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.
Husain
S R
SR
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.
Behari
N
N
Kreitman
R J
RJ
Pastan
I
I
Puri
R K
RK
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