Ontak (denileukin diftitox)

Efficacy and safety results show that DD-cxdl would potentially fulfill a serious, unmet medical need for patients with R/R CTCL.

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.

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.

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.

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.

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 T-cells including the alloreactive T cells remained.

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 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.

P1/2, N=30, Recruiting, Masonic Cancer Center, University of Minnesota | Not yet recruiting --> Recruiting

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.

P1/2, N=30, Not yet recruiting, Masonic Cancer Center, University of Minnesota

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.

P3, N=115, Recruiting, Eisai Inc. | Trial completion date: Mar 2021 --> Aug 2021 | Trial primary completion date: Mar 2021 --> Aug 2021

To target Treg/MDSCs cells, we have developed two diphtheria-toxin based fusion protein toxins and are currently evaluating the activity of these molecules both as monotherapies and dual therapies in combination with CPIs. To target MDSCs and TNBC tumor cells, we genetically constructed, expressed and purified a diphtheria toxin-based fusion protein, s-DAB389mIL-4 that targets the IL-4 receptor (IL-4Rα) on these cell populations... These findings suggest that s-DABmIL-4 both as a monotherapy and in combination with s-DABIL-2(V6A) results in transient reduction of both MDSCs and Tregs. These observations suggest that these novel fusion protein toxins may serve as an effective immunotherapeutic regimen for the treatment of TNBC. Based upon these results, we are currently testing these fusion protein toxins in combination with checkpoint blockade therapy.

P3, N=115, Recruiting, Eisai Inc. | Trial completion date: Apr 2020 --> Mar 2021 | Trial primary completion date: Mar 2020 --> Mar 2021

Recently, we have developed diphtheria toxin based recombinant Ontak -like human IL2 fusion toxin (IL2 fusion toxin) and anti-human CCR4 immunotoxin (CCR4 immunotoxin)...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.

P3, N=115, Recruiting, Eisai Inc. | Active, not recruiting --> Recruiting

P3, N=115, Active, not recruiting, Eisai Inc. | N=70 --> 115

The primary endpoint of the study was met with greater lower limit of 2-sided 95% CI in ORR than the predefined 5% threshold. The study results indicated the promising efficacy and acceptable safety profile of E7777 at the dose of 9 μg/kg/day in Japanese pts with relapsed or refractory PTCL and CTCL, regardless of the level of tumor CD25 expression. The common AEs were manageable, but ALT/AST increased, hypoalbuminemia and capillary leak syndrome should be carefully managed during the treatment.