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Archives of Dermatology Jun 2002
Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biopsy, Needle; Diphtheria Toxin; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Infusions, Intravenous; Interleukin-2; Lymphoma, T-Cell, Cutaneous; Panniculitis; Prednisone; Recombinant Fusion Proteins; Skin Neoplasms; Tomography, Emission-Computed; Treatment Outcome
PubMed: 12056952
DOI: 10.1001/archderm.138.6.740 -
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 -
Current Oncology Reports Mar 2018Cutaneous T-cell lymphoma (CTCL) is a rare form of non-Hodgkin lymphoma. Globally, the most common subtypes of CTCL are mycosis fungoides and Sézary syndrome. CTCL can... (Review)
Review
PURPOSE OF REVIEW
Cutaneous T-cell lymphoma (CTCL) is a rare form of non-Hodgkin lymphoma. Globally, the most common subtypes of CTCL are mycosis fungoides and Sézary syndrome. CTCL can confer significant morbidity and even mortality in advanced disease. Here we review the current and potential future treatments for advanced-stage CTCL.
RECENT FINDINGS
Heterogeneity of treatment choice has been demonstrated both in US and non-US centers. Systemic treatment choice is currently guided by prognostic features, incorporating stage, immunophenotypic and molecular findings, and patient-specific factors such as age and comorbidities. Randomized controlled studies are uncommon, and the literature is composed predominantly of retrospective, cohort, and early-phase studies. International consensus guidelines are available; however, the lack of comparative trials means that there is no clear algorithmic approach to treatment. This review article reports on the systemic treatment options in current use for advanced CTCL, and on the possible future therapies, acknowledging that an algorithmic approach is not yet forthcoming to guide treatment prioritization.
Topics: Combined Modality Therapy; Humans; Mycosis Fungoides; Prognosis; Sezary Syndrome; Skin Neoplasms
PubMed: 29572582
DOI: 10.1007/s11912-018-0678-x -
Current Opinion in Hematology Jul 2009To review new agents under investigation for the treatment of patients with peripheral T-cell lymphoma. (Review)
Review
PURPOSE OF REVIEW
To review new agents under investigation for the treatment of patients with peripheral T-cell lymphoma.
RECENT FINDINGS
New agents being evaluated in these patients include histone deacetylase inhibitors (e.g. romidepsin, vorinostat, and balinostat), purine analogs and agents that interfere with the purine metabolic pathway (e.g. forodesine), immunomodulatory agents, proapoptotic small molecules (e.g. oblimersen, obatoclax, and gossypol), antifols (e.g. pralatrexate), proteasome inhibitors (e.g. bortezomib), monoclonal antibodies against T-cell antigens (e.g. CD30 and CD52), and immunotoxins (e.g. denileukin diftitox).
SUMMARY
The development of rational combinations of such agents in clinical trials will be required to improve the outcome of these patients.
Topics: Antineoplastic Agents; Bendamustine Hydrochloride; Boronic Acids; Bortezomib; Cladribine; Enzyme Inhibitors; Histone Deacetylase Inhibitors; Humans; Lymphoma, T-Cell, Peripheral; Nitrogen Mustard Compounds; Pyrazines; Vidarabine
PubMed: 19367159
DOI: 10.1097/MOH.0b013e32832ad69a -
Expert Review of Anticancer Therapy Mar 2011Peripheral T-cell lymphomas (PTCLs) are a heterogeneous collection of lymphomas that are associated with very poor prognosis. Conventional therapies, historically based... (Review)
Review
Peripheral T-cell lymphomas (PTCLs) are a heterogeneous collection of lymphomas that are associated with very poor prognosis. Conventional therapies, historically based on protocols for aggressive B-cell lymphomas, deliver less than adequate outcomes; the majority of patients experience early relapse after front-line treatment and current 5-year overall survival is only 10-30%. Clearly, new approaches are needed. In recent years there has been a plethora of novel agents showing activity in PTCL, often in patients with advanced relapsed or refractory disease. These agents include antifolate drugs (pralatrexate), histone deacetylase inhibitors (vorinostat, romidepsin, panobinostat and belinostat), nucleoside analogues (gemcitabine, forodesine and clofarabine), monoclonal antibodies (anti-CD52, anti-CD4 and anti-CD2), fusion toxins (denileukin diftitox), immunomodulatory agents (lenalidomide) and proteasome inhibitors (bortezomib). This is an exciting time in the treatment of PTCL, as our ever improving understanding of the distinguishing features, pathogenesis, molecular biology and progression of PTCL, and the knowledge of the mechanism and efficacy of novel therapies, may see a real improvement in outcomes for patients. The purpose of this article is to focus on these novel therapies and the results of recent clinical trials in PTCL.
Topics: Antibodies, Monoclonal; Antineoplastic Agents; Clinical Trials as Topic; Folic Acid Antagonists; Histone Deacetylase Inhibitors; Humans; Lymphoma, T-Cell
PubMed: 21417858
DOI: 10.1586/era.11.4 -
The Cochrane Database of Systematic... Sep 2012Mycosis fungoides is the most common type of cutaneous T-cell lymphoma, a malignant, chronic disease initially affecting the skin. Several therapies are available, which... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Mycosis fungoides is the most common type of cutaneous T-cell lymphoma, a malignant, chronic disease initially affecting the skin. Several therapies are available, which may induce clinical remission for a time.
OBJECTIVES
To assess the effects of interventions for mycosis fungoides in all stages of the disease.
SEARCH METHODS
We searched the following databases up to January 2011: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library, MEDLINE (from 2005), EMBASE (from 2010), and LILACS (from 1982). We also checked reference lists of included studies for further references to relevant RCTs. We searched online trials registries for further references to unpublished trials and undertook a separate search for adverse effects of interventions for mycosis fungoides in non-RCTs in MEDLINE in May 2011.
SELECTION CRITERIA
Randomised controlled trials (RCTs) of interventions for mycosis fungoides in people with any stage of the disease. At least 90% of participants in the trials must have been diagnosed with mycosis fungoides (Alibert-Bazin-type).
DATA COLLECTION AND ANALYSIS
Two authors independently assessed eligibility and methodological quality for each study and carried out data extraction. We resolved any disagreement by discussion. Primary outcomes were the impact on quality of life and the safety of interventions. When available, we reported on our secondary outcomes, which were the improvement or clearance of skin lesions, disease-free intervals, survival rates, relapse rates, and rare adverse effects. When possible, we combined homogeneous studies for meta-analysis. We used The Cochrane Collaboration's 'Risk of bias' tool to assess the internal validity of all included studies in six different domains.
MAIN RESULTS
The review included 14 RCTs involving 675 participants, covering a wide range of interventions. Eleven of the included trials assessed participants in clinical stages IA to IIB only (please see Table 1 for definitions of these stages).Internal validity was considerably low in studies with a high or unclear risk of bias. The main reasons for this were low methodological quality or missing data, even after we contacted the study authors, and a mean dropout rate of 26% (0% to 72%). Study size was generally small with a minimum of 4 and a maximum of 103 participants. Only one study provided a long enough follow-up for reliable survival analysis.Included studies assessed topical treatments, such as imiquimod, peldesine, hypericin, nitrogen mustard, as well as intralesional injections of interferon-α (IFN-α). The light therapies investigated included psoralen plus ultraviolet A light (PUVA), extracorporeal photopheresis (photochemotherapy), and visible light. Oral treatments included acitretin, bexarotene, and methotrexate. Treatment with parenteral systemic agents consisted of denileukin diftitox; a combination of chemotherapy and electron beam radiation; and intramuscular injections of active transfer factor. Nine studies evaluated therapies by using an active comparator; five were placebo-controlled RCTs.Twelve studies reported on common adverse effects, while only two assessed quality of life. None of these studies compared the health-related quality of life of participants undergoing different treatments. Most of the reported adverse effects were attributed to the interventions. Systemic treatments, and here in particular a combined therapeutic regimen of chemotherapy and electron beam, bexarotene, or denileukin diftitox, showed more adverse effects than topical or skin-directed treatments.In the included studies, clearance rates ranged from 0% to 83%, and improvement ranged from 0% to 88%. The meta-analysis combining the results of 2 trials comparing the effect of IFN-α and PUVA versus PUVA alone showed no significant difference in the relative risk of clearance: 1.07 (95% confidence interval 0.87 to 1.31). None of the included studies demonstrated a significant increase in disease-free intervals, relapse, or overall survival.
AUTHORS' CONCLUSIONS
This review identified trial evidence for a range of different topical and systemic interventions for mycosis fungoides. Because of substantial heterogeneity in design, small sample sizes, and low methodological quality, the comparative safety and efficacy of these interventions cannot be established on the basis of the included RCTs. Taking into account the possible serious adverse effects and the limited availability of efficacy data, topical and skin-directed treatments are recommended first, especially in the early stages of disease. More aggressive therapeutic regimens may show improvement or clearance of lesions, but they also result in more adverse effects; therefore, they are to be considered with caution. Larger studies with comparable, clearly-defined end points for all stages of mycosis fungoides, and a focus on safety, quality of life, and duration of remission as part of the outcome measures, are necessary.
Topics: Antineoplastic Agents; Humans; Mycosis Fungoides; Neoplasm Staging; Photochemotherapy; Photopheresis; Randomized Controlled Trials as Topic; Skin Neoplasms
PubMed: 22972128
DOI: 10.1002/14651858.CD008946.pub2 -
Best Practice & Research. Clinical... Sep 2018Novel systemic therapies are generally prescribed to patients with advanced-stage disease or those with early-stage disease refractory to skin-directed therapies. In... (Review)
Review
Novel systemic therapies are generally prescribed to patients with advanced-stage disease or those with early-stage disease refractory to skin-directed therapies. In general, systemic chemotherapy should be reserved for patients who fail to respond to biological agents. Such biological agents include interferon alfa, bexarotene, histone deacetylase inhibitors (vorinostat, romidepsin), brentuximab vedotin and mogamulizumab. Extracorporeal photopheresis is particularly effective for patients with Sézary Syndrome. Allogeneic transplantation is becoming increasing used for younger patients. Novel agents in advanced development include the monoclonal antibody IPH4102,duvelisib,and the new modified formulation of denileukin diftitox. The choice of agents for patients is typically a balance of patient factors (age, co-morbidities, geographic location), relative efficacy and toxicity.
Topics: Allografts; Antineoplastic Agents; Hematopoietic Stem Cell Transplantation; Humans; Mycosis Fungoides; Photopheresis; Sezary Syndrome
PubMed: 30213403
DOI: 10.1016/j.beha.2018.07.007 -
Journal of the American Academy of... Jun 2011
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Diphtheria Toxin; Female; Humans; Interleukin-2; Lymphoma, Primary Cutaneous Anaplastic Large Cell; Middle Aged; Recombinant Fusion Proteins; Skin Neoplasms; Treatment Failure
PubMed: 21571160
DOI: 10.1016/j.jaad.2010.11.001 -
Clinical Lymphoma, Myeloma & Leukemia Aug 2013We aimed to determine duration of response in patients with CTCL treated using DD who experienced partial response, complete clinical response, or complete response. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
We aimed to determine duration of response in patients with CTCL treated using DD who experienced partial response, complete clinical response, or complete response.
PATIENTS AND METHODS
Data from 3 phase III studies were pooled. Patients received up to 8 courses of 9 or 18 μg/kg intravenous DD daily for 5 days every 21 days, or placebo. Data on DD-treated patients were analyzed by dose and CD25 status. Kaplan-Meier product limit estimates and 95% confidence intervals were calculated for duration of response and time to response.
RESULTS
The pooled population comprised 263 DD-treated and 44 placebo-treated patients, and 100 and 7, respectively, had at least a partial response. Median duration of response using DD was 277 days vs. 81 days using placebo. Overall response vs. placebo (n = 7; 16%) as (n = 25; 31%) for DD 9 μg/kg (P = .05), (n = 56; 47%) for DD 18 μg/kg (P = .004), (n = 8; 28%) for re-treated patients (DD 18 μg/kg; P = .21), and (n = 11; 31%) for CD25 low-expression patients (DD 18 μg/kg; P = .14). Overall response rates were similar between patients who did (n = 95; 36%) and did not (n = 105; 40%) develop capillary leak syndrome (CLS); median duration of response was longer in patients who developed CLS, but was not significant (619 vs. 267 days, respectively; P = .28). Adverse events occurred in 98% of DD-treated patients; most frequent were nausea, pyrexia, fatigue, CLS, and rigors.
CONCLUSION
These data indicate a durable response with DD in CTCL, even in heavily pretreated patients and those with CD25 low-expression disease.
Topics: Antineoplastic Agents; Diphtheria Toxin; Female; Humans; Interleukin-2; Lymphoma, T-Cell, Cutaneous; Male; Middle Aged; Recombinant Fusion Proteins; Skin Neoplasms; Treatment Outcome
PubMed: 23770157
DOI: 10.1016/j.clml.2013.02.020