- |||||||||| Ontak (denileukin diftitox) / Eisai, TSD Japan
Journal: T cell activation is insufficient to drive SIV disease progression. (Pubmed Central) - Jul 24, 2023
We dissociated T cell activation from inflammation through regulatory T cell (Treg) depletion with Ontak (interleukin-2 coupled with diphtheria toxin) during early SIV infection of AGMs...Persistent T cell activation influenced SIV pathogenesis, shifting the ramp-up in viral replication to earlier time points, prolonging the high levels of replication, and delaying CD4+ T cell restoration yet without any clinical or biological sign of disease progression in Treg-depleted AGMs. Thus, by inducing T cell activation without damaging mucosal barrier integrity, we showed that systemic T cell activation per se is not sufficient to drive disease progression, which suggests that control of systemic inflammation (likely through maintenance of gut integrity) is the key determinant of lack of disease progression in natural hosts of SIVs.
- |||||||||| Novel Drugs in the Treatment of Steroid Refractory Acute Graft Versus Host Disease () - Nov 29, 2022 - Abstract #ASH2022ASH_7880;
treated 62 patients with daclizumab in a phase II trial with reportef ORR of 68.80% at 44 months follow up.Groth et al...Monoclonal antibodies in particular showed good treatment outcomes with tolerable safety profile. Further studies are required to identify a valuable therapeutic option, SR-aGVHD.
- |||||||||| Efficacy of Combinatorial Treatment Approaches in CTCL () - Nov 29, 2022 - Abstract #ASH2022ASH_7346;
Over the past 20 years only six novel biological/targeted agents (bexarotene, denileukin diftitox, vorinostat, romidepsin, brentuximab vedotin, mogamulizumab) have been FDA approved for systemic therapy of relapsed/refractory MF/SS however, none render curative approach...Out of the 7 pts that did respond, the most prevailing treatment was the combination of Venetoclax and Duvelisib with 6 out of 7 pts samples having a response to this combination...Our observations on MF/SS pts samples thus far demonstrates various sensitivities to treatments for individual pts. This may account for genetic and epigenetic changes which highlight the unmet need for personalization of treatment and sensitivity screening for each patient, with the decisive goal to offer a personalized and efficacious treatment modalities.
- |||||||||| Opdivo (nivolumab) / Ono Pharma, BMS, Ontak (denileukin diftitox) / Eisai, TSD Japan
Gene Expression Profiling and Signaling Pathway Analysis of Tolerant T Cells Circulating in Adult Patients after Ptcy Haplotransplantation (ENMCC - Hall D) - Nov 4, 2022 - Abstract #ASH2022ASH_6556;
We found Treg, Tr1 activity or T-cell exhaustion to be insignificant as their blockade or removal did not lead to ‘flare’ in circulating tolerant T-cell reactivity against patient DC. T-cell clonal deletion appears to be the dominant mechanism explaining the in vitro hyporeactive proliferation, cytokine secretion, and alloreactive TCR clonotype attrition, along with systemically altered signaling pathways in tolerant T-cells including the alloreactive T cells remained.
- |||||||||| Journal: Immunotherapy in indolent Non-Hodgkin's Lymphoma. (Pubmed Central) - Jun 8, 2022
Other agents include MAB targeting T-Cells like mogamulizumab, Denileukin Diftitox and BiTEs or bispecific T cell engagers like Mosunetuzumab, Glofitamab, and Epcoritamab...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.
- |||||||||| Ontak (denileukin diftitox) / Eisai, TSD Japan
Clinical, Journal: Interferon-α augments clinical efficacy of regulatory T cell depletion with denileukin diftitox in ovarian cancer. (Pubmed Central) - Apr 2, 2022
Adding interferon-α increased toxicities but was tolerable, and reduced human Treg numbers in blood, and function through dendritic cell-induced IL-6 in vitro Treg depletion is clinically useful but unlikely alone to cure OC. Rational treatment agent combinations can salvage clinical failure of Treg depletion alone, even when neither single agent provides meaningful clinical benefit.
- |||||||||| Review, Journal: Current treatment strategies and emerging therapies for cutaneous lymphoma. (Pubmed Central) - Feb 4, 2022
Chemotherapy agents such as gemcitabine and pralatrexate have been introduced; they are expected to have meaningful efficacy as monotherapy. Allogeneic hematopoietic stem cell transplantation is still considered for young patients with advanced CTCL as the only potentially curative treatment.
- |||||||||| Lumoxiti (moxetumomab pasudotox) / AstraZeneca, Innate, Elzonris (tagraxofusp) / Menarini, Nippon Shinyaku, Ontak (denileukin diftitox) / Eisai, TSD Japan
Review, Journal: Pseudomonas Exotoxin-Based Immunotoxins: Over Three Decades of Efforts on Targeting Cancer Cells With the Toxin. (Pubmed Central) - Jan 4, 2022
Here, we will review these ITs to highlight the advances in PE-based anticancer strategies, as well as review the targeting moieties that are used to reduce the non-specific destruction of non-cancerous cells. Although we tried to be as comprehensive as possible, we have limited our review to those ITs that have proceeded to clinical trials and are still under active clinical evaluation.
- |||||||||| Ontak (denileukin diftitox) / Eisai, Dr. Reddy’s, TSD Japan
Clinical, P2 data, Journal: Phase 2 study of E7777 in Japanese patients with relapsed/refractory peripheral and cutaneous T-cell lymphoma. (Pubmed Central) - Jun 11, 2021
Our results indicated that a 9 µg/kg/day dose of E7777 shows efficacy and a manageable safety profile in Japanese patients with relapsed or refractory PTCL and CTCL, with clinical activity observed across the range of CD25 expression. The common AEs were manageable, but increase in ALT/AST, hypoalbuminemia, and capillary leak syndrome should be carefully managed during the treatment.
- |||||||||| Ontak (denileukin diftitox) / Eisai, Dr. Reddy’s, TSD Japan
Journal, IO biomarker: Bispecific human IL2-CCR4 immunotoxin targets human cutaneous T-cell lymphoma. (Pubmed Central) - May 11, 2021
Recently, we have developed diphtheria toxin-based recombinant Ontak®-like human IL2 fusion toxin (IL2 fusion toxin) and anti-human CCR4 immunotoxin (CCR4 IT)...The bispecific immunotoxin was significantly more effective than either IL2 fusion toxin or CCR4 immunotoxin alone. The bispecific immunotoxin is a promising novel targeted therapeutic drug candidate for the treatment of refractory and recurrent human CD25 and/or CCR4 CTCL.
- |||||||||| Lumoxiti (moxetumomab pasudotox) / AstraZeneca, Innate, Elzonris (tagraxofusp) / Menarini, Ontak (denileukin diftitox) / Eisai, Dr. Reddy’s, TSD Japan
Review, Journal: Critical issues in the development of immunotoxins for anticancer therapy. (Pubmed Central) - Mar 26, 2021
The issues include off-target and on-target toxicities, immunogenicity, human cytotoxic proteins, antigen target selection, cytosolic delivery efficacy, solid-tumor targeting, and developability. To realize the therapeutic promise of ITs, novel strategies for safe and effective cytosolic delivery into designated tumors, including solid tumors, are urgently needed.
- |||||||||| Ontak (denileukin diftitox) / Eisai, Dr. Reddy’s, TSD Japan
Journal: Expression and purification of soluble and functional fusion protein DAB IL-2 into the E. coli strain Rosetta-gami (DE3). (Pubmed Central) - Feb 3, 2021
DAB IL-2 (Denileukin diftitox) is considered an immunotoxin, and it is the first immunotoxin approved by Food and Drug Administration...In the following, the nuclease activity of soluble DAB IL-2 and its cytotoxicity activity were determined. It is concluded that the soluble recombinant protein expressed in the E. coli Rosetta-gami (DE3) has an intact structure and also functional; hence, this form of immunotoxin could be competitive with its commercial counterparts.
- |||||||||| Ontak (denileukin diftitox) / Eisai, TSD Japan
Trial termination, Metastases: Vaccination Plus Ontak in Patients With Metastatic Melanoma (clinicaltrials.gov) - Oct 29, 2020
P2, N=17, Terminated,
An expanded phase is planned to evaluate the efficacy of this regimen followed by a randomized trial of BEAM alone plus a combination of aTac- BEAM. Active, not recruiting --> Terminated; The immune monitoring data failed to demonstrate an improvement in any biologic endpoint with denileukin diftitox.
- |||||||||| Targretin oral (bexarotene oral) / ReXceptor, doxorubicin hydrochloride / Generic mfg.
Review, Journal: Interventions for mycosis fungoides. (Pubmed Central) - Sep 27, 2020
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.
- |||||||||| Ontak (denileukin diftitox) / Eisai, Dr. Reddy’s, TSD Japan
Journal: Recent advances with Treg depleting fusion protein toxins for cancer immunotherapy. (Pubmed Central) - May 28, 2020
These agents capitalize on the well-characterized bacterial toxins, diphtheria toxin and Pseudomonas aeruginosa 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.
- |||||||||| Elzonris (tagraxofusp) / Stemline Therapeutics, Ontak (denileukin diftitox) / Eisai, Dr. Reddy’s
Review, Journal: Targeted Diphtheria Toxin-Based Therapy: A Review Article. (Pubmed Central) - Nov 5, 2019
Despite some success with immunotoxins, suicide-gene therapy strategies, whereby controlled tumor-specific expression of DT is used for the eradication of malignant cells, are gaining prominence. The first part of this review focuses on DT-based immunotoxins, and it then discusses recent developments in tumor-specific expression of DT.
- |||||||||| Rituxan (rituximab) / Roche, Biogen
Recombinant immunotoxins for hematologic malignancies (Level 3 - Ballroom C) - Sep 18, 2019 - Abstract #AACRNCIEORTC2019AACR_NCI_EORTC_566;
Recombinant immunotoxins are similar to but distinct from growth-factor fusions toxins like denileukin diftitox and Tagraxofusp, FDA-approved in 1999 and 2018, respectively...Anti-CD25 recombinant immunotoxin LMB-2 was active in several hematologic malignancies, notably hairy cell leukemia (HCL) and adult T-cell leukemia (ATL)...Improved targeting of HCL was achieved with anti-CD22 recombinant immunotoxin Moxetumomab Pasudotox (Moxe) that was stabilized with a disulfide bond in the Fv and has a high affinity for CD22...Molecular remissions assessed by blood analysis may be useful to determine the number of cycles of Moxe to administer to achieve long-term CR or possibly cure. To achieve molecular remissions with fewer cycles, Moxe is being tested with rituximab to facilitate tumor reduction and decrease anti-drug antibody formation.
- |||||||||| Ontak (denileukin diftitox) / Eisai
Journal: Frankia communities at revegetating sites in Mt. Ontake, Japan. (Pubmed Central) - Jun 28, 2019
Diversity in the Frankia community varied depending on revegetation progress. Cluster A, which was the most dominant in the disturbed region, was likely to have invaded from undisturbed forest.
- |||||||||| Targretin oral (bexarotene oral) / ReXceptor
Review, Journal: Integrating novel systemic therapies for the treatment of mycosis fungoides and Sézary syndrome. (Pubmed Central) - Jun 22, 2019
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.
- |||||||||| Targretin oral (bexarotene oral) / ReXceptor
Review, Journal: Systemic Treatment Options for Advanced-Stage Mycosis Fungoides and Sézary Syndrome. (Pubmed Central) - Jun 15, 2019
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.
- |||||||||| Campath (alemtuzumab) / Sanofi, Afinitor (everolimus) / Novartis
Review, Journal: Novel and Future Therapeutic Drugs for Advanced Mycosis Fungoides and Sézary Syndrome. (Pubmed Central) - Jun 14, 2019
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.
- |||||||||| Ontak (denileukin diftitox) / Eisai, TSD Japan
Trial completion, Metastases: Denileukin Diftitox Used in Treating Patients With Advanced Refractory Ovarian Cancer, Primary Peritoneal Carcinoma, or Epithelial Fallopian Tube Cancer (clinicaltrials.gov) - May 14, 2019
P1, N=11, Completed,
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. Active, not recruiting --> Completed
- |||||||||| Ontak (denileukin diftitox) / Eisai
Journal: Second-generation IL-2 receptor-targeted diphtheria fusion toxin exhibits antitumor activity and synergy with anti-PD-1 in melanoma. (Pubmed Central) - May 6, 2019
Denileukin diftitox (DAB-IL-2, Ontak) is a diphtheria-toxin-based fusion protein that depletes CD25-positive cells including regulatory T cells and has been approved for the treatment of persistent or recurrent cutaneous T cell lymphoma...In a sequential dual-therapy study in tumors that have progressed for 10 days, both s-DAB-IL-2(V6A) and s-DAB-IL-2 given before checkpoint inhibition with anti-programmed cell death-1 (anti-PD-1) antibodies inhibited tumor growth, while either drug given as monotherapy had less effect. s-DAB-IL-2(V6A), a fully monomeric protein with reduced vascular leak, is a second-generation diphtheria-toxin-based fusion protein with promise as a cancer immunotherapeutic both alone and in conjunction with PD-1 blockade.
- |||||||||| Ontak (denileukin diftitox) / Eisai, Dr. Reddy's, TSD Japan
Preclinical, Journal, Checkpoint inhibition: Age effects of distinct immune checkpoint blockade treatments in a mouse melanoma model. (Pubmed Central) - Apr 26, 2019
Regulatory T cell depletion with FDA-approved denileukin diftitox did not improve treatment by any single agent. Aged mice tolerated treatments as well as young mice without obvious toxicities at equivalent doses.
- |||||||||| Ontak (denileukin diftitox) / Eisai, TSD Japan
Trial completion, Metastases: ONTAK (clinicaltrials.gov) - Dec 5, 2018
P1/2, N=15, Completed,
Active, not recruiting --> Completed Active, not recruiting --> Completed
|
