This is a single center, phase I dose escalation study designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of deimmunized CD133KDEL (dCD133KDEL), a ligand-directed, deimmunized pseudomonas toxin against CD133, in patients with advanced, previously treated, refractory solid tumors.

开始日期2018-12-01

申办/合作机构

University of Minnesota Masonic Cancer Center

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2013-09-01·Gynecologic Oncology2区 · 医学

Targeting CD133 in an in vivo ovarian cancer model reduces ovarian cancer progression

2区 · 医学

Article

作者: Daniel A. Vallera ; Amy P.N. Skubitz ; Nate N. Waldron ; Elizabeth P. Taras ; Seunguk Oh ; Kristin L.M. Boylan ; Angela Panoskaltsis-Mortari

OBJECTIVESWhile most women with ovarian cancer will achieve complete remission after treatment, the majority will relapse within two years, highlighting the need for novel therapies. Cancer stem cells (CSC) have been identified in ovarian cancer and most other carcinomas as a small population of cells that can self-renew. CSC are more chemoresistant and radio-resistant than the bulk tumor cells; it is likely that CSC are responsible for relapse, the major problem in cancer treatment. CD133 has emerged as one of the most promising markers for CSC in ovarian cancer. The hypothesis driving this study is that despite their low numbers in ovarian cancer tumors, CSC can be eradicated using CD133 targeted therapy and tumor growth can be inhibited.METHODSOvarian cancer cell lines were evaluated using flow cytometry for expression of CD133. In vitro viability studies with an anti-CD133 targeted toxin were performed on one of the cell lines, NIH:OVCAR5. The drug was tested in vivo using a stably transfected luciferase-expressing NIH:OVCAR5 subline in nude mice, so that tumor growth could be monitored by digital imaging in real time.RESULTSOvarian cancer cell lines showed 5.6% to 16.0% CD133 expression. dCD133KDEL inhibited the in vitro growth of NIH:OVCAR5 cells. Despite low numbers of CD133-expressing cells in the tumor population, intraperitoneal drug therapy caused a selective decrease in tumor progression in intraperitoneal NIH:OVCAR5-luc tumors.CONCLUSIONSDirectly targeting CSC that are a major cause of drug resistant tumor relapse with an anti-CD133 targeted toxin shows promise for ovarian cancer therapy.

2013-04-01·Drug Delivery and Translational Research3区 · 医学

Immunotoxin targeting CD133+ breast carcinoma cells

3区 · 医学

Article

作者: Vallera, Daniel A. ; Zellmer, David M. ; Toma, Shoko ; Waldron, Nate N. ; Oh, Seunguk ; Ohlfest, John R. ; Panyam, Jayanth ; Swaminathan, Suresh Kumar

CD133 expression enriches for tumor-initiating cells and is a negative prognostic factor in numerous cancers. We previously developed an immunotoxin against CD133 by fusing a gene fragment encoding the scFv portion of an anti-CD133 antibody to a gene fragment encoding deimmunized PE38KDEL. The resulting fusion protein, dCD133KDEL, demonstrated potent antitumor activity following intratumoral delivery into head neck cell carcinoma xenografts. However, the efficacy against other tumors and the tolerability of systemic administration remained unclear. The purpose of this study was to evaluate the tolerability and efficacy of dCD133KDEL in a systemic human breast carcinoma model. Time course viability studies showed that dCD133KDEL selectively inhibited MDA-MB-231 ductal breast carcinoma cells that contained a minority CD133(+) subpopulation, implicating CD133(+) cells as a source for self-renewal within this cell line. Furthermore, systemic administration of dCD133KDEL caused regression or inhibition of tumor growth in mice bearing an intrasplenic MDA-MB-231 tumor challenge as a model for metastatic disease. In the same model, combined therapy with dCD133KDEL and another immunotoxin designed to target the bulk tumor mass was the most effective therapy, supporting the idea that such combination therapies might better address tumor heterogeneity. dCD133KDEL shows promise as a therapeutic agent and as a biologic tool to study cancer stem cells.

2011-10-01·Molecular Cancer Therapeutics2区 · 医学

Targeting Tumor-Initiating Cancer Cells with dCD133KDEL Shows Impressive Tumor Reductions in a Xenotransplant Model of Human Head and Neck Cancer

2区 · 医学

Article

作者: Oh, Seunguk ; Hexum, Melinda K. ; Vallera, Daniel A. ; Waldron, Nate N. ; Inde, Zintis ; Ohlfest, John R. ; Kaufman, Dan S.

AbstractA novel anticancer agent was constructed by fusing a gene encoding the scFV that targets both glycosylated and unglycosylated forms of CD133 to a gene fragment encoding deimmunized PE38KDEL. The resulting fusion protein, dCD133KDEL, was studied to determine its ability to bind and kill tumor-initiating cells in vitro and in vivo. The anti-CD133 scFV selectively bound HEK293 cells transfected with the CD133 receptor gene. Time course viability studies showed that dCD133KDEL selectively inhibited NA-SCC and UMSCC-11B, 2 head and neck squamous cell carcinomas that contain a CD133 expressing subpopulation. Importantly, the drug did not inhibit the viability of hematopoietic lineages measured by long-term culture-initiating cell and colony-forming assays from sorted human CD34+ progenitor cells. In addition to in vitro studies, in vivo tumor initiation experiments confirmed that CD133-sorted cells implanted into the flanks of nude mice grew faster and larger than unsorted cells. In contrast, cells that were pretreated with dCD133KDEL before implantation showed the slowest and lowest incidence of tumors. Furthermore, UMSCC-11B-luc tumors treated with multiple intratumoral injections of dCD133KDEL showed marked growth inhibition, leading to complete degradation of the tumors that was not observed with an irrelevant control-targeted toxin. Experiments in immunocompetent mice showed that toxin deimmunization resulted in a 90% reduction in circulating antitoxin levels. These studies show that dCD133KDEL is a novel anticancer agent effective at inhibiting cell proliferation, tumor initiation, and eliminating established tumors by targeting the CD133 subpopulation. This agent shows significant promise for potential development as a clinically useful therapy. Mol Cancer Ther; 10(10); 1829–38. ©2011 AACR.

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适应症	最高研发状态	国家/地区	公司	日期
实体瘤	临床申请	美国	University of Minnesota Masonic Cancer Center	2018-12-01
卵巢上皮癌	临床前	-	University of Minnesota	-
卵巢上皮癌	临床前	-	GT Biopharma, Inc.	-