Rw. Rand et al., Intratumoral administration of recombinant circularly permuted interleukin-4-Pseudomonas exotoxin in patients with high-grade glioma, CLIN CANC R, 6(6), 2000, pp. 2157-2165
Human glioblastoma but not normal brain cells express numerous receptors fo
r the cytokine interleukin (IL)-4. To target these receptors, we have inves
tigated the safety and activity of directly infusing IL-4(38-37)-PE38KDEL,
a chimeric protein composed of circularly permuted IL-4 and a truncated for
m of Pseudomonas exotoxin (PE), into recurrent malignant high-grade gliomas
, IL-4(38-37)-PE38KDEL (IL-4-toxin) was infused over a 4-8-day period into
gliomas of nine patients by one to three stereotactically placed catheters,
No apparent systemic toxicity occurred in any patient. The infusion of IL-
4-toxin in six of nine patients showed glioma necrosis as evidenced by dimi
nished gadolinium enhancement on magnetic resonance imaging. Seven of nine
patients underwent craniotomy because of increased intracranial pressure at
16-101 days after the beginning of infusion. In six of these seven patient
s, partial-to-extensive tumor necrosis with edema was confirmed pathologica
lly. No histological evidence of neurotoxicity to normal brain was identifi
ed in any patient. Two patients were not operated on; by magnetic resonance
imaging, one showed mottled gadolinium enhancement, and the other showed e
xtensive necrosis of tumor leading to complete remission; this patient rema
ins disease-free >18 months after the procedure. We conclude that direct gl
ioma injection of IL-4(38-37)-PE38KDEL is safe without systemic toxicity. L
ocal toxicity seemed attributable mainly to tumor necrosis or occasionally
to the volume of infusion. Histological evidence of toxicity to normal brai
n was not observed and in many patients, could be pathologically excluded.
Additional patients are being treated to determine the maximal tolerated co
ncentration and volume of IL-4(38-37)-PE38KDEL.