Ontak (denileukin diftitox) / Eisai, Dr. Reddy’s, TSD Japan - LARVOL DELTA

Outcomes of relapsed or refractory mature T/NK-cell lymphomas in the era of novel agents: A nationwide observational Study in Japan (ASH 2025) - P | "The median TTNT of each SA after 2nd- or later-linetherapies (mo, 95% CI) was 10.7 (3.9–17.3) for brentuximab vedotin (BV; n = 53, 21%), 5.0 (2.7–7.1) fortucidinostat (n = 36, 14%), 3.9 (2.6–4.8) for romidepsin (n = 80, 31%), 2.1 (0.4–5.2) for darinaparsin (n = 7,3%), 1.8 (1.3–2.5) for pralatrexate (n = 58, 23%), 1.5 (0.6–NE) for forodesine (n = 8, 3%), 1.1 (0.4–2.4) formogamulizumab (n = 22, 9%), 0.7 (0.4–3.5) for denileukin diftitox (n = 5, 2%), and NR (NE–NE) for alectinib(n = 1, 0.4%). In patients with TFHL, romidepsin (44%) and tucidinostat (18%) yielded median TTNTs (mo,95% CI) of 4.0 (2.6–8.7) and 5.5 (1.9–7.8), respectively... To the best of our knowledge, this study reports the most recent treatment patterns andprognoses for patients with R/R MTNKL. No standard of care has been established, as diverse treatmentpatterns have been observed. SAs resulted in similar survival outcomes to CCs in 2nd-line therapy,despite distinctive clinical Background of the groups."

Clinical • Observational data • Bone Marrow Transplantation • Cutaneous T-cell Lymphoma • Dermatology • Extranodal Natural Killer/T-cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Mycosis Fungoides • Natural Killer/T-cell Lymphoma • Non-Hodgkin’s Lymphoma • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • ALK

Clinically approved immunotoxins targeting hematological cancers: "the best of both worlds". (PubMed, Front Pharmacol) - "In this review, we analyze three FDA-approved RITs, namely, moxetumomab pasudotox, tagraxofusp, and denileukin diftitox, that utilize bacterial toxins from Pseudomonas and Corynebacterium diphtheriae to treat refractory/relapsed (R/R) HCL, BPDCN, and adult R/R cutaneous T-cell lymphoma (CTCL), respectively. We reviewed their comprehensive safety profiles, describe complications associated with these fusion proteins, and, finally, discuss potential risk management strategies that may enhance their clinical outcomes. Overall, RITs have demonstrated efficacy, and researchers continue to extend these findings to other indications."

Journal • Review • Cutaneous T-cell Lymphoma • Hairy Cell Leukemia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma

Clinically Approved Immunotoxins Targeting Hematological Cancers: "The Best of Both Worlds" (Front Pharmacol) - "In this review, we analyze three FDA-approved RITs, moxetumomab pasudotox, tagraxofusp, and denileukin diftitox, that utilize bacterial toxins from Pseudomonas and Corynebacterium diphtheriae to treat refractory/relapsed (R/R) HCL, BPDCN, adult R/R cutaneous T-cell lymphoma (CTCL), respectively."

Review • Blastic Plasmacytoid Dendritic Cell Neoplasm • Cutaneous T-cell Lymphoma • Hairy Cell Leukemia

Safety and efficacy of denileukin diftitox in patients receiving (Report on the results of a survey of all patients receiving Remitro ) (JSCS 2025) - No abstract available

Clinical • Hematological Malignancies • Lymphoma • Oncology

New nonchemotherapy treatment options for cutaneous T-cell lymphomas- an update. (PubMed, Expert Rev Anticancer Ther) - "Targeted therapies including brentuximab vedotin, lacutamab, denileukin diftitox, and mogamulizumab have shown activity in registrational trials. Novel agents which modulate tumor microenvironment and upregulate tumor-specific immune responses have been in clinical trials, including bispecific antibodies recruiting immune effectors, agents eradicating suppressive microenvironments, and engineered T cells targeting tumor epitopes. Checkpoint inhibitors may play a role in MF/SS but their role has not been well defined and they may induce hyper progression."

Journal • Review • Cutaneous T-cell Lymphoma • Dermatology • Hematological Malignancies • Lymphoma • Mycosis Fungoides • Non-Hodgkin’s Lymphoma • Oncology • Sezary Syndrome • T Cell Non-Hodgkin Lymphoma

An evaluation of denileukin diftitox for the treatment of relapsed or refractory cutaneous T-cell lymphoma. (PubMed, Expert Opin Biol Ther) - "In addition to direct targeting of CD25 expressing tumor cells, both drugs are also capable of depleting immunoregulatory T-cells. A clinical trial of DD-cxdl in Japan showed that responses were independent of CD25 expression, suggesting multiple mechanisms of action for DD-cxdl in MF/SS and potentially other malignancies."

Journal • Review • Cutaneous T-cell Lymphoma • Dermatology • Hematological Malignancies • Infectious Disease • Lymphoma • Mycosis Fungoides • Non-Hodgkin’s Lymphoma • Oncology • Sezary Syndrome • T Cell Non-Hodgkin Lymphoma • IL2 • IL2RA

Citius Oncology Enters into Distribution Services Agreement with Cardinal Health (PRNewswire) - "This agreement is designed to help provide access to LYMPHIR (denileukin diftitox-cxdl), an innovative immunotherapy FDA-approved for the treatment of adults with relapsed or refractory cutaneous T-cell lymphoma (CTCL), in support of its anticipated U.S. commercial launch."

Commercial • Cutaneous T-cell Lymphoma

Selecting appropriate therapy for cutaneous T-cell lymphomas (CTCLs): recent advances and the unmet need. (PubMed, Expert Opin Pharmacother) - No abstract available

Journal • Cutaneous T-cell Lymphoma • Hematological Malignancies • Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma

A Phase II Study of Denileukin Diftitox in Patients with Advanced Treatment Refractory Breast Cancer. (PubMed, Vaccines (Basel)) - "Denileukin diftitox modulated regulatory T cells. However, the majority of patients experienced disease progression in the study."

Journal • P2 data • Breast Cancer • Infectious Disease • Oncology • Solid Tumor • CD4 • CD8 • FOXP3 • IL2 • IL2RA

Efficacy and Safety of Denileukin Diftitox-Cxdl, an Improved Purity Formulation of Denileukin Diftitox, in Patients With Relapsed or Refractory Cutaneous T-Cell Lymphoma. (PubMed, J Clin Oncol) - "Efficacy and safety results show that DD-cxdl would potentially fulfill a serious, unmet medical need for patients with R/R CTCL."

Journal • Cutaneous T-cell Lymphoma • Dermatology • Fatigue • Hematological Malignancies • Hepatology • Immunology • Infectious Disease • Lymphoma • Mycosis Fungoides • Oncology • Sezary Syndrome • Skin Cancer • T Cell Non-Hodgkin Lymphoma • IL2

Compromising the immunogenicity of diphtheria toxin-based immunotoxins through epitope engineering: An in silico approach. (PubMed, J Pharmacol Toxicol Methods) - "Pseudomonas exotoxin A and diphtheria toxin (DT) have been abundantly used in immunotoxins, with the latter applied as the toxin moiety of the FDA-approved drug Denileukin diftitox (ONTAK®)...By subtracting conserved and ligand-binding residues, K33, T111, and E112 were identified as common epitopes across all platforms...Finally, a 3D model of the mutant was generated and verified. The model was then docked with its native ligand NADH, and the complex's molecular behavior was simulated using molecular dynamics."

Journal • Infectious Disease

Denileukin diftitox therapy for relapsed refractory PTCL (JSH 2024) - "Sponsored by Eisai Co., Ltd."

Hematological Malignancies • Peripheral T-cell Lymphoma

Intraperitoneal immunotherapy with denileukin diftitox (ONTAK) in recurrent refractory ovarian cancer. (PubMed, Gynecol Oncol) - P1 | "Denileukin diftitox (ONTAK) can be safely administered intraperitoneally to recurrent refractory ovarian cancer patients. Regulatory T cells were reduced in ascites and peripheral blood, but there were no significant changes in cytokine levels."

Journal • Infectious Disease • Oncology • Ovarian Cancer • Refractory Ovarian Cancer • Solid Tumor • CXCL8 • IL2RA • TGFB1

Novel Pharmacological Treatment Options of Steroid-Refractory Graft-versus-Host Disease. (PubMed, Adv Hematol) - "These include anti-CD2, anti-CD147, IL-2 antagonist, a mixture of anti-CD3 and anti-CD7 antibodies, anti-CD25, monoclonal antibody to a4b7 on T-cells, anti-CD26, pentostatin, sirolimus, denileukin diftitox, infliximab, itacitinib, and alpha-1 antitripsin...For chronic GVHD, approved options include ruxolitinib with an ORR of up to 62%, ibrutinib with an ORR of up to 77%, and belumosudil with an ORR of up to 77%. Meanwhile, emerging treatments include tyrosine kinase inhibitors such as nilotinib, rituximab, and low-dose IL-2, as well as axatilimab and pomalidomide. While their efficacy needs to be better evaluated through large-scale, multicenter, randomized clinical trials, these novel agents show potential and could provide a better alternative for SR-GVHD treatment in the future."

Clinical • Journal • Review • Acute Graft versus Host Disease • Bone Marrow Transplantation • Chronic Graft versus Host Disease • Graft versus Host Disease • Immunology • Transplantation • DPP4

Targeting regulatory T cells by E7777 enhances CD8 T-cell-mediated anti-tumor activity and extends survival benefit of anti-PD-1 in solid tumor models. (PubMed, Front Immunol) - "This study evaluated whether adding E7777 (a new formulation of denileukin diftitox [DD]) improved the efficacy of anti-PD-1 antibody therapy. Treatment with E7777 was safe and well-tolerated. Combined E7777 and anti-PD-1 therapy was well tolerated and more effective than monotherapy with either drug."

Journal • Preclinical • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Hepatology • Infectious Disease • Liver Cancer • Oncology • Solid Tumor • IL2

T cell activation is insufficient to drive SIV disease progression. (PubMed, JCI Insight) - "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."

Journal • Human Immunodeficiency Virus • Infectious Disease • Inflammation • CD4 • IL2

CCR4-IL2 bispecific immunotoxin is more effective than brentuximab for targeted therapy of cutaneous T-cell lymphoma in a mouse CTCL model. (PubMed, FEBS Open Bio) - "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 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."

Journal • Preclinical • Cutaneous T-cell Lymphoma • Dermatology • Hematological Malignancies • Infectious Disease • Lymphoma • Mycosis Fungoides • Non-Hodgkin’s Lymphoma • Oncology • Sezary Syndrome • T Cell Non-Hodgkin Lymphoma • CCR4 • IL2 • IL2RA • TNFRSF8

Gene Expression Profiling and Signaling Pathway Analysis of Tolerant T Cells Circulating in Adult Patients after Ptcy Haplotransplantation (ASH 2022) - "All received Flu+TBI (+/- Cy) pre-conditioning and haplo-HSCT with post-transplant Cytoxan (PTCy) and FK506 as GvHD prophylaxis...We described previously Treg depletion from purified T cells with IL2-immunotoxin (Denileukin Diftitox, Seragen Inc™) to test the involvement of these cells in long-term tolerance...T-cell exhaustion was tested by blocking the PD1 pathway with anti-PD1 MoAb (OPDIVO, Bristol Myers Squibb™)... Hypo-reactivity of donor-derived circulating T cells to recipient DC and graft T cells to graft DC (negative control) were evident. 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..."

Clinical • IO biomarker • Bone Marrow Transplantation • Graft versus Host Disease • Hematological Malignancies • Immune Modulation • Immunology • Inflammation • Leukemia • Myelodysplastic Syndrome • Oncology • Transplant Rejection • Transplantation • CD33 • PD-L1

An electrochemiluminescence assay for quantification of Denileukin Diftitox and its anti-drug antibodies in rat serum. (PubMed, J Pharmacol Toxicol Methods) - "Drug-induced ADA was detected by screening assay followed by confirmatory assay. The developed method was successfully applied to assess pharmacokinetics and immunogenicity to support toxicity studies in rats."

Journal • Preclinical • Hematological Malignancies • Infectious Disease • Lymphoma • Oncology • IL2

Efficacy of Combinatorial Treatment Approaches in CTCL (ASH 2022) - "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."

Clinical • Cutaneous T-cell Lymphoma • Dermatology • Hematological Malignancies • Lymphoma • Mycosis Fungoides • Non-Hodgkin’s Lymphoma • Oncology • Sezary Syndrome • T Cell Non-Hodgkin Lymphoma

Novel Drugs in the Treatment of Steroid Refractory Acute Graft Versus Host Disease (ASH 2022) - "A summary of the results is described here.Result s :Denilekin diftitox (Ontak), a recombinant protein composed of IL-2 fused to diphtheria toxin, was studied in a phase 1 trial by Vincent et al...OS at 1 and 2 years was 50% and 38.6%, respectively.Pentostatin, an adenosine deaminase inhibitor, was studied by Meade et al...On an average dose of 5 mg/m2, sirolimus showed a CR of 23% and PR of 33%.Couriel et al., in a phase III trial, 63 patients were randomized and received either methylprednisone (MP) 2mg/kg or infliximab plus MP...reported the results of a phase II trial in which 44 patients were treated with visilizumab with ORR of 32% at day 42.Bordigoni et al. 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."

Acute Graft versus Host Disease • Bone Marrow Transplantation • Graft versus Host Disease • Hematological Malignancies • Immunology • Infectious Disease • Oncology • IL2

Denileukin diftitox-induced systemic capillary leak syndrome with acute kidney injury. (PubMed, CEN Case Rep) - "However, the pathophysiology of this disease is not well understood. Herein, we report a case of denileukin diftitox-induced systemic capillary leak syndrome."

Journal • Acute Kidney Injury • Cutaneous T-cell Lymphoma • Hematological Malignancies • Hypotension • Infectious Disease • Lymphoma • Nephrology • Oncology • Renal Disease • T Cell Non-Hodgkin Lymphoma

Immunotherapy in indolent Non-Hodgkin's Lymphoma. (PubMed, Leuk Res Rep) - "Other than that, a resistance mechanism to rituximab emerged by inducing a failure in the apoptosis mechanism...Here came the development of 90Y-ibritumomab tiuxetan and 131I-tositumomab. After it, humanized anti-CD20 emerged ofatumumab, IMMU106 (veltuzumab) in 2005, and ocrelizumab which are considered as second generation anti-CD20 and 3 generation anti-CD20 include AME-133v (ocaratuzumab), PRO131921 and GA101 (obinutuzumab). Also multiple other agents emerged targeting different surface cell antigens like CD52 (alemtuzumab), CD22 (unconjugated epratuzumab and calicheamicin conjugated CMC-544 [inotuzumab ozogamicin]), CD80 (galiximab), CD2 (MEDI-507 [siplizumab]), CD30 (SGN-30 and MDX-060 [iratumumab], Brentuximab vedotin), CD40 (SGN-40), and CD79b (Polatuzumab). 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..."

Journal • Allergy • Chronic Lymphocytic Leukemia • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Immune Modulation • Indolent Lymphoma • Inflammation • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Waldenstrom Macroglobulinemia • CD22 • CD40 • CD52 • CD79B • TNFRSF8

"Anyone familiar with $CTXR ? Developing a modified version of Ontak (discontinued 2014 bc of manufacturing difficulties), and founded by Ukrainians https://t.co/9vK2voYgFi" (@JacobPlieth)

Pseudomonas Exotoxin-Based Immunotoxins: Over Three Decades of Efforts on Targeting Cancer Cells With the Toxin. (PubMed, Front Oncol) - "To date, three ITs have gained Food and Drug Administration (FDA) approval for human use, including denileukin diftitox (FDA approval: 1999), tagraxofusp (FDA approval: 2018), and moxetumomab pasudotox (FDA approval: 2018). 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."

Journal • Review • Infectious Disease • Oncology