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Clinical Trials |
Departments of Gynecologic Oncology [R. S. F., C. B., B. M., M. E. G.], Bioimmunotherapy [S. V-R., J. K. F.], Surgical Oncology [C. S.], Gynecologic Medical Oncology [C. V., J. J. K.], Diagnostic Radiology [M. E. H.], and Biomathematics [L. B. L.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Experimental Design: Patients with peritoneal carcinomatosis or mesothelioma were randomly assigned to treatment with Flt3-L (25 µg/kg, maximum 1500 µg), i.p. or s.c., days 1–5 and 8–12, then changed to the alternative route at 4 weeks. Treatment was continued s.c. or i.p. at 8 weeks.
Results: Fifteen patients (14 evaluable) were randomized to receive i.p. (n = 8) or s.c. (n = 7) injections. Their median age was 55 years (range, 40–68 years). Primary tumors were as follows: ovarian/peritoneal cancer (n = 9); gastrointestinal cancer (n = 2); and mesothelioma (n = 4). Treatment was well tolerated without serious toxicity (24 i.p. cycles; 32 s.c. cycles). Treatment (i.p. or s.c.) resulted in significant increases in WBCs (WBC, monocytes, and Lin-DR+ DCs), and platelets (during washout). Both interleukin (IL)-12(p70) and IL-10 were secreted by monocyte-derived DCs after in vitro exposure to maturation factors. Increased IL-12 versus IL-10 secretion responses and higher proportions of the CD11c+ DC subset in post-Flt3-L specimens suggested a maturational shift toward the monocyte-derived DC phenotype had occurred. Three patients (2 with mesothelioma and 1 with gastrointestinal cancer) had stable disease for 8, 8, and 12+ months, respectively.
Conclusions: Flt3-L, administered either i.p. or s.c., is well tolerated and produced similar increases in monocytes, DCs, and platelets. DCs from peripheral blood and peritoneal fluids showed cell surface phenotypic and cytokine maturational responses to activation stimuli. These findings suggested that Flt3-L, in combination with suitable activating agents, could be developed further in patients with epithelial ovarian cancer.
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The administration of Flt3-L to mice with established tumors resulted in some regression or inhibition of growth of a variety of tumor types, including melanoma, fibrosarcoma, mesothelioma, rhabdomyosarcoma, colon cancer, lymphoma, prostate cancer, and sarcoma models, and human breast tumors in mice with severe combined immunodeficiency (1, 2, 3) . Also, in severe combined immunodeficiency mice, the growth rate of a human papillary serous ovarian adenocarcinoma decreased after Flt3-L administration. These antitumor effects were observed after s.c. administration of Flt3-L in dosages ranging from 10 to 30 µg/day for 10–21 days (4) .
In healthy volunteers (5 , 6) and in patients with various malignancies (7) , Flt3-L induced significant increases in the numbers and differentiation characteristics of DCs in peripheral blood without serious adverse effects. The DC-enhancing effect plateaued after 9 days of s.c. administration (5) . i.p. doses of 10 mg/day have been administered to mice, successfully preventing breast cancer metastasis (Investigators Manual for Flt3-L). There has been no previous human experience with i.p. Flt3-L.
Peritoneal carcinomatosis associated with Müllerian and GI tract cancers and mesothelioma causes significant morbidity and mortality. The i.p. method of administering bioimmunotherapy agents has immunopharmacokinetic and immunopharmacodynamic advantages and has shown responses in several trials, particularly in patients with small tumors (8) . Disadvantages of the i.p. route include requirements that patients undergo i.p. catheter placement, that they have no adhesions, and that optimum candidates for efficacy studies have small-volume disease.
We conducted a randomized clinical trial in patients with peritoneal carcinomatosis to determine whether i.p. and s.c. routes were comparable in regard to their effect on clinical and hematological parameters and on DC differentiation patterns in the blood and in the peritoneal cavity. Our primary objectives were to determine whether Flt3-L can be administered safely by the i.p. route, to measure the proportions, numbers, and maturational cytokine responses of Lin-DR+ DCs, and to document any antitumor activity. We used a dose of 25 µg/kg (maximum dose, 1500 µg). Doses between 10 and 100 µg/kg have been administered to trial subjects without a clear dose-response effect.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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18 years, Zubrod performance status of 
2, no concurrent chemotherapy, radiotherapy, or immunotherapy, adequate bone marrow function (WBC 1500/mm3, hemoglobin level 9 g/dl, platelet count 100,000/mm3), and adequate hepatic and renal function.
Exclusions included bulky abdominal disease (10-cm lesions), significant adhesions or symptoms of obstruction, extra-abdominal or hepatic disease that was symptomatic or 2 cm in maximum diameter, clinically significant pleural effusion(s), brain metastasis, serum albumin level of <3.0 g/100 ml, weight loss of >10% over a period of 4 months, lymphocyte count of <800 cells/mm3, prior radiation treatment to the whole abdomen, history, clinical findings, or electrocardiographic findings suggestive of significant heart disease, active ulcer disease or a history of inflammatory bowel disease (e.g., Crohn’s disease or ulcerative colitis), autoimmune disease, or long-term steroid usage. Women who were pregnant or lactating also were excluded from the study.
Treatment Plan.
This was a two-arm, equally randomized pilot study of Flt3-L (Amgen, Seattle, WA). The randomization was done by computer, using the Protocol Data Management System with randomization tables and selecting a new randomization set after every 4 patients. All patients had placement of an i.p. catheter before treatment. Patients were treated with Flt3-L in cycles of either i.p. then s.c. or s.c. then i.p. administration with a treatment-free interval of 2 weeks according to the dose and schedule shown in Fig. 1
. The drug was given by i.p. push via a 5- to 7-French catheter inserted under fluoroscopic guidance as previously described (9)
and by s.c. injection. For patients undergoing surgery before entering the study, the surgeon determined the most appropriate area for catheter insertion. Patients received prophylactic antibiotics, as is our practice with all i.p. therapy protocols (9)
, consisting of 500 mg of ciprofloxacin, p.o. twice a day, on Monday, Wednesday, and Friday, unless they were allergic, in which case they received 800 mg of sulfmethoxazole, with 160 mg of trimethoprim (Bactrim DS), 1 twice a day Monday, Wednesday, and Friday. In the absence of ascites, 1 liter of dextrose 5% in water 0.25 normal saline, which is near iso-osmotic (
320 milliosmol/liter), was given i.p. before the Flt3-L. Additional fluid (500 ml to 1 liter of dextrose 5% in water 0.25 normal saline) could be injected to facilitate specimen collection for immunological studies. After the Flt3-L was administered, 10 ml of sterile water was administered to flush the drug from the catheter. A more complete description of the method of i.p. delivery of immunotherapy agents and catheter management is found elsewhere (9)
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All patients in the study were evaluated using the National Cancer Institute Common Toxicity Criteria. If only grade 1 or 2 toxicity attributable to Flt3-L occurred, the treatment was continued at the full dose. However, if grade 3 or 4 nonmajor organ toxicity attributable to Flt3-L occurred, the treatment was withheld for that cycle and restarted in the next cycle if the toxicity had resolved to grade 2. If grade 3 or 4 major organ toxicity attributable to Flt3-L occurred, the treatment was discontinued.
The efficacy of Flt3-L was evaluated in all patients who received at least one cycle of therapy. For most patients, a minimum of two cycles was administered before the evaluation of efficacy. However, patients who received only a single cycle of therapy because of progressive disease were also included in this evaluation efficacy. All patients were considered evaluable in this regard.
Methods for Determining DC Phenotype.
DCs in both blood and peritoneal fluids were identified as Lin-DR+ using two-color and three-color FACS analysis, as previously described, using a mixture of mAbs against cells isolated from 60-ml blood specimens and from 500-ml ascites or peritoneal washings (10)
. An attempt was made to obtain samples from the blood and peritoneal cavity of all patients, although for technical reasons, samples in the crossover patients of the study had fewer specimens.
Cell surface phenotyping was performed by three-color FACS analysis. A mixture of mAbs anti-CD3, -CD14, -CD16, -CD19, -CD20, and -CD56 conjugated to FITC was used to select lineage-negative DCs (Lin-1; Becton Dickinson, San Jose, CA), and antibodies conjugated to peridinin chlorophyll protein were used to positively select DCs that expressed the MHC class II molecule HLA-DR. The presence or absence of other surface markers of differentiation or costimulation was analyzed using the mAbs anti-CD11c, -CD80, -CD86, -CD83, -CD33, -CD4, -CD40, -CD123, and -CD34 conjugated to phycoerythrin. At least 106 cells were analyzed.
Cells were incubated in FACS buffer with 15 µl of mAbs specific for a surface marker, with up to three types of mAbs/tube for 45 min to 1 h at 4°C. Cells were washed and fixed using 2% paraformaldehyde in FACS buffer. After the cells were fixed, they were analyzed using a FACScan flow cytometer (Becton Dickinson). At least 1000 events of cells gated for negative expression of Lin-1 mAbs and positive expression of HLA-DR, and the proportions of cells that coexpressed other markers of differentiation and costimulation were determined after subtracting values from the appropriate conjugated isotype control mAbs.
Production of Cytokines by DCs.
DCs from blood or ascites specimens are considered immature (10)
. We therefore tested the maturation potential of DCs before and after the administration of Flt3-L using a previously described protocol that measures the concentration of cytokines after in vitro exposure of pre-DC monocytes to GM-CSF/IL-4 activation factors (11)
. The production of cytokines by monocyte-derived DCs was determined using a cytokine-specific ELISA (Pierce-Endogen, Rockford, IL) for IL-12 (p70) and IL-10. Concentrations of IL-12 and IL-10 were determined in supernatants of mononuclear leukocytes that had been cultured for 5 days in GM-CSF (Peprotech, Rocky Hill, NJ) at 100 ng/ml and IL-4 (Peprotech) at 500 ng/ml, according to a previously described protocol (11)
. After day 1, nonadherent cells were removed by aspiration, and cultures were washed with PBS followed by the addition of a medium containing GM-CSF and IL-4. Five-day cultures were followed by activation with sCD40Lt alone (Amgen) at 500 ng/ml, LPS alone (Sigma-Aldrich, St. Louis, MO) at 500 ng/ml, or LPS plus sCD40Lt at the same concentrations as described previously (12)
. IL-12 and IL-10 levels were measured in cultures after 48 h and in the presence of maturation agents, according to the manufacturer’s instructions.
Statistics.
The curves for WBCs, monocyte, platelet, and eosinophil counts, percentage of DCs, and DC/ml, displayed in Figs. 2
and 3B
were fitted with linear piecewise regression models with random intercepts. A separate line segment was fitted for each of the four time periods: i.p.; s.c.; and the two nontreatment periods shown in Fig. 2
. Similarly, a separate line segment was fitted for each of the three time periods: i.p.; s.c.; and one nontreatment period shown in Fig. 3B
. Comparisons of the differences between the means on days 1 and 12, presented in Tables 3
and 4
, were analyzed with t tests. Statistical calculations were done with the software packages Stata (13)
and SAS (14)
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. One patient with ovarian cancer, assigned to the i.p. arm, was removed after the first dose because of the development of acute pancreatitis, although it was considered unrelated to the treatment. Seven of the remaining patients were randomly assigned to the i.p. route and 7 to the s.c. route. Eight of the 14 evaluable patients had ovarian cancer, 4 had abdominal mesothelioma, and 2 had a GI primary cancer.
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. Table 2
also shows the numbers of total events and grade 2 and 3 events by treatment route. Overall, treatment was well tolerated, and frequencies of systemic effects were similar for both routes of treatment. As might be anticipated, abdominal discomfort or pain effects occurred more frequently after i.p. administration; however, s.c. injections were sometimes associated with abdominal discomfort, which may have been related to an inflammatory response at the site of the abdominal metastasis. There was no grade 4 clinical toxicity.
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and Table 3
). WBC and monocyte counts significantly increased daily during both i.p. and s.c. treatments and with both the first and second cycle (Fig. 2)
. In contrast, platelet counts increased significantly only during the nontreatment period after the first cycle. Eosinophil counts increased during the second treatment in both s.c. and i.p. arms but appeared to increase more in those patients who started with s.c. injections. Mean values on days 1 and 12 are shown in Table 3
, and the increased values generally followed the day-to-day changes shown in Fig. 2
. Statistically significant differences in the mean WBC and monocyte counts were seen for patients given i.p. injections in the first cycle, whereas monocyte counts only approached statistical significance only in patients given s.c. injections in the first cycle. This apparent difference between patients who started with either s.c. or i.p. injections may be attributed to the sample size. Notably, WBCs and monocyte counts continued to be elevated just before the start of the second cycle. There were no differences in WBC or monocyte counts in terms of either day-to-day changes or differences in the means between days 1 and 12 between patients given i.p. and s.c. injections as the first treatment. When the i.p. route was used for the first cycle, the mean increase in WBCs (from the start of treatment) was 3100/mm3 (P < 0.05 by matched t test) at the start of the second course. When the s.c. route was used for the first cycle, the mean increase in WBCs was only 1500/mm3 (P = 0.1). The effect was different for the platelets in patients who received i.p. or s.c. injections as the initial injection route. The increase in the mean platelet count at the start of the second course was not significant (P = 0.1) at 107,000/mm3 after the i.p. route. In contrast, the increase in the platelet count of 128,000/mm3 was significant (P = 0.0038) after the s.c. route. Eosinophil counts were significantly increased but only after the second course, regardless of the treatment route (i.p., daily change value = 0.075, P < 0.05; s.c., daily change value = 0.022, P < 0.05). Eosinophil counts decreased to baseline in the nontreatment periods in both instances. Lymphocyte and neutrophil counts did not change significantly during this time (data not shown).
DCs.
The day-to-day changes (see "Materials and Methods") of DCs (Lin-DR+ cells) significantly increased in the blood of patients during either i.p. or s.c. administration (Fig. 3, A and B)
. The mean proportions of Lin-HLA-DR+ DCs also increased at the end of a cycle of treatment from pretreatment baseline readings in blood or ascites regardless of the route of administration (Table 4)
. The absolute numbers of DCs increased in blood specimens, but the changes were not statistically significant in peritoneal fluid specimens. However, one hindrance in this analysis was that fewer ascites specimens were obtainable from the patients who started with s.c. injections.
The proportions of DCs that expressed the differentiation antigens CD33, CD34, CD4, CD80, CD83, CD86, CD11c, and CD123 are shown in Figs. 4, A and B
, and 5
. Wide SE values shown in Fig. 5
could indicate biological variability in expression within certain individual patients. The proportions of CD11c+ and CD33+ DCs increased in peripheral blood after either i.p. or s.c. injections of Flt3-L. There was no increase in the proportions of CD123+ DCs. The proportions of DCs that expressed the CD86 costimulatory antigen increased slightly in peripheral blood and peritoneal fluid after s.c. injection. There were no significant changes in the other costimulatory markers, CD80 and CD83. DCs expressing the CD34 stem cell marker were detected in peripheral blood, and their proportions tended to decrease during the treatment phase. However, peritoneal fluid specimens showed absent or only low levels of CD34+ DCs.
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, and 10 healthy subjects showed similar elevations after activation by sCD40Lt, LPS, or both. Concentrations of IL-12 were higher in supernatants of DCs from peritoneal fluid specimens after treatment with Flt3-L than before pretreatment, but no increases were seen in supernatants of DCs from blood specimens.
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(pretreatment, 50.1%; day 5, 70.6%; and day 12, 78.79%); recombinant IL-2 (pretreatment, 51.5%; day 5, 49.3%; and day 12, 92.55%); and GM-CSF (pretreatment, 7.2%; day 5, 0%; and day 12, 33%).
Tumor Response.
There were no objective responses. Three patients (2 with mesothelioma and 1 with a GI primary) had stable disease, as shown by CT scan, that was associated with improvement of symptoms and a decrease in the frequency of paracentesis in 2 patients (1 with mesothelioma and 1 with a GI primary). Stable disease lasted for at least 8 months from the beginning of treatment in each patient. One of these patients had disappearance of ascites and no tumor progression after an additional 4 months of treatment.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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8 months, and treatment was associated with improved symptomatology, including reductions in effusions. All patients received both i.p. and s.c. routes of administration. There have been no larger-scale studies to determine the clinical effectiveness of Flt3-L. In our studies, both i.p. and s.c. injections of Flt3-L resulted in increased total WBC and monocyte counts and increased proportions and absolute numbers of Lin-DR+ DCs in the blood. Our findings were similar to those reported for cancer patients who received a 14-day cycle of Flt3-L by s.c. injection (7) . Proportions of DCs, in the blood and, in some instances, in the peritoneal fluid, also increased after i.p. or s.c. injection. In the current study, platelet counts decreased slightly during the treatment phase but increased significantly during the nontreatment period. The increase in platelet counts coincided with the decrease in monocyte counts. Interestingly, we found that baseline levels of WBC and platelet counts at the start of the second cycle were higher and reached significance for platelet counts when the s.c. route was used first and for WBC when the i.p. route was used first. It is unclear why there is a difference between s.c. and i.p. routes. These findings overall suggest that Flt3-L is adequately absorbed from the peritoneal cavity after i.p. injection and that i.p. injection of Flt3-L at a total dose of 1500 µg produced hematological and biological effects that were similar to those of the s.c. Flt3-L injection. LIN-DR+ cells that are also CD34+ are usually detectable in the peripheral blood but were absent or present in very small numbers in the peritoneal cavity of these patients. This was expected because DCs in the peritoneal cavity could have better differentiation, reflecting the migration of DC precursors from the bone marrow. The blood and peritoneal fluids generally showed increased absolute numbers of DCs, although the increases in peritoneal fluid DC after i.p. injection were not statistically significant.
The activation markers CD11c and CD33, representing committed myeloid progenitors, increased in blood DCs after either i.p. or s.c. injections. There was also an increase in the proportions of CD123+ DCs, although the increase was more prominent in the CD11c+ DC subset. In selected experiments (data not shown), only small numbers of double-positive (CD11c+ CD123+) DCs were detected by four-color analysis. Therefore, the assumption made here is that the CD11c+ cells were largely CD123-, and similarly, the CD123+ cells were largely CD11c-. Our findings are similar to those in a study conducted on peripheral blood DCs in healthy subjects (6) , who received s.c. Flt3-L and showed a 48-fold increase in CD11c+ DCs and a 13-fold increase in IL-3R+ DCs (CD123+). The dosage used in that study was 10 µg/kg/day. In a related study performed in healthy subjects, similar findings were made with dosages ranging from 10 to 100 µg/kg/day (5) , indicating that there was no clear dose response in the dose range studied. The increase in proportions of CD11c+ and CD33+ DCs, accompanied by a downward trend in CD34+ Lin-DR+ cells in the blood, suggests that Flt3-L facilitated a differentiation process in these cells. A subset of prelymphocyte-derived DCs expresses the CD34 antigen in addition to CD4, CD45RA, and the IL-3 receptor (15) . This is consistent with a smaller increase in the proportions of the CD123+ subset. CD86+ cells, but not CD80+ or CD83+ cells, increased in both peripheral blood DCs and peritoneal fluid DCs after s.c. injection. Others also found an increase in CD86+ DCs but not in CD80+ or CD83+ DCs after s.c. injection of Flt3-L (7) . Additional evidence of an altered differentiation pattern was evident from functional studies that involved the in vitro treatment of cells obtained from the blood or peritoneal cavity before and after treatment with Flt3-L. Cells from peritoneal fluid and blood obtained before treatment and on day 12 were cultured in GM-CSF and IL-4 and then activated with sCD40Lt, LPS, or both. The peritoneal fluid, but not the blood samples, showed increased levels of IL-12 secretion in the day 12 posttreatment samples, whereas IL-10 concentrations were lowest in the peritoneal fluid samples after treatment. The increased secretion of IL-12 relative to the reduced IL-10 secretion suggested a possible shift toward a monocyte-derived DC phenotype in the peritoneal cavity DCs after Flt3-L treatment, although the functionality of these subsets has not yet been clearly defined. The higher pretreatment concentrations of IL-10 in response to maturation agents in peritoneal fluids were not detected in specimens from the blood, similar to the findings in samples obtained from healthy people who had not been treated with Flt3-L. The DC subsets that could be responsible for the production of IL-10 have not been identified, although prior studies suggested that the lymphoid or CD123+ cells are primarily responsible. Because peritoneal fluids may include CD14+DR- IL10+ macrophages (16) , it is also possible that these cells contribute to IL-10 production in the cultures. Higher concentrations of IL12 in DCs derived from peritoneal fluid after priming with GM-CSF and IL-4 additionally suggest that the peritoneal DCs, although derived from the tumor environment, may be capable of functioning as antigen-presenting cells. Additional studies might determine whether interference with IL-10 production facilitates tumor-specific T-cell responses. We have shown previously that antibodies to the IL-10 receptor and to neutralizing antibody to transforming growth factor-ß were able to block the T-cell inhibitory effects of ascites-derived monocytes that had the IL-10 and transforming growth factor-ß phenotype (16) .
In one experiment, peritoneal monocyte cytotoxicity was measured before and after in vivo treatment with Flt3-L. Flt3-L not only increased monocyte numbers, but also contributed to the enhancement of IFN--, IL-2-, and GM-CSF-induced monocyte toxicity in these in vitro experiments, supporting a differentiating effect of Flt3-L on these cells. When properly activated, monocytes exhibit potent cytotoxic activity against tumor cells (17)
. Flt3-L could have a possible role together with other monocyte-activating molecules in the treatment of patients.
Flt3-L could also have an important role in vaccine protocols. In one clinical trial, DCs mobilized with Flt3-L and loaded with a peptide derived from a carcinoembryonic antigen were used to immunize patients with advanced cancer, and there were two responders with colorectal cancer (18)
. In another recently reported study in patients with HER2/neu-overexpressing cancers, Flt3-L enhanced the precursor frequency of IFN--secreting HER-2/neu-specific T cells (19)
.
In summary, a clinical trial that compared the i.p. and s.c. administration of Flt3-L showed that both routes of administration resulted in clinically manageable toxicity and that Flt3-L administered i.p. and s.c. produced similar hematological effects, including increased levels of WBC, monocytes, and DCs during treatment phases and increased platelet levels during the nontreatment period. Our studies also suggested that Flt3-L facilitated the differentiation of DCs. The i.p. injection routes have shown some beneficial effects in patients with ovarian cancer who have received treatment with other cytokines in nonrandomized trials (8) and may be helpful especially to those patients who have only a small amount of residual disease after initial surgery and/or chemotherapy. Although our study was not confined to patients with minimal residual disease, our results suggest that either the i.p. or s.c. injection routes could be used in future efficacy trials for patients with minimal residual disease. Because it is unlikely that monotherapy with Flt3-L will be highly efficacious, future trials using the i.p. route should explore combinations with activation molecules such as sCD40L, which may enhance the production of IL-12, an important cytokine for adaptive or innate immunity or other cytokines that might enhance monocyte-mediated cytotoxicity.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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This work was supported in part by a grant from Immunex Corporation and by NIH Grant MO1 RR-02558.
1 To whom requests for reprints should be addressed, at The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 440, Houston, TX 77030. Phone: (713) 792-2764; Fax: (713) 792-7586; E-mail: rfreedma{at}mdanderson.org 
2 The abbreviations used are: Flt3-L, fms-like tyrosine kinase 3 ligand; CT, computed tomography; DC, dendritic cell; FACS, fluorescence-activated cell sorting; GI, gastrointestinal; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL, interleukin; Lin-DR+, lineage-negative human leukocyte antigen-DR-positive; LPS, lipopolysaccharide; mAb, monoclonal antibody; sCD40Lt, soluble CD40 ligand trimer.
Received 1/31/03; revised 5/16/03; accepted 7/10/03.
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}}-producing predendritic cell (pre-DC)2 from human CD34+ hematopoietic stem cells. J. Exp. Med., 192: 1785-1796, 2000.This article has been cited by other articles:
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 R Hassan, R Alexander, K Antman, P Boffetta, A Churg, D Coit, P Hausner, R Kennedy, H Kindler, M Metintas, et al. Current treatment options and biology of peritoneal mesothelioma: meeting summary of the first NIH peritoneal mesothelioma conference Ann. Onc., November 1, 2006; 17(11): 1615 - 1619. [Abstract] [Full Text] [PDF]
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 K. A. Whartenby, P. A. Calabresi, E. McCadden, B. Nguyen, D. Kardian, T. Wang, C. Mosse, D. M. Pardoll, and D. Small Inhibition of FLT3 signaling targets DCs to ameliorate autoimmune disease PNAS, November 15, 2005; 102(46): 16741 - 16746. [Abstract] [Full Text] [PDF]
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, posttreatment (day 12). Numbers represent difference in change between day 12 and day 1.
