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Safety and Biological Activity of Repeated Doses of Recombinant Human Flt3 Ligand in Patients with Bone Scan-Negative Hormone-Refractory Prostate Cancer

¹ University of Washington Medical Center, Seattle, Washington;² University of Chicago Medical Center, Chicago, Illinois;³ Vanderbilt University Medical Center, Nashville, Tennessee;⁴ Immunex Corporation, Seattle, Washington; and⁵ University of California San Francisco Comprehensive Cancer Center University of California, San Francisco, California

ABSTRACT

Purpose: The purpose of this study was to evaluate the safety, biological activity, and feasibility of repeated doses of the dendritic cell (DC)-stimulating agent Flt3 ligand (FL) in patients with bone scan-negative hormone-refractory prostate cancer.

Experimental Design: Thirty-one patients with hormone-refractory prostate cancer who had elevated prostate-specific antigen (PSA) levels and negative bone scans were enrolled. Six cycles (28 days each) were planned. In the first cycle, patients were randomized to FL or placebo. All patients received open-label FL during the next five courses. DC, anti-FL antibody, and PSA levels were measured every 15 days to assess biological activity.

Results: DCs increased markedly in FL-treated patients from precycle to day 15, and the increase was consistent in each cycle. Mean percentages of DCs in peripheral blood ranged from 1.4% to 1.9% precycle and from 10.1% to 13.9% on day 15, and after the first cycle, absolute counts on day 15 were approximately 29-fold higher than precycle levels. Natural killer cell counts (CD56⁺) were found to be elevated after cycle 1 (154% increase versus 2.8% decrease in placebo group at day 22). Twenty-two of 27 patients tested developed nonneutralizing anti-FL antibody. The most frequently experienced toxicity was injection site reaction, followed by asthenia, rash, and diarrhea. Although median PSA levels did not vary during any cycle, a significant slowing in velocity of PSA was observed while patients were on-study (relative velocity = 0.002) compared with prestudy PSA velocity (relative velocity = 0.007).

Conclusions: FL was well tolerated. FL consistently produced an increase in DC count without any evidence of decreasing response with continued exposure. The expansion of DCs and the slowing of PSA velocity after administration of FL suggest potential clinical applications in the immunotherapy of prostate cancer.

INTRODUCTION

Recombinant human Flt3 ligand (FL) stimulates the proliferation and differentiation of hematopoietic progenitors both in vivo and in vitro by binding to and activating distinct tyrosine kinase receptors. Preclinical data have demonstrated the ability of FL to mobilize large numbers of CD34⁺ stem cells (1 , 2) and CD56⁺ natural killer cells (3) . In animal models, FL increases the number of dendritic cells (DCs) that are normal in morphology and function, based on their ability to present alloantigens in a mixed lymphocyte reaction (4) . FL also produces high concentrations of circulating DCs both in healthy volunteers and in patients with metastatic colon cancer (5 , 6) .

DCs are the most potent antigen-presenting cells identified to date. They have the unique ability to sensitize naïve T cells to protein antigens and elicit potent antigen-specific responses (7) . DCs express high levels of MHC class I and II molecules, adhesion molecules, and various costimulatory molecules on their surface. They are identified as lineage negative (CD14^-, CD56^-, CD19^-, CD3^-) and either myeloid type (CD11c⁺, CD123^-) or plasmacytoid or lymphoid type (CD11c^-, CD123⁺). The ability to mobilize DCs may have significant clinical impact on guiding cytolytic immune responses to destroy tumor cells (8) . DCs have been successful in generating antitumor immune responses in several animal models (9, 10, 11, 12, 13, 14, 15, 16, 17) . A variety of approaches to DC-based immunotherapy are currently under clinical investigation to evaluate whether DCs loaded with tumor antigens can be used to induce tumor immunity. Vaccination with specific tumor antigens is one setting for using large numbers of DCs. DCs are amplified ex vivo and then pulsed with tumor antigen and infused into a patient as a vaccine (18) .

In vivo studies in mice have shown that daily injections of recombinant murine FL can produce markedly high levels of DCs in the bone marrow, gastrointestinal lymphoid tissue, liver, lymph nodes, lungs, peripheral blood, peritoneal cavity, spleen, and thymus. These cells coexpress the characteristic DC markers of MHC class II, CD11c, DEC205, and CD86. Five distinct DC subpopulations were identified in the spleens of these FL-treated mice. The cells were as efficient as the rare, mature DCs isolated from untreated mice at presenting alloantigen to T cells (4) . Similarly, when FL was administered at various doses to healthy human volunteers, DC populations were significantly increased and consisted of both CD11c⁺/CD123^- and CD11c^-/CD123⁺ populations (5) . These results suggest that FL could be used to expand the numbers of DCs in vivo, resulting in higher levels of endogenous cells and eradicating the need to generate DCs ex vivo.

FL has been evaluated as an immunotherapy agent in several tumor-bearing animal models. In a mouse model of fibrosarcoma, FL administration led to complete tumor regression in 50% of animals. Biopsy of regressing tumor showed infiltration of DC-like cells. This antitumor activity was transmissible by the transfer of splenocytes (19) . FL has also been shown to stimulate the proliferation of natural killer cells in mice, which may heighten an antitumor immune response (20) .

With the availability of human FL, we conducted a multicenter, randomized, Phase II trial in patients with bone scan-negative hormone-refractory prostate carcinoma (HRPC) to assess the effects of repeated doses of FL over multiple cycles. The rationale for choosing prostate cancer was its association with a tumor-specific antigen [prostate-specific antigen (PSA)]. Eligible patients had elevated PSA levels and negative bone scans. The objectives were as follows: (a) to characterize tolerability and safety of FL; (b) to determine biological activity of FL by measuring DC production; and (c) to evaluate the effect of FL on PSA levels and progression of clinical disease.

PATIENTS AND METHODS

Patients.
Eligible patients had to have a rising PSA while receiving androgen ablation therapy and must have had a negative bone scan at the time of study entry. When appropriate, a rising PSA at 4 or 6 weeks after antiandrogen withdrawal was required for flutamide and nilutamide or bicalutamide, respectively. The PSA had to be at least 5 ng/ml but less than 30 ng/ml and had to have risen on at least two consecutive occasions at least 2 weeks apart. Patients were also required to have a Karnofsky performance status of >60%, castrate levels of testosterone, adequate hematological function (absolute neutrophil count 1,500 cells/mm³; platelet count 100,000/mm³; and hemoglobin > 8 g/dl), adequate renal function (serum creatinine 2.0 mg/dl or creatinine clearance 50 ml/min), and adequate hepatic function (total bilirubin < 2.0 mg/dl and aspartate aminotransferase < 2x the upper limit of normal). Patients were required to wait 2 weeks for study entry if they had received colony-stimulating factor therapy or nonchemotherapy investigational agents, and they were required to wait 4 weeks for study entry if they had received prior chemotherapy or radiation therapy. Patients were excluded if they were receiving systemic corticosteroids, had a serious active infection or intercurrent illness, had a history of other malignancy, or measurable bidimensional disease. All patients gave written informed consent in accordance with federal, state, and institutional guidelines.

Treatment Regimen.
The study was designed to have six 28-day cycles. Cycle 1 was a placebo-controlled, double-blind course with 1:1 randomization designed to obtain safety data. For cycle 1, 25 µg/kg FL or placebo was administered once daily for 14 consecutive days by s.c. injection given at approximately the same time each day. The dose of FL was calculated based on actual weight at enrollment and remained constant at 25 µg/kg throughout the study. For cycles 2 through 6, FL was administered to all patients once daily for 14 days by s.c. injection. No premedication was given before FL injections. All patients continued on gonadotropin-releasing hormone analog therapy throughout the study, unless they had had an orchiectomy.

After six cycles, patients could be retreated with up to four additional cycles of FL at the same dose and schedule as performed previously. To do so, they had to have stable PSA levels (PSA increase 25%) or a decrease in PSA levels of 50% from baseline and then a rise in PSA levels >25% (or a minimum of 5 ng/ml) after discontinuation of study drug in two consecutive determinations 2 weeks apart. During the retreatment phase, FL was discontinued if PSA levels continued to rise at the same rate.

Study Evaluations.
Pretreatment evaluations consisted of a history and physical examination, performance status, and laboratory studies including complete blood count, serum chemistries, thyroid panel, urinalysis, electrocardiogram, radionuclide bone scan, PSA level, anti-FL antibody titer, DC count, and CD34⁺ count. Precycle evaluations included physical examination, vital signs, complete blood count, serum chemistries, PSA level, and DC count. Adverse events were monitored daily; vital signs, complete blood count, DC count, and CD34⁺ count were monitored weekly; and serum chemistries and PSA level were evaluated on day 15 of cycle 1. During cycles 2 through 6, adverse events were monitored daily, and complete blood count, serum chemistries, PSA level, and DC counts were monitored on day 15.

Toxicity and Activity Assessments.
The type and grades of adverse events noted during study were tabulated and summarized. The intensity of each adverse event was graded according to National Cancer Institute Common Toxicity Criteria (21) . Serum was tested by ELISA for formation of antibodies to FL. Samples that tested positive in the ELISA were tested for neutralizing antibodies defined as antibodies that block the capability of FL to bind to its receptor.

Activity was assessed by DC counts and evaluation of PSA levels. Cells with classical dendritic determinants, including CD45⁺, CD14^-, and CD11c⁺, were measured. Both absolute DC counts and percentage of DCs in the peripheral blood were enumerated. DCs were measured by fluorescence-activated cell-sorting analysis. Two PSA indices were analyzed, median change from baseline and relative velocity of PSA change.

Cell Preparation and Flow Cytometric Isolation of Peripheral Blood Mononuclear Cell Populations.
The peripheral blood mononuclear cell fraction was isolated, prepared, incubated with antibodies including CD3, CD4, CD8, CD11, CD14, CD19, CD34, CD38, CD45, CD56 (PharMingen) and sorted by fluorescence-activated cell-sorting analysis as described previously (22) . DCs were identified as CD45⁺, CD11⁺, and CD14^-, and monocytes were identified as CD45⁺, CD11⁺, and CD14⁺. The percentage of DC was calculated from the total peripheral blood mononuclear cell count in the fraction containing Ficoll, and the DC number was the number of DCs per milliliter of blood.

Statistics.
DC counts and PSA levels were analyzed using descriptive statistics. Relative velocity of PSA was defined as follows:

where y₂ was the PSA value at time 2, and y₁ was the PSA value at time 1 (5) . Prestudy relative velocity was compared with on-study relative velocity using a Wilcoxon signed-rank test. Statistical analysis was performed using SAS Version 6.12 (SAS Institute, Cary, NC).

RESULTS

Patient Characteristics
A total of 31 patients enrolled in this trial. The demographic characteristics of the patient population are given in Table 1 . The median age was 70 years. Ninety-three percent of patients in the FL group were Caucasian, as were 88% of patients in the placebo group. For cycle 1, the mean DC percentages were 1.53% (SD, 0.98%) and 1.84% (SD, 1.23%) for the FL and placebo groups, respectively. Median pretreatment PSA levels were 15.9 ng/ml for the FL group and 20.8 ng/ml for the placebo group. Although eligibility criteria stated that patients were required to have baseline PSA levels between 5 and 30 ng/ml, six patients, who were otherwise eligible, had PSA levels above the limit and were allowed to enter the study (highest PSA level included was 49.3 ng/ml).

All Cycles.
The most frequent toxicities occurring in five or more patients during all cycles (including placebo patients in cycle 1) are listed in Table 3 . Similar to cycle 1, the most common toxicity was injection site reaction limited to grade 1 or 2 (71%). Asthenia (36%), rash (29%), and diarrhea (23%) also occurred frequently. The majority of these events were grade 1 or 2. Five patients experienced severe toxicities, including one patient each with kidney calculus, hematuria, asthenia, and deep vein thrombosis; the fifth patient had atrial fibrillation and cerebellar infarct. Of the serious events, only asthenia and deep vein thrombosis were events considered by the investigators to be possibly related to FL.

Biological Activity
Hematopoietic Progenitors and Lymphocyte Subset Analysis.
Data for hematopoietic progenitors and lymphocyte subsets are available only for cycle 1 and are displayed in Table 4 . Administration of FL increased the number of circulating CD34^+/CD38⁺ cells by 10–11-fold starting on day 8, with a peak between days 15 and 22. Analysis of lymphocyte subsets demonstrated minor increases (<50%) in total lymphocyte counts and CD3, CD4, and CD8 counts and a 154% increase in CD56 cells in the FL group compared with the placebo group. There was no difference between groups in the number of CD19 (B) cells.

PSA Levels.
PSA levels did not vary markedly with any cycle. In the FL-treated group, the median pretreatment PSA was 15.9 ng/ml and the cycle 6, day 15 median PSA level was 26.8 ng/ml. However, six patients had minor decreases in PSA levels, and five patients had PSA levels that were increased by 25%.

The relative velocities of PSA change prestudy and during study were compared. The median relative velocity prestudy was 0.007/day (range, 0.002–0.024/day), whereas the velocity while patients were treated with FL was slower [0.002/day (range, -0.006 to 0.021/day). This difference of –0.005/day was significant (P < 0.0001).

Retreatment
Five patients qualified for retreatment with FL. A range of 6–13 weeks elapsed between the end of the 6-month study period and the beginning of retreatment. At baseline of the retreatment period, four of the five patients had PSA levels that were equal to or higher than those at study entry. One patient experienced a reduction in PSA levels during the retreatment period similar to his response during the 6-month study (retreatment baseline PSA = 58.2; end of retreatment PSA = 49.4). One patient had a net decrease in PSA levels between study baseline (PSA = 20.7) and the end of treatment period (PSA = 11.7), although his PSA levels increased during retreatment (retreatment baseline PSA = 20.2; end of retreatment PSA = 25.1).

Antibody Formation
Twenty-seven patients were tested for anti-FL antibody in samples obtained at baseline and the end of study (11–14 days after last dose) using an ELISA method; 22 (81%) were positive. All specimens that tested positive were subjected to an assay for neutralizing antibody, and all 22 specimens were negative.

Ten patients who tested positive for anti-FL antibody at the end of study had additional samples available from the first 2 months of the study. Four of these patients were also positive in the earlier samples. Corresponding cycle day 15 DC counts (obtained approximately 2 weeks after these antibody samples) were elevated, consistent with day 15 counts for the patients’ other cycles, indicating that anti-FL antibody did not inhibit the biological activity of FL.

DISCUSSION

In this study, 31 men with HRPC and negative bone scans were given FL. Cycle 1 included a double-blind, placebo- controlled treatment arm, whereas all patients were treated with FL during the five remaining cycles. FL was found to be well tolerated. The most frequently reported toxicity was injection site reaction. Other than this self-limited, localized reaction, comparison with placebo-treated patients showed no clinically relevant differences in the incidence of toxicities. When safety data were assessed for all cycles combined, no other clinically significant adverse events were associated with administration of FL.

Although a high proportion of patients (22 of 27 patients) tested positive for anti-FL antibody at end of study, biological activity did not appear to be altered. All patients were negative for neutralizing antibodies, suggesting that the binding capacity of FL remained intact. The four patients who were anti-FL antibody positive during the first 2 months of the study had increases in day 15 DC counts consistent with other cycles.

Although overall PSA levels remained unchanged with FL treatment, 11 patients had a decrease or only a minor increase (<25%) in PSA. The median relative velocity was significantly less in patients after FL treatment. Unpublished results⁶ rule out the possibility that FL inhibits PSA production by prostate tumor cells. The human prostate carcinoma cell line LNCaP was used in assays for secreted PSA, intracellular PSA, and androgen receptor and the transcriptional effects of both. In each experiment, PSA levels did not decrease significantly when the cell line was treated with FL. These results indicate that FL does not directly interfere with PSA production or result in direct cytotoxicity.

To generate an immune response to tumor cells, barriers to antigen presentation must be overcome. Generally, tumor-specific antigens elicit weak immune responses in vivo (23, 24, 25) . DCs are the most efficient antigen-presenting cells; however, they normally make up only a small fraction of WBCs (<1%; Ref. 24 ). Expansion of DCs that acquire, process, and present antigen may heighten the immune response to tumor antigens. In this study, the 29-fold increase in DC numbers after FL administration approached the increase seen in FL-treated normal volunteers (10–44-fold; Ref. 5 ). The proliferation and expansion of DCs after FL has correlated with biological activity in animal models (4) and patients with metastatic colon cancer (6) . Whereas studies are evaluating in vitro, antigen-pulsed DCs as antitumor therapy (18 , 26, 27, 28, 29) , the procedure is labor-intensive, and there is no assurance that the DCs will migrate to lymph nodes, where antigen presentation takes place (30) . The results presented here demonstrate that HRPC patients treated with FL had an in vivo expansion of classical DCs.

Two distinct populations of DCs have been identified: a myeloid DC (CD11c⁺, lineage-negative, CD123^-) or DC1; and a plasmacytoid DC (CD11c^-, lineage-negative, CD123⁺) or DC2. Although the precise role of the two DC types is still being determined, there is evidence that they may differ in their ability to induce naïve T helper cells to differentiate to either TH1 or TH2 cells (31) . The clinical significance of the different DC types is unknown; however, FL administration in these prostate cancer patients resulted in the generation of both subtypes of DCs, as seen when FL was administered to normal volunteers (5 , 32) . FL is the only cytokine shown to expand both DC populations in vivo. The DC populations expressed low levels of CD80, CD86, and HLA-DR, indicating that they were immature DCs, which are very efficient at antigen uptake and processing (24) .

An antitumor effect may also depend on expansion of effector cells. In animal studies, FL has been shown to increase the natural killer cell population (20) . In this study, natural killer cell counts (CD56⁺) were found to be elevated after cycle 1 (154% increase versus 2.8% decrease in placebo group at day 22).

FL administration was found to be safe and well tolerated in a previous study of FL given to healthy volunteers as a single cycle and in patients with colon cancer, where one patient received three cycles (4 , 6) . A significant finding in the current study was that the biological response was consistent over five consecutive cycles, with no exhaustion of DC expansion. During the last cycle of FL treatment, the percentages of DCs generated were no different from the initial cycle of FL.

In summary, FL was well tolerated by patients with bone scan-negative HRPC. This confirms the safety profile seen in other human trials. DC expansion illustrated that FL provides in vivo biological activity in prostate cancer. The relative velocity of PSA change during FL treatment exhibited a stable slope compared with a significantly less steep slope of the velocity prestudy. The clinical significance of this observation is unknown but warrants further study.

FOOTNOTES

Grant support: Immunex Corporation (Seattle, WA).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: Dania Caron and Anyang Feng were full-time Immunex employees during the study.

Requests for reprints: Celestia S. Higano, University of Washington, c/o Seattle Cancer Care Alliance, 825 Eastlake Avenue East, Mailstop G3-200, Seattle, WA 98109. Phone: (206) 288-1152; Fax: (206) 288-1196; E-mail: thigano{at}u.washington.edu

⁶ W. D. Figg, personal communication.

Received 11/14/02; revised 11/ 4/03; accepted 11/14/03.

REFERENCES

1. Lyman S. D., Johnson J. L., Brasel K., de Vries P., Escobar S. S., et al Cloning of the human homologue of the murine Flt3 ligand: a growth factor for early hematopoietic progenitor cells. Blood, 83: 2795-2801, 1994.[Abstract/Free Full Text]
2. McKenna H. J., de Vries P., Brasel K., Lyman S. D., Williams D. E. The effect of Flt3 ligand on the ex vivo expansion of human CD34+ hematopoietic progenitor cells. Blood, 86: 3413-3420, 1995.[Abstract/Free Full Text]
3. Winton E. F., Bucur S. Z., Bray R. A., Toba K., Williams D. E., McClure H. M. The hematopoietic effects of recombinant human (rh) Flt3 ligand administered to non-human primates. Blood, 86: 424a 1995.
4. Maraskovsky E., Brasel K., Teepe M., Roux E. R., Lyman S. D., Shortman K., et al Dramatic increase in the numbers of functionally mature dendritic cells in Flt3 ligand-treated mice: multiple dendritic cell subpopulations identified. J. Exp. Med., 184: 1953-1962, 1996.[Abstract/Free Full Text]
5. Maraskovsky E., Daro E., Roux E., Teepe M., Maliszewski C. R., Hoek J., Caron D., Lebsack M. E., McKenna H. J. In vivo generation of human dendritic cell subsets by Flt3 ligand. Blood, 96: 878-884, 2000.[Abstract/Free Full Text]
6. Morse M. A., Nair S., Fernandez-Casal M., Deng Y., St Peter M., Williams R., et al Preoperative mobilization of circulating dendritic cells by flt3 ligand administration to patients with metastatic colon cancer. J. Clin. Oncol., 18: 3883-3893, 2000.[Abstract/Free Full Text]
7. Steinman R. M. The dendritic cell system and its role in immunogenicity. Annu. Rev. Immunol., 9: 271-296, 1991.[CrossRef][Medline]
8. McKenna H. J. Generating a T cell tumor-specific immune response in vivo: can flt3 ligand generated dendritic cells tip the balance?. Cancer Immunol. Immunother., 48: 281-286, 1999.[CrossRef][Medline]
9. Cohen P. J., Cohen P. A., Rosenberg S. A., Katz S. I., Mule J. J. Murine epidermal Langerhans cells and splenic dendritic cells present tumor-associated antigens to primed T cells. Eur. J. Immunol., 24: 315-319, 1994.[Medline]
10. Flamand V. T., Sornasse K., Thielemans C., Demanet C., Bakkus M., Bazin H., et al Murine dendritic cells pulsed in vitro with tumor antigen induce tumor resistance in vivo. Eur. J. Immunol., 24: 605-610, 1994.[Medline]
11. Celluzzi C. M., Mayordomo J. I., Storkus W. J. Peptide-pulsed dendritic cells induce antigen-specific, CTL-mediated protective tumor immunity. J. Exp. Med., 183: 283-287, 1996.[Abstract/Free Full Text]
12. Porgador A., Snyder D., Gilboa E. Induction of antitumor immunity using bone marrow-generated dendritic cells. J. Immunol., 156: 2918-2926, 1996.[Abstract]
13. Boczkowski D., Nair S. K., Snyder D., Gilboa E. Dendritic cells pulsed with RNA are potent antigen-presenting cells in vitro and in vivo. J. Exp. Med., 184: 465-472, 1996.[Abstract/Free Full Text]
14. Gabrilovich D. I., Nadaf S., Corak J., Berzofsky J. A., Carbone D. P. Dendritic cells in antitumor immune responses: dendritic cells grown from bone marrow precursors, but not mature DC from tumor-bearing mice, are effective antigen carriers in the therapy of established tumors. Cell. Immunol., 170: 111-119, 1996.[CrossRef][Medline]
15. Mayordomo J. I., Zorina T., Storkus W. J., Zitvogel L., Celluzzi C., Falo L. D., et al Bone marrow-derived dendritic cells pulsed with synthetic tumor peptides elicit protective and therapeutic antitumour immunity. Nat. Med., 1: 1297-1302, 1995.[CrossRef][Medline]
16. Paglia P., Chiodoni C., Rodolfo M., Colombo M. P. Murine dendritic cells loaded in vitro with soluble protein prime cytotoxic T lymphocytes against tumor antigen in vivo. J. Exp. Med., 183: 317-322, 1996.[Abstract/Free Full Text]
17. Zitvogel L., Mayordomo J. I., Tjandrawan T., Deleo A. B., Clarke M. R., Lotze M. T., et al Therapy of murine tumors with tumor peptide-pulsed dendritic cells: dependence on T cells, B7 costimulation, and T helper cell 1-associated cytokines. J. Exp. Med., 183: 87-97, 1996.[Abstract/Free Full Text]
18. Nestle F., Alijagic S., Gilliet M., Sun Y., Grabbe S., Dummer R., et al Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. Nat. Med., 4: 328-332, 1998.[CrossRef][Medline]
19. Lynch D. H., Andreasen A., Miller R. E., Schuh J. C. C. Flt3 ligand: a novel dendritic cell (DC)-stimulating cytokine that induces tumor regression and anti-tumor immune responses in vivo. Blood, 80(Suppl.1): 437a 1996.
20. Lyman S. D., Jacobsen S. E. c-kit ligand and Flt3 ligand: stem/progenitor cell factors with overlapping yet distinct activities. Blood, 91: 1101-1134, 1998.[Free Full Text]
21. Ajani J. A., Welch S. R., Raber M. N., Fields W. S., Krakoff I. H. Comprehensive criteria for assessing therapy-induced toxicity. Cancer Investig., 8: 147-159, 1990.[Medline]
22. Vollmer R. T., Dawson N. A., Vogelzang N. J. The dynamics of prostate specific antigen in hormone refractory prostate carcinoma: an analysis of cancer and leukemia group B study 9181 of megestrol acetate. Cancer (Phila.), 83: 1989-1994, 1998.
23. Ochsenbein A. F., Klenerman P., Karrer U., Ludewig B., Pericin M., Hengartner H., et al Immune surveillance against a solid tumor fails because of immunological ignorance. Proc. Natl. Acad. Sci. USA, 96: 2233-2238, 1999.[Abstract/Free Full Text]
24. Banchereau J., Steinman R. M. Dendritic cells and the control of immunity. Nature (Lond.), 392: 245-252, 1998.[CrossRef][Medline]
25. Lord E. M., Frelinger J. G. Tumor immunotherapy: cytokines and antigen presentation. Cancer Immunol. Immunother., 46: 75-81, 1998.[CrossRef][Medline]
26. Hsu F. J., Benike C., Fagnoni F., Liles T. M., Czerwinski D., Taidi B., et al Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed dendritic cells. Nat. Med., 2: 52-58, 1996.[CrossRef][Medline]
27. Reichardt V. L., Okada C. Y., Liso A., Benike C. J., Stockerl-Goldstein K. E., Engleman E. G., et al Idiotype vaccination using dendritic cells after autologous peripheral blood stem cell transplantation for multiple myeloma a feasibility study. Blood, 93: 2411-2419, 1999.[Abstract/Free Full Text]
28. Murphy G. P., Tjoa B. A., Simmons S. J., Ragde H., Rogers M., Elgamal A., et al Phase II prostate cancer vaccine trial: report of a study involving 37 patients with disease recurrence following primary treatment. Prostate, 39: 54-59, 1999.[CrossRef][Medline]
29. Holtl L., Rieser C., Papesh C., Ramoner R., Herold M., Klocker H., et al Cellular and humoral immune responses in patients with metastatic renal cell carcinoma after vaccination with antigen pulsed dendritic cells. J. Urol., 161: 777-782, 1999.[CrossRef][Medline]
30. Morse M. A., Coleman R. E., Akabani G., Niehaus N., Coleman D., Lyerly H. K. Migration of human dendritic cells after injection in patients with metastatic malignancies. Cancer Res., 59: 56-58, 1999.[Abstract/Free Full Text]
31. Rissoan M., Soumelis V., Kadowaki N., Grouard G., Briere F., de Waal Malefyt R., Liu Y. J. Reciprocal control of T helper cell and dendritic cell differentiation. Science (Wash. DC), 283: 1183-1186, 1999.[Abstract/Free Full Text]
32. Pulendran B., Burkeholder S., Kraus E., Guinet E., Fay J., Davoust J., Caron D., et al Differential mobilization of distinct DC subsets in vivo by flt3-ligand and G-CSF. Blood, 94 (Suppl. 1): 213a 1999.

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