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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 -
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 -
Biology of Blood and Marrow... Mar 2005Acute graft-versus-host disease (aGVHD) is partly mediated through activated T cells, and these cells are known to express the high-affinity receptor for interleukin 2... (Clinical Trial)
Clinical Trial
Acute graft-versus-host disease (aGVHD) is partly mediated through activated T cells, and these cells are known to express the high-affinity receptor for interleukin 2 (IL-2R). Denileukin diftitox is composed of human IL-2 and diphtheria toxin that is cytotoxic to activated lymphocytes expressing the high-affinity IL-2R. We describe the results of a phase II study of denileukin diftitox in 22 patients with steroid-resistant aGVHD. Twenty patients were treated at dose level 1 (4.5 microg/kg daily on days 1-5 and then weekly on study days 8, 15, 22, and 29), and 2 patients were treated at dose level 2 (9.0 microg/kg delivered on the same schedule). Dose level 2 was associated with grade 3/4 renal and hepatic toxicity and vascular leak syndrome, and no further patients were treated at this level. Dose level 1 was generally well tolerated. The response of aGVHD was assessed at study days 36 and 100. Nine patients (41%) responded, all with a complete response at study day 36, and 6 patients (27%) responded at study day 100 (4 complete responses and 2 partial responses). Denileukin diftitox has promising activity in steroid-resistant aGVHD, and further study is warranted.
Topics: Acute Disease; Capillary Leak Syndrome; Chemical and Drug Induced Liver Injury; Diphtheria Toxin; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Interleukin-2; Recombinant Fusion Proteins; Remission Induction; Steroids
PubMed: 15744237
DOI: 10.1016/j.bbmt.2004.11.022 -
Frontiers in Medicine 2019Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes of cutaneous T-cell lymphoma. The majority of MF cases present with only patches and... (Review)
Review
Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes of cutaneous T-cell lymphoma. The majority of MF cases present with only patches and plaques and the lesions are usually limited to the skin. On the other hand, in some cases, patients show skin tumors or erythroderma followed by lymph node involvement and rarely visceral organ involvement. SS is a rare, aggressive cutaneous T-cell lymphoma marked by exfoliative erythroderma, lymphadenopathy, and leukemic blood involvement. Because patients with relapsed or refractory MF/SS display a poor prognosis and the current treatment options are characterized by high rates of relapse, there is unmet need for the efficient treatment. This review provides a discussion of the recent and future promising therapeutic approaches in the management of advanced MF/SS. These include mogamulizumab, brentuximab vedotin, alemtuzumab, immune checkpoint inhibitors, IPH4102 (anti-KIR3DL2 antibody), histone deacetylase inhibitors (vorinostat, romidepsin, panobinostat, belinostat, and resminostat), pralatrexate, forodesine, denileukin diftitox, duvelisib, lenalidomide, and everolimus.
PubMed: 31192214
DOI: 10.3389/fmed.2019.00116 -
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 -
Oncology (Williston Park, N.Y.) May 2010Mycosis fungoides (MF), the most common cutaneous T-cell lymphoma, is a low-grade cutaneous lymphoma characterized by skin-homing CD4+ T cells. It is notable for highly... (Review)
Review
Mycosis fungoides (MF), the most common cutaneous T-cell lymphoma, is a low-grade cutaneous lymphoma characterized by skin-homing CD4+ T cells. It is notable for highly symptomatic progressive skin lesions, including patches, plaques, tumors, and erytheroderma, and has a poorer prognosis at later stages. Diagnosis remains difficult owing to MF's nonspecific skin presentation and identification of the optimal treatment strategy is challenging given the paucity of controlled trials and numerous and emerging treatment options. Management includes topical therapy with the addition of systemic therapy for patients with later-stage disease including tumors; erythroderma; and nodal, visceral, or blood involvement. Topical therapies include mechlorethamine (nitrogen mustard), carmustine (BCNU), steroids, bexarotene gel (Targretin Gel), psoralen plus ultraviolet A (PUVA), ultraviolet B (UVB), and either localized or total skin electron radiotherapy. Systemic therapies include interferon, retinoids, oral bexarotene (Targretin), denileukin diftitox (Ontak), vorinostat (Zolinza), extracorporeal photochemotherapy (photopheresis), and cytotoxic chemotherapy. Herein, we outline clinically relevant aspects of MF, including clinical presentation, pathology, diagnosis, and staging. We describe in detail existing and emerging therapeutics and offer specific recommendations for management of each stage of MF.
Topics: Humans; Mycosis Fungoides; Neoplasm Staging; Skin Neoplasms
PubMed: 20568590
DOI: No ID Found -
Annals of Oncology : Official Journal... Feb 2014Cytoreductive surgery and chemotherapy continue to be the mainstay of ovarian cancer treatment. However, as mortality from advanced ovarian cancer remains very high,... (Review)
Review
Cytoreductive surgery and chemotherapy continue to be the mainstay of ovarian cancer treatment. However, as mortality from advanced ovarian cancer remains very high, novel therapies are required to be integrated into existing treatment regimens. Immunotherapy represents an alternative and rational therapeutic approach for ovarian cancer based on a body of evidence supporting a protective role of the immune system against these cancers, and on the clinical success of immunotherapy in other malignancies. Whether or not immunotherapy will have a role in the future management of ovarian cancer is too early to tell, but research in this field is active. This review will discuss recent clinical developments of selected immunotherapies for ovarian cancer which fulfil the following criteria: (i) they are antibody-based, (ii) target a distinct immunological pathway, and (iii) have reached the clinical trial stage. Specifically, the focus is on Catumaxomab (anti-EpCAM×anti-CD3), Abagovomab, Oregovomab (anti-CA125), Daclizumab (anti-CD25), Ipilimumab (anti-CTLA-4), and MXD-1105 (anti-PD-L1). Catumaxomab has reached phase III clinical trials and exhibits promise with reports, showing that it can cause a significant and sustained reduction in ascites. Phase I-III clinical trials continue to be conducted on the other antibodies, some of which have had encouraging reports. We will also provide our perspective on the future of immunotherapy for ovarian cancer, and how it may be best employed in treatment regimens.
Topics: Animals; Antibodies, Bispecific; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; Clinical Trials as Topic; Daclizumab; Diphtheria Toxin; Female; Humans; Immunoglobulin G; Immunotherapy; Interleukin-2; Ipilimumab; Ovarian Neoplasms; Recombinant Fusion Proteins
PubMed: 24285017
DOI: 10.1093/annonc/mdt405 -
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 -
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 -
The Cochrane Database of Systematic... Jul 2020Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma, a malignant, chronic disease initially affecting the skin. Several therapies are available,... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Mycosis fungoides (MF) 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. This is an update of a Cochrane Review first published in 2012: we wanted to assess new trials, some of which investigated new interventions.
OBJECTIVES
To assess the effects of interventions for MF in all stages of the disease.
SEARCH METHODS
We updated our searches of the following databases to May 2019: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We searched 2 trials registries for additional references. For adverse event outcomes, we undertook separate searches in MEDLINE in April, July and November 2017.
SELECTION CRITERIA
Randomised controlled trials (RCTs) of local or systemic interventions for MF in adults with any stage of the disease compared with either another local or systemic intervention or with placebo.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane. The primary outcomes were improvement in health-related quality of life as defined by participants, and common adverse effects of the treatments. Key secondary outcomes were complete response (CR), defined as complete disappearance of all clinical evidence of disease, and objective response rate (ORR), defined as proportion of patients with a partial or complete response. We used GRADE to assess the certainty of evidence and considered comparisons of psoralen plus ultraviolet A (PUVA) light treatment as most important because this is first-line treatment for MF in most guidelines.
MAIN RESULTS
This review includes 20 RCTs (1369 participants) covering a wide range of interventions. The following were assessed as either treatments or comparators: imiquimod, peldesine, hypericin, mechlorethamine, nitrogen mustard and intralesional injections of interferon-α (IFN-α) (topical applications); PUVA, extracorporeal photopheresis (ECP: photochemotherapy), and visible light (light applications); acitretin, bexarotene, lenalidomide, methotrexate and vorinostat (oral agents); brentuximab vedotin; denileukin diftitox; mogamulizumab; chemotherapy with cyclophosphamide, doxorubicin, etoposide, and vincristine; a combination of chemotherapy with electron beam radiation; subcutaneous injection of IFN-α; and intramuscular injections of active transfer factor (parenteral systemics). Thirteen trials used an active comparator, five were placebo-controlled, and two compared an active operator to observation only. In 14 trials, participants had MF in clinical stages IA to IIB. All participants were treated in secondary and tertiary care settings, mainly in Europe, North America or Australia. Trials recruited both men and women, with more male participants overall. Trial duration varied from four weeks to 12 months, with one longer-term study lasting more than six years. We judged 16 trials as at high risk of bias in at least one domain, most commonly performance bias (blinding of participants and investigators), attrition bias and reporting bias. None of our key comparisons measured quality of life, and the two studies that did presented no usable data. Eighteen studies reported common adverse effects of the treatments. Adverse effects ranged from mild symptoms to lethal complications depending upon the treatment type. More aggressive treatments like systemic chemotherapy generally resulted in more severe adverse effects. In the included studies, CR rates ranged from 0% to 83% (median 31%), and ORR ranged from 0% to 88% (median 47%). Five trials assessed PUVA treatment, alone or combined, summarised below. There may be little to no difference between intralesional IFN-α and PUVA compared with PUVA alone for 24 to 52 weeks in CR (risk ratio (RR) 1.07, 95% confidence interval (CI) 0.87 to 1.31; 2 trials; 122 participants; low-certainty evidence). Common adverse events and ORR were not measured. One small cross-over trial found once-monthly ECP for six months may be less effective than twice-weekly PUVA for three months, reporting CR in two of eight participants and ORR in six of eight participants after PUVA, compared with no CR or ORR after ECP (very low-certainty evidence). Some participants reported mild nausea after PUVA but no numerical data were given. One participant in the ECP group withdrew due to hypotension. However, we are unsure of the results due to very low-certainty evidence. One trial comparing bexarotene plus PUVA versus PUVA alone for up to 16 weeks reported one case of photosensitivity in the bexarotene plus PUVA group compared to none in the PUVA-alone group (87 participants; low-certainty evidence). There may be little to no difference between bexarotene plus PUVA and PUVA alone in CR (RR 1.41, 95% CI 0.71 to 2.80) and ORR (RR 0.94, 95% CI 0.61 to 1.44) (93 participants; low-certainty evidence). One trial comparing subcutaneous IFN-α injections combined with either acitretin or PUVA for up to 48 weeks or until CR indicated there may be little to no difference in the common IFN-α adverse effect of flu-like symptoms (RR 1.32, 95% CI 0.92 to 1.88; 82 participants). There may be lower CR with IFN-α and acitretin compared with IFN-α and PUVA (RR 0.54, 95% CI 0.35 to 0.84; 82 participants) (both outcomes: low-certainty evidence). This trial did not measure ORR. One trial comparing PUVA maintenance treatment to no maintenance treatment, in participants who had already had CR, did report common adverse effects. However, the distribution was not evaluable. CR and OR were not assessable. The range of treatment options meant that rare adverse effects consequently occurred in a variety of organs.
AUTHORS' CONCLUSIONS
There is a lack of high-certainty evidence to support decision making in the treatment of MF. Because of substantial heterogeneity in design, missing data, small sample sizes, and low methodological quality, the comparative safety and efficacy of these interventions cannot be reliably established on the basis of the included RCTs. PUVA is commonly recommended as first-line treatment for MF, and we did not find evidence to challenge this recommendation. There was an absence of evidence to support the use of intralesional IFN-α or bexarotene in people receiving PUVA and an absence of evidence to support the use of acitretin or ECP for treating MF. Future trials should compare the safety and efficacy of treatments to PUVA, as the current standard of care, and should measure quality of life and common adverse effects.
Topics: Acitretin; Antineoplastic Agents; Bexarotene; Combined Modality Therapy; Humans; Immunologic Factors; Interferon-alpha; Mycosis Fungoides; Neoplasm Staging; PUVA Therapy; Photochemotherapy; Photopheresis; Randomized Controlled Trials as Topic; Skin Neoplasms
PubMed: 32632956
DOI: 10.1002/14651858.CD008946.pub3