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Department of Neuro-Oncology, John Wayne Cancer Institute, Santa Monica, California 90404 [R. W. R.]; Laboratory of Molecular Biology, Division of Basic Sciences, National Cancer Institute, NIH, Bethesda, Maryland 20892 [R. J. K., I. P.]; Neuroradiology Department, NIH, Bethesda, Maryland 20892 [N. P.]; Division of Biostatistics and Epidemiology, Center for Biologics Evaluation and Research, United States Food and Drug Administration, Rockville, Maryland 20850 [F. V.]; and Laboratory of Molecular Tumor Biology, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, United States Food and Drug Administration, Bethesda, Maryland 20892 [R. K. P.]
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ABSTRACT |
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 Top ABSTRACT IntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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Introduction |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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We have shown that IL-4Rs are present on the surface of malignant glioma/astrocytoma cells (9) . This surface protein is overexpressed on tumor cells but not on normal brain tissues (9 , 10) . To specifically target these receptors, we first produced a recombinant chimeric protein comprised of IL-4 and a mutated form of PE. This targeted toxin was highly cytotoxic to glioma cells in a specific manner (10, 11, 12, 13) but bound to IL-4R in glioma cells with 37-fold less affinity than native IL-4. To improve the binding affinity of the ligand, we altered the toxin ligand junction by producing a circularly permuted IL-4 and used it to make the recombinant toxin, IL-4(38-37)-PE38KDEL (13, 14, 15) . This single-chain recombinant molecule contains amino acids 38–129 of IL-4, fused via a peptide linker to amino acids 1–37, which in turn is fused to the toxin. PE38KDEL is composed of amino acids 253–364 and 381–608 of PE, with KDEL (an endoplasmic retaining sequence), at positions 609–612. This purified toxin was found to be highly cytotoxic to IL-4R-positive glioblastoma cells. IL-4(38-37)-PE38KDEL bound to glioblastoma cells with 16-fold higher affinity than the native (non-circularly permuted) IL-4-toxins, IL-4-PE4E, or IL-4-PE38KDEL. More importantly, IL-4(38-37)-PE38KDEL was 3- to 30-fold more cytotoxic to glioblastoma cell lines compared with the first generation IL-4-toxins (10) . These in vitro data indicated that glioblastoma cells are very sensitive to IL-4-toxins. In an in vivo model of human tumor in mice, it was shown that the increased binding and cytotoxic activity of IL-4(38-37)-PE38KDEL leads to increased antitumor activity (15 , 16) .
To assess in vivo activity of the IL-4-toxin against GBM,
immunodeficient nude mice were injected s.c. with human U251 glioma
cells, which resulted in the development of tumors with a mean size of
13–60 mm3 by day 3–4. Intratumoral
administration of IL-4(38-37)-PE38KDEL into U251 glioblastoma flank
tumors in nude mice on alternate days for three to four doses induced a
complete regression of small (
13 mm3) and
large (60 mm3) tumors in all of the animals
without any evidence of toxicity. Most of the IL-4(38-37)-PE38KDEL
remained localized on intratumoral administration. Significant
antitumor activity was also observed when IL-4-toxin was administered
via i.p. and i.v. routes. These results demonstrated that
IL-4(38-37)-PE38KDEL might have significant antitumor activity against
human glioblastoma (16)
.
The blood-brain barrier, which is a major impediment to the entry of many "small molecule" drugs into the CNS, effectively precludes any method of administration of macromolecules except by direct injection. Direct infusions into brain tumors can be safe and effective. When directly infused into white matter/tumors, fluids containing the targeted toxins can distribute by bulk flow (convection) through the interstitial spaces and can spread to distant areas of the brain (17, 18, 19) . High-flow microinfusion provides a high local drug concentration and enables a greater volume of tissue to be bathed with the drug than low-flow microinfusion or release of chemotherapeutic agents from tumor implants that rely on diffusion (20) . In the current study, to evaluate the toxicity and antitumor activity, we infused IL-4(38-37)-PE38KDEL in a dose-dependent schedule intratumoraly by the high-flow microinfusion technique (17, 18, 19, 20) in patients with recurrent malignant high-grade gliomas.
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Materials and Methods |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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Patients
Patients were eligible who showed MRI-documented recurrence or
progression of a malignant brain tumor (GBM) after standard therapy and
received no other treatment within 3 weeks of inclusion in this
protocol. All of the patients were previously treated with external
beam radiation but failed to show improvement. The tumors that
had no satellite lesions stereotactically accessible and no significant
mass effect were treated. Adult patients over 18 years of age with
Karnofsky performance score of 
60 were enrolled. Men and women of
childbearing potential were instructed to practice birth control. Women
of childbearing age had a negative serum or urine pregnancy test within
7 days of study entry. Patients were able to give informed consent,
were willing and medically capable of undergoing the surgical
operation, and were not receiving other investigational agents for the
treatment of malignant astrocytoma. All of the patients had adequate
baseline organ function as assessed by the following laboratory
parameters on their preoperative visit (e.g., within 21 days
of commencement of study drug infusion): serum creatinine, <2 mg/dl;
platelet count, >100,000/mm3; absolute
neutrophil count, >1,500/mm3; hemoglobin,
>9.5 mg/dl; prothrombin time/partial thromboplastin
time, at or below the upper limit of normal; bilirubin, <2
mg/dl; and aspartate aminotransferase and alanine aminotransferase,
less than twice the upper limit of normal.
Patients with diffuse subependymal or CSF disease, with anaplastic oligodendroglioma, with tumors involving the brainstem, cerebellum, or both hemispheres, unable or unwilling to give informed consent, with an active infection requiring treatment or having an unexplained febrile illness were excluded from the study. Institutional Review Boards of the United States Food and Drug Administration and of St. John’s Hospital (Santa Monica, CA) approved the protocol. The investigational new drug exception (IND 7004) was authorized by the USFDA in February 1997.
Treatment
All of the patients underwent a standard stereotactic biopsy under
magnetic resonance/computerized tomography guidance under
appropriate anesthesia before placement of catheters as described by
Laske et al. (20)
. Tumor biopsy of the
enhancing tissue was performed for histology. After a positive biopsy
for recurrent tumor, up to a maximum of three silastic-infusion
catheters (2.1-mm outer diameter, Pudenz catheter(s),
Medtronics, PS Medical, Galeta, CA) were placed with the tip at
a selected site in the tumor using stereotactic guidance through
small-twist drill holes. The shortest possible routes were chosen to
place catheters into tumors. The number of catheters was determined
based on the tumor size and the volume of drug to be administered to
ensure maximal saturation of tumor bed and margins in the designated
period of time. Patients who received the largest volumes were
implanted with three catheters. Wherever three catheters were used, one
catheter tip was advanced to the center of the tumor, and the second
and third catheter tips were placed at opposing poles of the tumor
adjacent to the largest volume of white matter. The proximal ends of
the catheters were sewn to the scalp. To maintain patency of the
catheter and attached tubing, the intratumoral catheter and tubing were
filled with IL-4-toxin after insertion. After surgery, the externalized
catheters were connected to Medex 2010 micropumps (Medtronic, Inc.,
Minneapolis, MN) and filled with IL-4(38-37)-PE38KDEL. These procedures
were performed under local and general anesthesia as necessary.
Infusion within each catheter began immediately, or within 24 h after catheter insertion, at a very slow pace over a 4–8 day period (0.3–0.6 ml/h). The pump was filled once only. Patients were treated with steroids and antibiotics at standard doses. The catheters were removed after completion of therapy at the bed site and antibiotics were discontinued; steroid dosage (up to 20 mg/day in divided doses) was slowly tapered to maintenance level. Some patients were given diuretics to relieve edema. A MR scan was performed, and patients were discharged after they were stable and had undergone an interim physical and neurological examination and had blood drawn for chemistry and hematology.
The starting dose was selected based on the preclinical animal studies. The first dose level of 0.2 µg/ml was 0.002 times lower than the dose that produced histological damage to normal brain when administered intra-brain parenchyma in rats and 0.0333 times of MTD injected intrathecally in monkeys. The dose was escalated one log in the next cohort of three patients and then one-half-logs to the highest dose (6 µg/ml). The volume of fluid infused was determined based on the tumor volume determined by MR scan, including 1- to 2-cm margins of normal brain tissue. The volume of each infusion was determined by the MRI computer including the space between each view to estimate the tumor volume. In the investigational new drug application, the MTD was defined as a dose lower than a dose at which two or more patients experienced higher than grade-2 CNS or systemic toxicity. However, no MTD was determined in this trial. In ongoing multicenter trials, we are escalating the concentration of drug from 6 µg/ml to 15 µg/ml. Once a maximum tolerated concentration is achieved, we intend to escalate the volume of infusion to determine maximum tolerated volume.
Patient Evaluation
Pretreatment.
All of the patients underwent a complete history and physical
examination and blood and serum chemistry tests to assess the
functioning of all of the major organs. These patients also underwent
baseline MRI scans, with and without gadolinium enhancement. MRIs were
reviewed by neuroradiologist (N. P.), and tumor histology slides were
reviewed by a neuropathologist (F. V.).
During and After Treatment.
During infusion, the patient’s vital signs and neurological status
were monitored closely each day of the infusion. No symptoms of
increased ICP were observed during infusion. Blood samples from every
day of treatment and on the third day posttreatment were obtained for
complete blood count and serum chemistry and demonstrated no
appreciable abnormalities.
Patients returned as outpatients for follow-up evaluation every 4 weeks (±5 days), unless otherwise indicated, for 16 weeks and every 8 weeks (±5 days) thereafter. At those visits, patients underwent an interim physical and physical/neurological examination and had blood drawn for chemistry and hematology and a brain MR scan, MR spectroscopy, or PET scan to determine antitumor effect. MR spectroscopy was performed in the last four patients who showed elevation of choline constant preoperatively with active malignant glioma.
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Results |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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. All of
these patients had undergone craniotomy and radiation therapy before
entry into the trial. The Karnofsky performance score of these patients
was at least 60. These nine patients with malignant gliomas were
infused with IL(38-37)-PE38KDEL via one to three small diameter
catheters. Because the goal of this trial was to saturate the entire
glioma bed and surrounding brain tissue, the IL-4-toxin was infused at
a very slow pace over a 4–8 day period (0.3–0.6 ml/h) using
micropumps. Pudenz catheter(s) of 2.1-mm outer diameter were placed
into and around the malignant glioma and positioned accurately after
stereotactic tumor biopsy, and IL-4(38-37)-PE38KDEL was infused using
one or more Medex 2010 micropumps. None of these patients showed any
additional discomfort with IL-4-toxin infusion. Patient 2 received two
additional infusions of IL-4-toxin in month 2 and 3 and patient 5
received one additional infusion 1 month after the initial infusion.
Four infusions were done at the 0.2-µg/ml dose, three at the
2.0-µg/ml, and five at the 6.0-µg/ml dose.
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. There
were no treatment-related deaths. Cerebral edema causing corresponding
signs and symptoms of increased ICP developed without evidence of
previous cerebral edema on days 27, 14, and 10 in patients 2, 4, and 6,
respectively. Four other patients developed increased ICP between 43
and 97 days post-IL-4-toxin infusion (Table 3)
. Craniotomy was performed with tumor
resection in seven patients because decadron (up to 20 mg/day) and
antidiuretic medications could not control the increased cerebral
edema. The symptoms and signs of the increased ICP improved as the
pressure diminished.
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. All of these patients
showed a slight but significant decrease in the thickness of
gadolinium-enhancing rim 4–9 days after IL-4-toxin therapy. However,
repeat scans about 1–4 months after infusion showed an increase in
necrotic cavity but also an increase in gadolinium enhancement with new
brain involvement or progression of tumor that grew at a site distant
from the infusion. Patient 3 developed two new cavities attributable
probably to tumor necrosis with ring enhancement as assessed 33 days
postinfusion. These cavities may have been generated because of
catheter-related tissue necrosis. All of these patients died after
progression of their disease. Patients 4 and 5 received the 2-µg/ml dose, whereas patient 5 also received an additional cycle at 6 µg/ml. Patient 4 showed a mottled pattern of gadolinium uptake, which decreased 7 days after IL-4-toxin infusion. In patient 5, MRI at the end of the first infusion (day 5) showed a decrease in gadolinium enhancement. However, 64 days after the first infusion, an increase in tumor size was observed. Craniotomy was performed because of uncontrolled ICP on day 66. The second infusion was begun on day 104 of first infusion. About 1 month after the second infusion, gadolinium enhancement was further increased. A repeat craniotomy was performed 18 days after the second infusion that showed no IL-4-toxin induced further necrosis of rapidly growing glioma. Both of the patients expired because of tumor progression.
The next four patients received the 6-µg/ml dose level. In patient 6,
MRI showed a marked decrease in gadolinium enhancement 9 days after the
infusion (Fig. 1)
. However, the patient
underwent craniotomy to relieve increased ICP with a subsequent
improvement of contralateral extremity weakness. The tumor at
craniotomy appeared to be extensively necrosed with residual areas of
GBM and focal oligodendroglial differentiation. Sixteen weeks after
IL-4-toxin infusion and surgery, the patient went into coma shortly
before his death. A premorbid PET scan showed no evidence of increased
metabolic activity in the region of glioma (not shown). The cause of
death was attributed to uncontrollable mass effect caused by ongoing
edema, but because an autopsy was refused, it could not be
histologically confirmed whether viable tumor remained.
|
. An
enhanced MRI 9 months (Fig. 3)
and 15 months postinfusion demonstrated
no evidence of neoplasm recurrence (data not
shown). The right lateral ventricle had
expanded into the area of the original tumor site. The patient is
without neurological deficits and, 18 months postinfusion, is well,
doing daily gardening and holding a part-time job. This patient is
currently not taking any anticonvulsive medications.
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Of the nine patients treated, six patients (patients 2, 4, 5, 6, 7, and
9) showed necrosis of their treated tumor as determined by MRI obtained
7 days to 15 months after IL-4-toxin infusion. Among these, three
patients (patients 3, 4, and 6) were operated on 2–12 days after MRI
scanning to reduce ICP that was not controlled by decadron and
antidiuretic medications. Tumor necrosis was documented histologically
in all three of these patients, as well as in a third patient (patient
2) who did not have evidence of tumor necrosis by MRI. Fig. 4
shows sections from three of these
patients (patients 2, 3, and 6) in which normal brain was included in
the sample of necrotic tumor. The surgical procedure in patients 3 and
6 was performed after the first cycle of the 0.2-µg/ml and 6-µg/ml
dose levels, respectively, whereas patient 3 had a third cycle at
the 2-µg/ml dose level. Thus, whereas pathological confirmation of
selective targeting of glioma was not possible in all of the patients,
Fig. 4
represents evidence at all of the 3 dose levels that
IL-4(38-37)-PE38KDEL treatment was associated with necrosis of tumor
but not of normal brain.
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Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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Two patients developed communicating hydrocephalus corrected by V-P shunt procedures. The exact mechanism of this phenomenon is not known. However, a reasonable explanation is that necrotic malignant glioma cells that were adjacent to the subarachnoid spaces gained access to the cerebrospinal fluid, which damaged the arachnoid villae similar to what often happens after a serious subarachnoid hemorrhage from a ruptured cerebral aneurysm. Recent studies have hypothesized that inflammatory reactions triggered by the inflammation or blood-clotting products could result in obstruction of CSF flow through arachnoid villi into the venous sinus (24) . Thus, if necrosed malignant glioma tissue is present adjacent to the subarachnoid spaces, postinfusion resection of the tissue in the second week may prevent this complication.
Targeted toxins can be enormously tumor-specific, and they have limited
systemic toxicity when administered directly into the tumor site
(25, 26, 27, 28, 29)
. Hypoxia renders neoplastic cells more resistant
to radiation therapy and/or chemotherapy but may have less effect on
the benefit of targeted toxins. Gliomas, which are radiation- or
chemotherapy-resistant, may be sensitive to targeted toxins because of
a difference in mechanism of action (30)
. Moreover, the
cytotoxic potency of targeted toxins is five to ten times greater than
that of chemotherapeutic agents (26)
. Thus targeted toxins
provide a unique approach to treating cancers that express unique
tumor-associated antigen or receptors. Many targeted toxins have been
tested in the clinic. LMB-1 and LMB-2 were administered to numerous
patients with solid cancer (31)
and refractory hairy cell
leukemia (32
, 33) , respectively. LMB-1 was found to be
active in 5 of 38 patients with solid tumors. IL-2-diphtheria toxin has
been tested against cutaneous T-cell lymphoma and has been
found to be effective in this disease (34)
. A mouse CD22
monoclonal antibody, chemically coupled to deglycosylated ricin A
chain, has been tested in the clinic and found effective in 20% of
patients with B-cell lymphomas (35
, 36)
. Recently,
transferrin-receptor-targeted transferrin-diphtheria toxin has been
administered to 18 patients with brain tumors using high-flow
microinfusion technique similar to that used in our present study
(20)
. Transferrin-CRM107 was found to cause brain tumor
regression in 60% of the patients, including complete responses in two
patients. This study demonstrated that direct interstitial infusion
could be used successfully to distribute a large protein
(Mr 140,000) in the tumor bed
and surrounding brain tissue. Despite these successes,
transferrin-CRM107 was found to show peritumoral brain injury at doses
1 µg/ml This brain injury occurred up to 4 cm from the infusion
point (20)
. However, in our studies, no
normal-brain-tissue injury was identified at drug concentration up to 6
µg/ml These data indicate that IL-4(38-37)-PE38KDEL is highly
specific for cells that express large numbers of IL-4Rs. The lack of
toxicity to normal brain is consistent with our previous observation of
the lack of IL-4Rs in normal brain tissues from six individuals
(10)
.
The results of our study demonstrate that regional administration of targeted toxin that is directed at IL-4Rs on GBM can elicit antitumor response while limiting systemic drug exposure, inasmuch as no systemic toxicity was observed in any patient. This observation is consistent with our previous study in monkeys in which, on intrathecal administration of IL-4(38-37)-P338KDEL, high concentration of drug in the CSF was detected, although no detectable systemic drug levels or systemic toxicities were observed (10) .
Although most patients showed significant necrosis of their treated tumor as a result of IL-4(38-37)-PE38KDEL infusion, all but one patient exhibited tumor recurrence and death attributable to progressive disease. Most patients recurred at the same sites or at different sites that were not treated with our drug. One patient who remains a complete responder had a smaller tumor recurrence, which suggests that we succeeded in saturating the entire tumor bed with IL-4-toxin. Additional patients with similar tumor volume need to be treated at this and higher dose levels to confirm our initial observation. On the basis of these observations, our extended clinical trial is ongoing at fourteen additional centers in the United States and Germany.
We conclude that direct glioma injection of IL-4(38-37)-PE38KDEL toxin can be accomplished without systemic toxicity and is associated with a high incidence of cerebral edema that appears to be related to necrosis of the treated high-grade glioma. Additional clinical trials are under way to fully explore efficacy of IL-4(38-37)-PE38KDEL for malignant high-grade glioma, a particularly deadly form of human cancer.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported in part by the Kadoorie Foundation,
the Lou Ehlers Foundation, the Frank G. Lyon foundation, and individual
donations that were made in memory of patients. 
2 To whom requests for reprints should be
addressed, at Laboratory of Molecular Tumor Biology, Division of
Cellular and Gene Therapies, Center for Biologics Evaluation and
Research, Food and Drug Administration, NIH, Building 29B, Room 2NN10,
29 Lincoln Drive, MSC 4555, Bethesda, Maryland 20892. E-mail: puri{at}cber.fda.gov
3 The abbreviations used are: GBM,
glioblastoma multiforme; MR, magnetic resonance; MRI, MR imaging; CNS,
central nervous system; IL, interleukin; IL-4R, IL-4 receptor; PE,
Pseudomonas exotoxin; PET, positron emission tomography;
USFDA, United States Food and Drug Administration; MTD, maximum
tolerated dose; ICP, intracranial pressure; V-P, ventriculoperitoneal
(shunt); CSF, cerebrospinal fluid.
Received 1/27/00; revised 3/ 9/00; accepted 3/ 9/00.
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c chain in RCC cells does not improve sensitivity. Cell. Immunol., 171: 80-86, 1996.[CrossRef][Medline]
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