB. Bexarotene was administered at flat doses corresponding to 91 to 339 mg/m(2)/d. Two of 15 patients received concurrent denileukin diftitox. Two children received bexarotene as maintenance therapy and were not evaluable for response.
RESULTS
Among those treated with bexarotene alone, the overall response rate (ORR) was 82% (6/11 complete response [CR], 3/11 partial response [PR]). One of the 2 patients treated with concomitant denileukin diftitox responded for an ORR of 10/13 (77%), including 54% CR and 23% PR. Median progression-free survival was 38.4 months; median duration of response was 26.3 months. Six patients developed hypothyroidism and 9 developed hyperlipidemia; one patient developed dose-limiting hypertriglyceridemia. One pediatric patient developed insulin-dependent diabetes mellitus.
CONCLUSIONS
In this retrospective series, bexarotene showed a high response rate in SPTL-AB and CGD-TCL. It was generally well-tolerated with durable responses; therefore, bexarotene represents a promising therapy for children and adults with these disorders.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticarcinogenic Agents; Bexarotene; Child; Child, Preschool; Diabetes Mellitus, Type 1; Disease-Free Survival; Female; Humans; Hyperlipidemias; Hypertriglyceridemia; Hypothyroidism; Lymphoma, T-Cell, Cutaneous; Male; Middle Aged; Neoplasm Staging; Panniculitis; Skin Neoplasms; Tetrahydronaphthalenes; Treatment Outcome; Young Adult
PubMed: 22001256
DOI: 10.1016/j.clml.2011.06.016 -
American Journal of Hematology Nov 2011Cutaneous T-cell lymphomas are a heterogenous group of T-cell lymphoproliferative disorders involving the skin, the majority of which may be classified as Mycosis... (Review)
Review
DISEASE OVERVIEW
Cutaneous T-cell lymphomas are a heterogenous group of T-cell lymphoproliferative disorders involving the skin, the majority of which may be classified as Mycosis fungoides (MF) or Sézary syndrome (SS).
DIAGNOSIS
The diagnosis of MF or SS requires the integration of clinical and histopathologic data.
RISK-ADAPTED THERAPY
Tumor, node, metastasis, and blood (TNMB) staging remains the most important prognostic factor in MF/SS and forms the basis for a "risk-adapted," multidisciplinary approach to treatment. For patients with disease limited to the skin, expectant management or skin-directed therapies is preferred, as both disease-specific and overall survival for these patients is favorable. In contrast, patients with advanced-stage disease with significant nodal, visceral, or blood involvement are generally approached with biologic-response modifiers, denileukin diftitox, and histone deacetylase inhibitors before escalating therapy to include systemic, single-agent chemotherapy. Multiagent chemotherapy may be used for those patients with extensive visceral involvement requiring rapid disease control. In highly-selected patients with disease refractory to standard treatments, allogeneic stem-cell transplantation may be considered.
Topics: Antineoplastic Agents; Combined Modality Therapy; Diphtheria Toxin; Disease Management; Histone Deacetylase Inhibitors; Humans; Immunohistochemistry; Interleukin-2; Lymphoma, T-Cell, Cutaneous; Mycosis Fungoides; Neoplasm Staging; Prognosis; Recombinant Fusion Proteins; Risk Assessment; Sezary Syndrome; Skin; Stem Cell Transplantation; T-Lymphocytes; Transplantation, Homologous; Treatment Outcome
PubMed: 21990092
DOI: 10.1002/ajh.22139 -
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 -
Cancer Immunology, Immunotherapy : CII Mar 2012Disrupting tumor-mediated mechanisms suppressing host immunity represents a novel approach to tumor immunotherapy. Depletion of regulatory T cells (Tregs) increases...
Disrupting tumor-mediated mechanisms suppressing host immunity represents a novel approach to tumor immunotherapy. Depletion of regulatory T cells (Tregs) increases endogenous anti-tumor immunity and the efficacy of active immunotherapy in experimental tumor models. HLA-A2.1/HLA-DR1 (A2.1/DR1) × BALB- neuT+ (neuT+) triple transgenic mice represent an improvement over neuT+ mice for evaluating vaccination regimens to overcome tolerance against HER-2/neu. We questioned whether depletion of Tregs with Denileukin diftitox (Ontak) enhances the efficacy of a therapeutic vaccine consisting of HER-2(85-94) (p85) CTL and HER-2(776-790) (p776) Th peptides against the growth of TUBO.A2 transplantable tumor in male A2.1/DR1 × neuT+ Tg mice. While the therapeutic vaccine primed the tumor-reactive CD8+ CTLs and CD4+ effector T lymphocytes (Teffs) compartment, inducing activation, tumor infiltration, and tumor rejection or delay in tumor growth, treatment with Ontak 1 day prior to vaccination resulted in enhanced CD4+ and CD8+ T-cell-mediated vaccine-specific immune responses in the periphery. This was closely associated with greater infiltration and a striking change in the intratumor balance of Tregs and vaccine-specific CTLs/Teffs that directly correlated with markedly enhanced antitumor activity. The data suggest that Tregs control both CD4+ and CD8+ T-cell activity within the tumor, emphasize the importance of the intratumor ratio of vaccine-specific lymphocytes to Tregs, and demonstrate significant inversion of this ratio and correlation with tumor rejection during Ontak/vaccine immunotherapy.
Topics: Animals; Antineoplastic Agents; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cancer Vaccines; Cell Line, Tumor; Diphtheria Toxin; Female; HLA-A2 Antigen; HLA-DR1 Antigen; Humans; Immune Tolerance; Immunosuppressive Agents; Interleukin-2; Male; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Mice, Transgenic; Rats; Receptor, ErbB-2; Recombinant Fusion Proteins; T-Lymphocytes, Cytotoxic; T-Lymphocytes, Regulatory; Tumor Burden; Tumor Microenvironment; Vaccination
PubMed: 21928125
DOI: 10.1007/s00262-011-1113-4 -
American Journal of Hematology Jul 2011
Meta-Analysis
Topics: Antineoplastic Agents; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Diphtheria Toxin; Interleukin-2; Lymphoma, T-Cell, Cutaneous; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Recurrence; Skin Neoplasms; Time Factors
PubMed: 21674574
DOI: 10.1002/ajh.22039 -
Biology of Blood and Marrow... Aug 2011In the dog leukocyte antigen (DLA)-identical hematopoietic cell transplantation (HCT) model, stable marrow engraftment can be achieved with total-body irradiation (TBI)...
Pharmacological immunosuppression reduces but does not eliminate the need for total-body irradiation in nonmyeloablative conditioning regimens for hematopoietic cell transplantation.
In the dog leukocyte antigen (DLA)-identical hematopoietic cell transplantation (HCT) model, stable marrow engraftment can be achieved with total-body irradiation (TBI) of 200 cGy when used in combination with postgrafting immunosuppression. The TBI dose can be reduced to 100 cGy without compromising engraftment rates if granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood mononuclear cells (G-PBMC) are infused with the marrow. T cell-depleting the G-PBMC product abrogates this effect. These results were interpreted to suggest that the additional T cells provided with G-PBMC facilitated engraftment by overcoming host resistance. We therefore hypothesized that the TBI dose may be further reduced to 50 cGy by augmenting immunosupression either by (1) tolerizing or killing recipient T cells, or (2) enhancing the graft-versus-host (GVH) activity of donor T cells. To test the first hypothesis, recipient T cells were activated before HCT by repetitive donor-specific PBMC infusions followed by administration of methotrexate (MTX) (n = 5), CTLA4-Ig (n = 4), denileukin diftitox (Ontak; n = 4), CTLA4-Ig + MTX (n = 8), or 5c8 antibody (anti-CD154) + MTX (n = 3). To test the second hypothesis, recipient dendritic cells were expanded in vivo by infusion of Flt3 ligand given either pre-HCT (n = 4) or pre- and post-HCT (n = 5) to augment GVH reactions. Although all dogs showed initial allogeneic engraftment, sustained engraftment was seen in only 6 of 42 dogs (14% of all dogs treated in 9 experimental groups). Hence, unless more innovative pharmacotherapy can be developed that more forcefully shifts the immunologic balance in favor of the donor, noncytotoxic immunosuppressive drug therapy as the sole component of HCT preparative regimens may not suffice to ensure sustained engraftment.
Topics: Animals; Disease Models, Animal; Dogs; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppression Therapy; Male; Transplantation Chimera; Transplantation Conditioning; Whole-Body Irradiation
PubMed: 21220032
DOI: 10.1016/j.bbmt.2011.01.003 -
Cancer Management and Research Feb 2010Denileukin diftitox (Ontak(®)) is indicated for the treatment of patients with persistent or recurrent cutaneous T-cell lymphoma (CTCL), a rare lymphoproliferative...
Denileukin diftitox (Ontak(®)) is indicated for the treatment of patients with persistent or recurrent cutaneous T-cell lymphoma (CTCL), a rare lymphoproliferative disorder of the skin. Denileukin diftitox was the first fusion protein toxin approved for the treatment of a human disease. This fusion protein toxin combines the IL2 protein with diphtheria toxin, and targets the CD25 subunit of the IL2 receptor, resulting in the unique delivery of a cytocidal agent to CD-25 bearing T-cells. Historically, immunotherapy targeting malignant T-cells including monoclonal antibodies has been largely ineffective as cytocidal agents compared to immunotherapy directed against B-cells such as rituximab. This review will summarize the development of denileukin diftitox, its proposed mechanism of action, the pivotal clinical trials that led to its FDA approval, the improvements in quality of life, and the common toxicities experienced during the treatment of patients with CTCL. CTCL is often a chronic progressive lymphoma requiring the sequential use of treatments such as retinoids, traditional chemotherapy, or biological response modifiers. The incorporation of the immunotoxin denileukin diftitox into the sequential or combinatorial treatment of CTCL will also be addressed.
PubMed: 21188096
DOI: 10.2147/cmar.s5009