Complete regression of established human glioblastoma tumor xenograft by interleukin-4 toxin therapy.
No curative therapy is available for malignant gliomas. We have discovered that human glioblastoma cells express high affinity interleukin-4 receptor (IL-4R), which is an attractive target for receptor-directed IL-4 toxin therapy. The IL-4 toxin, IL-4(38-37)-PE38KDEL, is a fusion protein containing translocation and enzymatic domains of Pseudomonas exotoxin and a circularly permuted human IL-4. The IL-4 toxin binds specifically to the IL-4R and is highly cytotoxic to glioblastoma cells, as determined by clonogenic and protein synthesis inhibition assays. Intratumoral administration of the IL-4 toxin given on alternate days for 3-4 doses into U251 glioblastoma flank tumors in nude mice, showed a complete remission of small (approximately 13 mm3) and large (approximately 60 mm3) tumors in all animals, without any evidence of toxicity. A significant antitumor activity was also observed when the IL-4 toxin was administered via i.p. and i.v. routes. These results demonstrate that the IL-4 toxin may be a new therapeutic drug for the treatment of human glioblastoma. Therefore, we have begun a Phase I clinical trial with IL-4(38-37)-PE38KDEL for treatment of human glioblastoma.
Laboratory of Molecular Tumor Biology, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, USA.
S R
SR
Husain
N
N
Behari
R J
RJ
Kreitman
I
I
Pastan
R K
RK
Puri
D036002:ADP Ribose Transferases; D000818:Animals; D001427:Bacterial Toxins; D005098:Exotoxins / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D005260:Female; D005909:Glioblastoma / Q000378:metabolism* / Q000628:therapy*; D006801:Humans; D015552:Injections, Intralesional; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D015847:Interleukin-4 / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D051379:Mice; D019948:Receptors, Interleukin-4 / Q000378:metabolism*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D005098:Exotoxins; D015847:Interleukin-4; D019948:Receptors, Interleukin-4; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A