Biomedical Engineering Reference
In-Depth Information
IL-13 (IL-13R) is expressed on many human cancer cells,
including GBM, AIDS-associated Kaposi's sarcoma, ovar-
ian carcinoma, renal cell carcinoma, and fibroblast cell lines
[42]. The IL-13R structure varies according to cell type,
existing in three different forms known as type I, type II, and
type III [59,60].
Subunit structure studies of the IL-13R complex in
primary brain tumor cells established the IL-13R
a
2 subunit
as a tumor-specific protein [42]. Immune cells, endothelial
cells, and normal glia and neurons generally express none or
very low amounts of IL-13R [20].
IL-13-PE38 was found to be highly selective and potent
in killing human GBM cells in culture. The activity of IL-13-
PE38 is mediated via IL-13R, as its cytoxicity is blocked by
exposing cell lines to 10-100-fold excess of human IL-13
[41]. Furthermore, IL-13R-negative cell lines or cell lines
expressing low numbers of IL-13R, including human bone
marrow-derived cells and PHA-activated T-cells, are not
susceptible to IL-13-PE38-mediated cytotoxicity [58].
Significant antitumor activity of IL-13-PE38 was
observed in animal models of human glioma, with intra-
tumoral injection proving more efficacious than i.v. or
intraperitoneal (i.p.) administration [20]. In nude mice
with intracerebral glioma, the MTD of IL-13-PE38 was
4
m
g when delivered by bolus injection, and 10
m
g when
delivered by CED. Intracerebral injections of IL-13-PE38
into the right frontal lobe of normal rats were carried out at
total doses of 0.001, 0.01, 0.1, and 1.0
m
g in a constant
volume of 10
m
L. No morphological changes were evident
in the brain tissue removed after 4 days and assessed by light
microscopy. There was no evidence of neuroglial cell toxic-
ity with total toxin doses of up to 1.0
m
g. In a similar
intracerebral toxicity study, IL-13-PE38 at 100, 500,
1000, and 2000
m
g/mL was injected into the right frontal
lobe of rats. There were no changes detected in weight,
behavior, or hematologic or chemistry values after 4 days.
No residual drug was detected in serum. However, IL-13-
PE38 at high dose levels (500
m
g/mL and above) caused
severe brain necrosis and edema around the injection site.
Inflammatory reaction was comparatively minimal [20].
Interstitial infusion of IL-13-PE38 into the rat brain stem
was well tolerated. IL-13-PE38 (10
m
g/mL) delivered as a
24-h infusion of 200
m
L total volume did not cause any
neurological deficits. Post-mortem examination of the brain
up to 2 weeks after treatment did not reveal any histological
changes beyond the site of the cannula [61].
Several Phase I and II studies have been initiated to
investigate IL-13-PE38 as an antitumor agent for the treat-
ment of patients with recurrent malignant glioma. In a Phase
I/II study, IL-13-PE38 was infused intratumorally in adult
patients with recurrent malignant glioma (including ana-
plastic oligoastrocytoma) to determine the MDT of the drug
[62]. Patients received two IL-13-PE38 infusions at 8-week
intervals via two stereotactically placed intratumoral
catheters at a constant infusion rate. One aim of the study
was to determine MTD and toxicity of IL-13-PE38 admin-
istered by CED via intratumoral catheters at 200
m
L/h per
catheter for 96 h (total 38.4 mL), in two courses 8 weeks
apart. Escalation was planned through nine levels ranging
from 0.125 to 12.0
m
g/mL (total dose 4.8 to 460.8
m
g) in
cohorts of three patients per level. Cohorts of three patients
received 0.5, 1.0, 2.0, and 4.0
m
g/mL. Concentrations of up
to 2.0
m
g/mL were safe and well tolerated. Adverse events
reported across all dose ranges were mild and mainly
neurological. The incidence of the most frequent drug-
related AE was 24%, 24%, 14%, 10%, and 10%, respec-
tively, for headache, hemiparesis, brain edema, aphasia, and
ataxia. In the Phase 1 portion of the study, two histopatho-
logical and two radiographic responses were observed, with
progression-free survival ranging from 3 to 88 weeks and
overall survival of 147 weeks. No results have been pub-
lished yet for the Phase II portion of this study [62].
Another Phase I study investigated IL-13-PE38 in adult
supratentorial malignant glioma. In this four-stage study, the
primary objectives were to determine effective dose of IL-
13-PE38 either prior to or post-resection of the tumor
[63,64]. In stage 1, after biopsy and intratumoral catheter
placement on day 1, IL-13-PE38 was administered for 48 h
at 400
m
L/h on days 2 to 4 at escalating doses ranging from
0.25 to 2
m
g/mL. Tumor was resected on day 8 and tissue
was evaluated for necrosis adjacent to the catheter. Follow-
ing resection, 2 or 3 catheters were placed into the brain
adjacent to the tumor resection cavity, and on days 10 to 14,
IL-13-PE38 was given at 750
m
L/h for 96 h at a fixed dose of
0.25
m
g/mL (total dose 18
m
g). In stage 2, intratumoral
infusion was omitted and patients underwent resection of
tumor followed by a 96-h peritumoral infusion of IL-13-
PE38 at 0.5 and 1.0
m
g/mL. In stage 3, the duration of
peritumoral infusion was increased from 5 to 7 days at a
fixed dose of 0.5
m
g/mL. Tumor necrosis up to 2.5 cm from
the catheter tip was demonstrated radiologically in at least
five patients with preoperative intratumoral toxin infusion.
Tumor specimens from at least two patients after intra-
tumoral injection of 0.5
m
g/mL IL-13-PE38 toxin revealed
regional necrosis in an ovoid zone extending 1-2 cm from
the catheter tip. Peritumoral post-resection MTD was
defined as 0.5
m
g/mL. Similar adverse events occurred
across all cohorts, most being neurological. Incidence of
the most frequent AE was 53%, 27%, 20%, 17%, 13%, 13%,
13%, 10%, 10%, and 10%, respectively, for headache,
hemiparesis, sensory disturbance, fatigue, aphasia, facial
paresis, abnormal gait, convulsions, hypesthesia, and lym-
phopenia. Prolonged individual patient survival has been
observed after peritumoral therapy at concentrations of
0.25
m
g/mL (total dose 18
m
g) and above [20,65,66].
A further multicenter Phase I/II study investigated IL-13-
PE38 in adult recurrent supratentorial malignant glioma
with confirmed radiographic evidence of
recurrent or
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