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Clinical Trials |
Departments of Gastrointestinal Medical Oncology [R. L., J. L. A.], Bioimmunotherapy [M. R.], Gynecologic Medical Therapeutics [C. V., A. P. K., J. J. K.], Diagnostic Radiology [M. E. H.], and Pathology [E. A. L.], Memorial Hermann Hospital, Houston, Texas; Departments of Gynecologic Oncology [M. A. N., M. E. G., R. S. F.] and Biomathematics [L. B. L.], The University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030; and Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, Pennsylvania [C. D. P.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Experimental Design: rhIL-12 was administered to 29 previously treated patients with peritoneal carcinomatosis from Müllerian carcinomas, gastrointestinal tract carcinomas and peritoneal mesothelioma in a Phase I trial. rhIL-12 doses were increased from 3 to 600 ng/kg. Three or more patients at each level received weekly i.p. injections of rhIL-12.
Results: Dose-limiting toxicity (elevated transaminase) occurred in 2 of 4 patients at the 600 ng/kg dose. More frequent toxicities included fever, fatigue, abdominal pain, nausea, and catheter-related infections. Ten patients received 300 ng/kg with acceptable frequency and severity of side effects. Two patients (one with ovarian cancer and one with mesothelioma) had no remaining disease at laparoscopy. Eight patients had stable disease and 19 progressive disease. At 300 ng/kg i.p., IL-12 was cleared from peritoneal fluid in a biphasic manner with a terminal-phase half-life of 18.7 h; peritoneal fluid levels of IL-12 5 min after i.p. injection were 100–200 pg/ml, and serum levels reached 
10 pg/ml between 24 and 36 h. IL-1-
, IL-2, IL-10, tumor necrosis factor , and IFN-
were determined in serum and peritoneal fluid. IFN-, IL-10, and tumor necrosis factor were detected most frequently. Immunobiological effects included peritoneal tumor cell apoptosis, decreased tumor cell expression of basic fibroblast growth factor and vascular endothelial growth factor, elevated IFN- and IFN-inducible protein 10 transcripts in peritoneal exudate cells, and increased proportions of peritoneal CD3+ relative to CD14+ cells.
Conclusions: rhIL-12 at 300 ng/kg by weekly i.p. injection is biologically active and adequately tolerated for Phase II studies.
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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(2
, 7
, 8)
, and to exhibit inhibitory activity against tumor cell lines (6
, 7
, 9)
. Murine IL-12 stimulates T-cell progenitors to mature into Th1 cells and stimulates Th1 cells to secrete IFN- (10)
while inhibiting the activation of Th2 cells (11)
. In humans, T-cell clones may secrete both IL-10 and IFN- in response to exogenous and endogenous antigens (12)
. A combination of rIL-12 and other IFN--inducing agents leads to additive effects (5
, 7
, 8)
. rIL-12 induces tumor regression in experimental models (13
, 14) . T-cell infiltrates in these studies were predominantly of the CD8+ phenotype, suggesting an important functional role for CD8+ T cells. IL-12 produces an antiangiogenic effect that is abrogated by neutralizing antibodies to IFN-, possibly mediated by the CXC chemokine IP10 (15, 16, 17)
. Clinical responses to rhIL-12 administered by i.v. or s.c. injection have occurred in renal cell carcinoma (18)
, melanoma (19)
, and cutaneous T-cell lymphoma (20)
at doses from 50 to 500 ng/kg.
Peritoneal carcinomas that metastasize from ovarian and other peritoneal malignancies are associated with substantial numbers of MNLs, primarily T-cells, NK, and dendritic and B cells (21
, 22) . PECs from EOC patients include T cells, many of which express activation characteristics (23
, 24)
. TCR sequencing analysis has revealed high proportions of clonally expanded ß-TCR+ tumor-infiltrating lymphocytes, which appear to be responding to unknown tumor antigen(s) in vivo (25)
. These findings overall suggest that tumor-infiltrating lymphocyte associated with EOC and, possibly, gastrointestinal tract tumors could be responsive to i.p. treatment with rhIL-12. Because recombinant IFN-2b became the first recombinant cytokine to be tested in i.p. clinical therapy trials (26)
, the i.p. route has been used for several other cytokines [reviewed in Freedman et al. (24)
]. In a previous study of i.p. recombinant human IFN- by Pujade-Lauraine et al. (27)
, significant responses were observed even in patients with either microscopic or macroscopic disease.
This is the first report of a clinical trial in which patients with peritoneal carcinomatosis attributable to ovarian and other intra-abdominal malignancies received i.p. injections of rhIL-12. Prior studies with other cytokines of lower molecular weight (24) suggest a lengthened peritoneal cavity residence times for rhIL-12. A weekly schedule of i.p. injections with slow dose escalation was considered appropriate for a Phase I clinical trial.
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PATIENTS AND METHODS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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2 were also required. Hematological requirements included absolute granulocyte count 
1500 cells/mm3, platelets 100,000 cells/mm3, lymphocytes > 800/m3, hemoglobin 9 g/dl, bilirubin 1.5 mg/dl, aspartate aminotransferase or alanine aminotransferase < 2.5x the upper limits of normal, serum creatinine 1.5 mg/dl, and serum albumin 3.5 g/dl. Patients with histories of autoimmune disease on chronic steroid treatment or testing positive for hepatitis C or B were ineligible. Systemic chemotherapy had to be completed at least 3 weeks before entry (6 weeks after mitomycin C and 3 months after pelvic radiation). Patients were ineligible if they had intra-abdominal tumors 10 cm in maximum diameter, hepatic or extra-abdominal disease symptomatic or maximum diameter 2 cm, brain metastasis, and clinical or electrocardiogram findings indicating significant heart disease, positive pregnancy test, active ulcer, or inflammatory bowel disease.
Study Design.
The study was a single-arm nonrandomized, Phase I trial, approved by the National Cancer Institute’s Cancer Therapy Evaluation Program. Patients were treated at the University Clinical Research Center at the University of Texas Memorial Hermann Hospital after obtaining informed consents approved by both M. D. Anderson Cancer Center and Memorial Hermann Hospital Institutional Review Boards. A percutaneous i.p. French no. 5-7 catheter was placed in the Interventional Radiology Department at M. D. Anderson Cancer Center as described previously (24)
. Catheter position and adequacy of distribution was ascertained by fluoroscopy. Patients received prophylactic antibiotic treatment with ciprofloxacin, 500 mg p.o. twice a day 3 times/week, and patients allergic to ciprofloxacin received trimethoprim/sulfamethoxazole, 160/800 mg 3 times/week (24)
. Acetaminophen was taken as needed for fever that followed rhIL-12 injections. In the absence of ascites, 1 liter of D5W/1/4 NS was injected i.p. to facilitate peritoneal cavity distribution of rhIL-12. Additional fluid was injected as necessary to facilitate specimen collection for laboratory studies. rhIL-12 was injected weekly through the catheter, followed by a 100-ml D5W1/4 NS flush. Treatment was given on an outpatient basis. Patients were monitored for 72 h after administration of the first rhIL-12 dose and for 24 h after each subsequent dose. Four weeks of treatment constituted a cycle. Patients were evaluated for response after two cycles. All patients were monitored for toxicity.
Cohorts of 3 patients received a starting dose of 3 ng/kg. Entry to the next dosage level was permitted if at least 2 of 3 patients at the prior level had been evaluated for 2 weeks without DLTs. Ten patients were treated at the MTD to obtain a sufficient number of observations for correlative laboratory studies and to assess more reliably toxicity at that dose level. Toxicity was measured according to Common Toxicity Criteria of the National Cancer Institute. MTD was defined as the dose at which no more than 1 in 6 patients developed a DLT. DLT was defined as reversible grade 3 or 4 hematological toxicity or reversible nonhematological grade 3 toxicity (grade 2 for neurotoxicity) in 33% of patients treated at a given dose level. The following grade 3 or 4 toxicities were not considered dose limiting: grade 3 elevation of liver function tests returning to grade 1 or lower by the next scheduled dose; grade 3 anemia; grade 3 leukopenia, neutropenia, or thrombocytopenia returning to grade 1 or lower by the next scheduled dose; or grade 3 or 4 lymphopenia. MTD was assessed only on patients receiving their first courses of therapy. Three patients/cohort were entered on dose escalation, and if one of the 3 patients developed a DLT, up to an additional 3 patients were entered at that dose level. If 2 patients in a cohort developed DLT, accrual to the cohort was stopped, and the MTD was determined to have been exceeded. Dosage was then decreased to the previous dose level.
Assessment of Response.
Patients were assessed for response by CT scan, peritoneal fluid cytology and physical examination at the end of each 8 weeks of rhIL-12 treatment. Patients with minimal tumor burden were evaluated by laparoscopy.
Pharmacology of i.p. rhIL-12.
Serum and peritoneal concentrations of rhIL-12 were determined during the initial administration of rhIL-12 at the following time intervals: preinjection and then after 5, 10, 15, 30 min, then 1, 2, 4, 6, 8, 10, 24, 36, and 48 h. An additional blood sample was taken at 72 h. All samples were stored at -60°C and were batch processed later.
Cytokine Analysis.
Analyses of different cytokines (IL-1, IL-2, IL-10, TNF-, and IFN-) in serum and peritoneal fluid were performed using specific, quantitative ELISA kits (R&D Systems, Inc., Minneapolis, MN). Analysis of IL-12 was performed using an ELISA modification of procedures and reagents supplied by Genetics Institute, Inc. (Cambridge, MA). Lowest detectable levels in pg/ml were 0–1.6 for rhIL-12, 0–3 for IFN-, 0–0.18 for TNF-, 0–7 for IL-2, 0–1 for IL-10, and 0–1 for IL-1.
Quantitative Analysis of RNA Extracts for Specific Transcripts of IFN-, IL-10, and IP10.
Quantitative analysis of cDNAs prepared from PECs for IFN-, IL-10, and IP10 were determined by reverse transcription-PCR. Cytokine and IP10 analyses were performed, and transcripts were quantitated as we have described previously (23
, 28)
. The IP10 primers used in these experiments were forward 5'-GGAACCTCCAGTCTCAGCACC-3' and reverse: 5'-CAGCCTCTGTGTGGTCCATCC-3' and produce a 375-bp product (15)
.
Immunohistochemistry for Surrogate Angiogenesis Markers bFGF and VEGF.
Immunohistochemical staining and quantitation of antigens on PECs were performed using methods that we have used in previous i.p. therapy trials (22)
. Briefly, cytospin slides were prepared from PECs, fixed with acetone, and frozen at -20°C until ready for staining (22)
. Primary antibodies were added for 2.5 h at room temperature. Slides were incubated for 1 h with secondary antibodies and then with avidin-biotin-peroxidase complex (1/50) for 30 min. 3,3'-Diaminobenzidine plus nickel chloride substrate was used, and slides were counterstained with 1% methyl green. Primary antibodies included anti-VEGF epitope-specific polyclonal rabbit antibody at a concentration of 1/20 (BioGenex, San Ramon, CA), anti-bFGF affinity-purified rabbit polyclonal antibody, 0.1 µg/ml (Santa Cruz Biotechnology, Inc., Santa Cruz, CA), rabbit IgG (Vector Laboratories, Burlingame, CA), and negative control rabbit serum (Supersensitive Rabbit; BioGenex). Secondary antibodies included rabbit biotinylated antigoat IgG at a concentration of 1/200 (Vector Laboratories). Quantitation was done by measuring the mean absorbance parameter on a Samba 4000 image analyzer (22)
.
Terminal Deoxynucleotidyl Transferase-mediated Nick End Labeling Assay for Quantitating Apoptosis.
The method developed by Dr. Mien-Chie Hung (University of Texas M. D. Anderson Cancer Center) for monitoring patients on gene therapy trials was used (29)
. In brief, cytospin slides were prepared from peritoneal fluids and fixed in 4% paraformaldehyde at 4°C for 24 h. Cells were washed in PBS, air dried, immersed in 0.5% triton100, diluted in PBS for 15 min, and washed in distilled water. Deproteination was done with 1:1000 proteinase K (20 µg/ml) at 37°C for 15 min. Slides were washed in distilled water and 1x TDT buffer 0.3 units/µl (1:40). Biotinylated dUTP in 1x TDT buffer was added, slides were incubated for 1 h at 37°C, washed six times in PBS, and blocked with 1 or 10% normal horse serum. Avidin-biotin-peroxidase complex 1:100 was added for 1 h. Slides were washed and developed with 0.125% 3-amino-9-ethylcarbazole buffer and counterstained with Meyer’s hematoxylin.
Immunofluorescence Analysis of Peritoneal MNL Population Determination.
MNLs from PECs that expressed differentiation antigens and early intermediate and late activation markers were determined by immunofluorescence using a fluorescence-activated cell sorter, as we have described previously (22)
.
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RESULTS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. All had peritoneal carcinomatosis. Of these patients, 28 had received prior chemotherapy, and the patient with peritoneal mesothelioma had received only surgical treatment. Minimal residual disease (<1 cm) was present in 7 patients.
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) were observed in this study. DLTs were encountered in 2 of 4 patients who received 600 ng/kg; grade 3 transaminase elevation was seen that did not return to grade 1 or less by the time the next dose was due, and the MTD was therefore exceeded. Dose reductions to 300 ng/kg were required for these patients. One of 11 patients evaluable for toxicity required reduction from 300 to 100 ng/kg because of delayed recovery from a grade 3 transaminase elevation. Two patients at the 100 ng/kg level received 2 and 6 unscheduled doses of 500 ng/kg, respectively, because of a dilution error. These dose variances occurred after completion of the response assessments and without any toxicities above grade 1. During the same study period, 2 patients at the 300 ng/kg level received 3 and 1 unscheduled doses of 1500 ng/kg, respectively. Except for grade 3 lymphopenia in 1 patient and grade 3 fever in the other, the following toxicities experienced by these 2 patients were lower than grade 3: flu-like symptoms; chills; headache; abdominal pain; anorexia; diarrhea; aspartate aminotransferase elevation; headache; chills; granulocytopenia; and alkaline phosphatase elevation. The fever secondary to administration of IL-12 occurred fairly regularly, 12 h from i.p. administration and was resolved within 48 h. Subsequent patients received 300 ng/kg dose levels to characterize toxicity better and to perform laboratory correlates on a larger cohort. Five of 29 (17%) patients experienced catheter-related infections. Five of 29 patients required catheter replacements once (2)
or twice (3)
.
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. Of 9 patients treated at 3, 10, and 30 ng/kg, 8 had progressive disease and 1 stable disease. At 100 ng/kg, a patient showed complete response at laparoscopy, supported by negative cytology tests, negative peritoneal biopsies for tumor, normalization of CA-125, and resolution of CT abnormalities. Two other patients treated at this dose level had stable disease based on CA-125 levels and CT results. At the 300 ng/kg dose, a patient with epithelial papillary mesothelioma was found at surgical restaging to have only granulomas without residual mesothelioma. This patient had progressive disease after a prior abdominal surgery had demonstrated multiple sites that were positive for epithelial papillary mesothelioma. Before the treatment with i.p. rhIL-12, the patient was re-explored because of abdominal pain and a pelvic mass that involved a segment of small bowel. A segment of bowel was resected and had multiple nodules of mesothelioma. Of 29 enrolled patients, 2 experienced complete response (the patient with mesothelioma is without progression at 2 years), 8 had stable disease, and the remainder had progressive disease.
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Pharmacokinetics of IL-12.
Levels of IL-12 in serum and peritoneal fluid were monitored and assessed in most of the patients and were found to be variable. Eight patients at the 300 ng/kg dose level provided more extensive pharmacokinetic observations. Clearance of IL-12 from peritoneal fluid was subjected to nonlinear regression analysis (PK Analyst; MicroMath, Inc.) for development of pharmacokinetic parameters. Clearance of IL-12 closely fit a two-compartment mathematical model. The values for initial- and terminal-phase half-lives were 1.5 min and 18.7 h, respectively. Calculated residence time was 26.8 h and the area under the concentration curve was 2670 pg/ml x h. The appearance and clearance of IL-12 in serum could not be fitted accurately, however, maximal concentration of IL-12 occurred between 24 and 36 h after injection (Fig. 1)
and was 10–50-fold lower than the contemporaneous peritoneal fluid concentrations.
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, TNF-, IL-2, IL-10, and IL-1 by quantitative ELISA. These cytokines were selected as indicators of activation of T cells (IFN-, TNF-, IL2, IL-10), NK cells, (IFN-), or macrophages (TNF-, IL-I, IL-10) and because of the functions of these cytokines. Because cytokine production was not detected in patients treated at rhIL-12 doses < 30 ng/kg, results shown are for patients treated at doses of 30 ng/kg (Table 4, a and b)
. Peritoneal fluid concentrations of IFN- increased after i.p. rhIL-12 injection in 13 of 19 (68%) patients tested. At the 300 ng dose level, IFN- was detected in 8 of 9 peritoneal fluids and 9 of 10 serum specimens taken after treatment. Similar patterns of cytokine production were detected in contemporaneous serum specimens. Levels of IFN- started to increase at 6 h and generally achieved peak concentrations 24 h after i.p. IL-12 administration (Fig. 2A)
. The median times to maximum cytokine concentration in the peritoneal fluid were: IFN-, 36 h (range, 10–48); TNF-, 36 h (range, 24–48); IL-10, 30 h (range, 6–72); and IL-1, 30 h (range, 24–36). The median times to maximum cytokine concentration in serum were: IFN, 36 h (range, 24–48); TNF-, 36 h (range, 6–48); and IL-10, 24 h (range, 6–48). Several patients had constitutive levels of IL-10 or TNF- in peritoneal fluid and in serum. At the 300 ng dose level, no significant difference was detected between the pre- and posttreatment values for IL-10 (Fig. 2B)
.
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/IL-10 and IP10 Transcripts in cDNAs from PECs before and after Treatment. RNA transcripts from the pretreatment PECs ranged from 0 to 1260 agm/µl with a median level of 0 agm (n = 19). After one to three i.p. injections of rhIL-12, IFN- transcripts ranged from 0 to 2,697,400 agm, with a median level of 1,000 agm (n = 19). IL-10 pretreatment transcripts ranged from 0 to 19,680 agm, with a median value of 0.6 agm (n = 19), and posttreatment IL-10 transcripts ranged from 0 to 19,760 agm, with a median value of 0 agm. The CXC chemokine IP10 transcript pretreatment ranged from <0.134 to 60,200 agm, with a median value of 1,880 agm/µl (n = 19). Post-i.p. rhIL-12, IP10 transcript levels ranged from 0.135 to 1,035,400 agm, with a median value of 1,809 agm/µl (n = 19).
The effects of i.p. rhIL-12 injections on the expression of transcripts for IFN- and IP10 were examined after one and two injections for all patients for whom follow-up values were available and for ovarian and gastrointestinal cancer patients separately. Using the signed rank test of change in IFN- from the pretreatment, significant differences for treatment effect were detected for IFN-/transcripts after two i.p. injections (P = 0.016) for both ovarian and gastrointestinal patients (n = 14). There was also a significant difference for the ovarian cancer patients (P = 0.031) but not for the smaller group of patients with gastrointestinal tract cancers (P = 1.0).
Overall, no significant differences were seen in the transcripts for IP10 or IL-10; however, the patient with EOC who had pathologically confirmed complete response to i.p. rhIL-12 showed a decrease in IP10 transcripts that paralleled an increase in IFN- transcripts and a decrease in IL-10 transcripts and their encoded proteins (Tables 5
and 6)
.
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). After weekly i.p. injections of rhL-12, patients had significant decreases in bFGF expression after either one or three injections. Differences in expression of VEGF at the same time points were not significant, but the responding patient whose cytokine data was shown in Tables 5
and 6
showed a decrease in bFGF expression from 10.8 (pretreatment) to 1 (1 week posttreatment) and 5.9 (4 weeks posttreatment) and VEGF of 3.5, 0.7, and 1.1 at the same time points.
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. None of the patients who had apoptosis studies done were clinical responders.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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protein or cytokine-specific transcripts for IFN- after treatment. IFN- production was also detected in the serum of these patients but at lower levels than in the peritoneal cavity. The presence of higher peritoneal concentrations of IL-12 and its induced-cytokine IFN- relative to their serum concentrations could contribute to an overall lower intensity of systemic IFN--related toxicities. One of 2 patients who received unscheduled doses of 1500 ng/kg did not develop toxicities above grade 2, except for lymphopenia. Interestingly, IL-1 but not IFN- was detected in this patient. The patient had received high-dose chemotherapy and stem cell transplantation 6 months earlier. Perhaps this patient failed to produce IFN- because of a dysfunctional lymphocyte response, which has been observed after high-dose chemotherapy (30)
.
TNF- was detected in 7 of 17 patients after treatment, and increased concentrations of both IFN- and TNF- were detected in the 2 patients who responded. IFN- and TNF- have synergistic cytotoxic antitumor activity in preclinical studies (31)
. An antiangiogenic mechanism has also been suggested for IFN- and TNF- through down-regulation of Vß-3 integrin receptor activity, resulting in apoptosis of the tumor neovasculature (32)
. bFGF expression on PECs decreased after treatment with i.p. IL-12, but expression of VEGF was not significantly decreased overall. However, substantial decrease in VEGF expression was observed in the responding EOC patient. The decreased expression of bFGF and VEGF and increased expression of IP10 transcript in certain patients suggest the possibility of different antiangiogenesis mechanisms in these patients.
Lymphocyte populations responsible for producing IFN- after i.p. IL-12 have not been determined. IL-2 secretion was not detected either pre- or posttreatment. Although IL2 is transiently expressed by producer lymphocytes, in vitro experiments have shown that peak IL-2 gene expression occurs at 6 h with peak protein production at 12–24 h (33)
. In consideration of evidence that the pharmacokinetic characteristics of the peritoneal cavity favor a lengthened residence time for molecules the size of cytokines, it would not be unexpected if IL2 were detected after i.p. injections of rhIL12. IL-2 could possibly be produced by PECs at autocrine levels, however, no increase in IL-2 transcripts was detected in these patients. It is also possible that IFN- production in the absence of IL-2 could indicate an NK-type response or an associated T-cell defect. Decreased expression of TCR phosphorylation and of CD3 
chain expression has been observed in PECs and solid tumors of certain patients, however, this effect was reversible after in vitro treatment of these cells with rhIL-2 (34
, 35)
. Lack of IL-2 production by T cells could also be attributable to absent costimulation or presence of suppressor cell populations that inhibit T-cell activation directly or through production of molecules such as IL-10 and transforming growth factor ß. Peritoneal macrophages with the CD14+DR-IL-10+transforming growth factor ß2+ phenotype have been identified from EOC patients (36)
. Although 13 of 19 patients produced IFN- after injection of i.p. rIL-12 and 8 of 20 patients produced IL-10, significant increases in IL-10 were not detected at the 300 ng dose. In contrast, we have observed a positive relationship between i.p. rIL-2 administration and IL-10 production in vivo (22
, 37)
. It may be that an adaptive immune response (tumor vaccine) in combination with the IL-12 could be an additional approach that warrants investigation in ovarian cancer. Such an approach has been studied in patients with melanoma who received a multipeptide vaccine combined with low-dose IL-12 (38)
. If specific T-cell responses are deficient or disrupted in vivo, it may be possible to overcome this problem by providing costimulation or by developing strategies to interfere with suppressor cell or inhibitory cytokine pathways.
We conclude that IL-12 at a weekly dose of 300 ng/kg by i.p. injection has acceptable safety and immunobiological effects that provide a basis for a Phase II trial in patients with small residual disease, recently initiated in EOC patients who have completed first-line chemotherapy.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported, in part, by NIH Grant MO1 RR-02558, Shannon Award R55 CA-77241 (to R. L.), and NCI Grant UO1-62461. 
2 To whom requests for reprints should be addressed, at University of Texas, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 440, Houston, TX 77030. Phone: (713) 792-2764; Fax: (713) 792-7586; E-mail: rfreedma{at}mdanderson.org
3 The abbreviations used are: IL, interleukin; NK, natural killer; MNL, mononuclear leukocyte; PEC, peritoneal exudate cell; rIL, recombinant IL; rhIL, recombinant human IL; IP10, IFN-inducible protein 10; EOC, epithelial ovarian cancer; TCR, T-cell receptor; DLT, dose-limiting toxicity; MTD, maximum-tolerated dose; TNF-, tumor necrosis factor ; bFGF, basic fibroblast growth factor; VEGF, vascular endothelial growth factor; CT, computed tomography; CR, complete remission.
Received 3/22/02; revised 7/29/02; accepted 7/30/02.
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