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2Divisions of Medical Oncology [P. A. B., J. C. B., J. A. K., H. C. P., R. L. R.], Transfusion Medicine [D. A. G., D. J. P.], and Stem Cell Laboratory [S. V-P.], Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, and Dendreon Corporation, Seattle, Washington 98121 [R. L. L., M. V. P., B. J. S., P. S., G. S., F. H. V.]
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ABSTRACT |
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 Top ABSTRACT IntroductionPatients and MethodsResultsDiscussionREFERENCES |
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Introduction |
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TopABSTRACTIntroductionPatients and MethodsResultsDiscussionREFERENCES |
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Recent advances in immunology, particularly in isolation and characterization of dendritic cells, have raised hopes that immunotherapy might provide such an additional therapeutic modality (5) . Dendritic cells are the only antigen-presenting cells that can prime naive T cells and initiate an immune response (6) . Isolated dendritic cells can be exposed to tissue- or disease-associated antigens in vitro and reinfused to stimulate immunity to those antigens (5 , 7 , 8) . Indeed, such ex vivo-processed cells have been used successfully in experimental models (9 , 10) and clinical trials (5 , 8 , 11, 12, 13, 14) . These trials used dendritic cells exposed to disease-associated antigens (i.e., idiotypic monoclonal protein, tumor cell lysate, and HIV-derived antigens). In this Phase I study of treatment safety, our secondary goal was to investigate if ex vivo-processed autologous dendritic cells can prime cellular immunity against a normal tissue antigen such as PAP,3 characteristic both of normal prostate (15 , 16) and prostate carcinoma (15 , 16) .
Studies in rats in vivo indicate that rat dendritic cells exposed to rat PAP induce anti-PAP cellular immunity but do not induce antibodies to PAP (17) . However, when the same antigen was injected s.c., it raised a strong antibody response (17) . Accordingly, in this Phase I trial we administered two doses of dendritic cells "pulsed" ex vivo with antigen, followed by three injections of soluble antigen to men suffering from advanced hormone-refractory prostate cancer and monitored treatment safety and effects on cellular and humoral immunity.
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Patients and Methods |
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TopABSTRACTIntroductionPatients and MethodsResultsDiscussionREFERENCES |
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5.0 ng/ml; PAP equal to or above twice the upper limits of
normal; negative serological tests for HIV, human T-cell lymphotrophic
virus type I, hepatitis B, and hepatitis C; adequate hematological
parameters (WBC 2,000/mm3
; absolute neutrophil
count 1,000/mm3
; platelets
100,000/mm3
; and hemoglobin >9.0 g/dl),
creatinine 
2.0 mg/dl; total bilirubin equal to or less than twice the
upper limit of normal; and aspartate aminotransferase and alanine
aminotransferase equal to or less than five times the upper limit of
normal.
Treatment and Assessment.
The clinical trial included i.v. infusion of two doses of PAP
antigen-loaded autologous dendritic cells [APC8015, autologous
dendritic cells exposed ex vivo to PA2024 (see below);
Dendreon] 1 month apart and followed by three monthly s.c. doses of
the PAP antigen (PA2024, a fusion protein consisting of human GM-CSF
and PAP; Dendreon; Fig. 1
). Two days
before each treatment, the patients underwent leukopheresis (1.5–2.0
blood volumes) to collect mononuclear cells, the fraction containing
dendritic cell precursors. Patients received no chemotherapy or growth
factors before leukopheresis. The APC8015 dose contained all dendritic
cells prepared from one leukopheresis product and was infused i.v. over
30 min in the outpatient setting. The patients were observed for acute
side effects for 1 h after infusion and then discharged. The dose
of APC8015 applied in this study had already been shown to be safe in a
Phase I trial (18)
. We tested three dose levels of
s.c.-injected soluble antigen PA2024: 0.3, 0.6, and 1.0 mg. Cohorts of
three patients were entered at each level as long as dose-limiting
grade 3 toxicity (NIH Common Toxicity Criteria) was not observed in
more than one patient/level. Six patients were to be treated at the
final dose level determined either by grade 3 toxicity or by the
attainment of the highest planned dose. PA2024 was injected s.c. in the
thigh (one site for the first two dose levels and two sites for the
third dose level). Patients were observed for acute side effects and
then followed as outpatients. All adverse events were evaluated for the
relationship to treatment with APC8015 or PA2024, and the severity was
scored according to the NIH Common Toxicity Criteria.
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Preparation of Antigen-loaded Dendritic Cells (APC8015).
PA2024 antigen is a recombinant protein consisting of human PAP fused
through its COOH terminus to the NH2 terminus of
GM-CSF by a Gly-Ser linker. The GM-CSF portion targets the fusion
protein to dendritic cells (19)
. The PA2024
gene was cloned into the pBacPak8 vector (Clontech, Palo Alto,
CA) and transfected into Sf21 insect cells by the use of a commercially
available kit (Clontech). Recombinant baculovirus was then cloned by
plaque purification and propagated in Sf21 cells adapted to grow in
protein-free Sf900–2 medium (Life Technologies, Inc., Grand Island,
NY) supplemented with hydrolyzed yeast extract (Life Technologies,
Inc.). The PA2024 protein was released into the culture supernatant and
purified for this trial by three sequential column chromatography steps
to >90% purity.
Antigen-loaded Dendritic Cells (APC8015).
PAP-loaded autologous dendritic cells were prepared at the Mayo Clinic
Cell Processing Center. The Cell Processing Center comprises
environmental control, staffing, and process controls that comply with
the current Good Manufacturing Practices for somatic cell therapy. It
contains a Class 10,000 clean room with Class 100 biosafety cabinets
and other equipment for cell isolation and culture.
APC8015 was prepared by a modification of the method described by Hsu et al. (5) . The leukopheresis product was collected at the adjacent Mayo Blood Bank and transferred to the Cell Processing Center. PBMCs were isolated by centrifuging over a buoyant density solution of 1.0770 g/ml, 320 mosM, and washed twice to remove platelets. The cells were then centrifuged over the second buoyant density solution of 1.0650 g/ml, 320 mosM, to deplete monocytes. The high-density cells in the pellet containing dendritic cell precursors were suspended in AIM-V medium (Life Technologies, Inc.) at 1.0 x 107/ml and incubated with PA2024 (10 µg/ml) in the absence of exogenous serum or cytokines in a humidified 5% (v/v) CO2 in air at 37°C. After 40-h of culturing, the cells were washed, suspended in lactated Ringer’s solution, and transported to the outpatient Mayo Infusion Therapy Center for infusion. Quality control for each cell lot included cell number and viability, Gram’s stain, cell surface marker phenotype, and tests of sterility, Mycoplasma, and endotoxin. The results of tests for sterility, Mycoplasma, and endotoxin were available only after APC8015 had been infused. Twenty-five lots of APC8015 were prepared for 13 patients. APC8015 contained 18.6 ± 9.4% (median, 18.0%; range, 6.0–39.0%) dendritic cells, defined as CD54bright, 65.1 ± 12.0% T cells (CD3+), 16.6 ± 7.8% monocytes (CD14+), and 5.0 ± 2.4% B cells (CD19+). In APC8015 prepared for another prostate cancer immunotherapy study (18) , we found that the CD54bright cells were also bright in CD40, CD86, HLA-A,B,C, and HLA-DR (data not shown); in APC8015 prepared from the blood of normal healthy donors, >90% of CD54bright cells were HLA-DRbright (data not shown).
Assessment of Immune Function.
To assess the immune response to therapy, 20–40 ml of venous blood was
collected in heparinized tubes at week 0 (baseline values before
dendritic cell infusion) and in weeks 4, 8, 12, 16, and 20. Immediately
after drawing, blood was transported at ambient temperature overnight
from the Mayo Clinic to Dendreon (Mountain View, CA). There,
serum was separated and frozen. Mononuclear cells containing
lymphocytes were isolated by centrifuging over a buoyant density
solution of 1.0770 g/ml and 320 mosM and washed twice to remove
platelets. Isolated PBMCs were resuspended in AIM-V medium (Life
Technologies, Inc.) containing 5.0% human AB serum (Gemini
Bioproducts, Calabas, CA) and used for functional testing on the day of
receipt.
Antigen-dependent T-cell proliferation was tested against PA2024, human seminal fluid PAP (Biodesign International, Kennebunk, ME), and GM-CSF (Leukine; Immunex, Seattle, WA). One hundred thousand PBMCs were plated per well of round-bottomed, 96-well microtiter plates. Antigens were dissolved in AIM-V medium containing 5.0% human AB serum and added to triplicate wells at the final concentration of 0.4, 2.0, 10, or 50 mg/ml in the total volume of 200 µl. Control wells contained no antigen. The cells were incubated at 37°C in 5% CO2 for 5 days. Tritiated thymidine (Amersham, Piscataway, NJ), 1.0 µCi/well, was added for the last 16 h of incubation, after which the cells were harvested with a Tomtec harvester (Wallac, Gaithersburg, MD). The radioactivity of incorporated thymidine was measured as cpm in a Wallac-LKB Betaplate counter (Wallac). T-cell proliferation response was considered significant when the mean radioactivity of the wells containing antigen was at least twice above the mean radioactivity of the control wells.
Proliferation is expressed as proliferation index calculated from the
formula.
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Statistics.
Changes in antigen-specific cellular immunity were analyzed by
comparing proliferation of T cells drawn at successive times before and
during treatment at 4-week intervals. By the use of the PROC MIXED
program package (SAS Institute, Cary, NC), the relationship was
examined by comparing radioactivity (cpm) incorporated by cells from
each of nine patients stimulated by four concentrations of each
antigen. Each time/antigen combination was compared separately,
yielding the respective P. The significance of differences
between mean values was assessed by the two-tailed Student’s
t test for unequal variances (see Table 2
). The difference
between median levels of antibodies to PAP was determined by the
two-tailed Mann-Whitney test. The significance level for all
comparisons was set at P < 0.05.
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Results |
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TopABSTRACTIntroductionPatients and MethodsResultsDiscussionREFERENCES |
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. Seven patients had
primarily osseous metastases, and five patients had soft tissue/nodal
disease. At the time of entry into the study, no patient suffered from
any apparent visceral metastases. All patients failed prior hormone
therapy and were ambulatory. Most tumor-related symptoms were mild.
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shows the number of dendritic
cells and the dose of PA2024 administered to each patient group. All
patients received two doses of APC8015 except patient 7. The patients
received the full course of PA2024 at each dose level except patients 5
and 8, who received only one injection, and patients 9 and 12, who
received two injections. The achieved numbers of dendritic cells in the
first and second doses of APC8015 were similar, demonstrating that cell
processing was consistent. Variation in the total number of nucleated
cells was slightly larger and ranged among patients between 1.1 x
109 and 5.4 x 109.
Adverse Events.
Generally, the treatment was well tolerated. Five patients developed
mild fever (grade 1–2) and/or chills within 1 h after infusion of
APC8015; these symptoms lasted less than 24 h. Five patients developed
mild (grade 1–2) myalgia or pain, usually 1–2 days after treatment
with APC8015; these symptoms were fully resolved within 1 week. Six
patients reported transient grade 1–2 fatigue, and one experienced
prolonged grade 3 fatigue that was temporally related to treatment.
Four patients developed mild (grade 1) local reactions after injection
of PA2024: patient 2 upon injections on weeks 12 and 16, patient 3 on
week 8, patient 4 on weeks 12 and 16, and patient 10 on week 12. There
were no adverse events related to leukopheresis, and all procedures
were performed using peripheral venous access.
Response to Treatment.
Twelve patients could be evaluated for the response to treatment. In
patients 5, 10, and 11, PSA levels were reduced by more than one-half
in the course of treatment (Fig. 2
; note
the logarithmic scale on the ordinate), although in patient 5, PSA
declined despite the rapid progression of disease. Three patients (4
, 10 , and 11)
experienced significant drops in circulating PAP levels
(Fig. 2)
. No response was detected by radiography. The median time to
disease progression was 135 days after registration (range, 30–274
days).
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show the
T-cell response measured from week 0 every 4 weeks until week 20, or
until the withdrawal from trial because of disease progression. The
cells from patients 1–3 could not be evaluated because they
proliferated strongly in the absence of antigens; the reason for this
phenomenon is unclear. Four weeks after the first treatment with
APC8015, T cells from all evaluated patients proliferated in
vitro in response to PA2024 (P = 0.0001). The
change in the proliferation index differed among patients and ranged
from 3 to 120. The response to PA2024 persisted for the duration of
treatment or duration of monitoring (Fig. 3
, top).
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, middle) and PAP
isolated from human seminal fluid (Fig. 3
, bottom). Both
GM-CSF and PAP induced T-cell proliferation (P = 0.0004
and 0.0001, respectively), in some patients more than 10 times above
the baseline. Thus, infusion of APC8015 clearly induced T cells
specific for GM-CSF and for PAP, the components of the fusion protein
PA2024.
On week 8, we administered the first of three s.c. injections of the
soluble antigen and evaluated the effects on T-cell proliferation
monthly. Within the limits of resolution of the assay, soluble antigen
contributed little to the antigen-specific T-cell response induced by
APC8015 (compare T-cell proliferation before week 12 with the
proliferation on or after week 12; Fig. 3
).
Antibody Response to Dendritic Cells and Soluble Antigen.
Eleven patients were evaluable for antibody responses to PA2024 (Table 3)
. After treatment, all patients
developed antibodies to PA2024. Nine patients responded after
administration of antigen-loaded dendritic cells alone (before
administration of PA2024) and two patients after administration of
PA2024 (week 12). We evaluated also the antibodies to GM-CSF and PAP.
We found that three patients contained low titers of preexisting
antibodies to GM-CSF (Table 3)
.
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To determine the effects of soluble PA2024 on circulating antibody
levels, we compared the titers of antibodies to PAP in this study with
the titers obtained in a similar study of prostate cancer that used
APC8015 only (18)
. In this study, 2 of 12 evaluated
patients developed titers >40 (Table 3)
. In the other study, 15 of 31
patients developed titers >40. This difference is statistically
significant (P = 0.01, Mann-Whitney test).
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Discussion |
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TopABSTRACTIntroductionPatients and MethodsResultsDiscussionREFERENCES |
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Antigen-specific T cells and antibodies raised by APC8015 and PA2024 have provided important insights into the efficacy of antigen-loaded dendritic cells and the elicited immune response. Antigen-loaded dendritic cells were highly efficacious in eliciting antigen-specific T cells; in most patients, antigen-specific T cells were present within 4 weeks of the first infusion of APC8015. The immune response to the fusion protein PA2024 could be clearly dissected into immunity against the constituent PAP and GM-CSF. This is a direct demonstration that the treatment broke tolerance to a normal tissue-associated antigen (PAP) and a normal cytokine (GM-CSF).
Overall, the treatment was tolerated well. Infusions of APC8015 resulted in mild symptoms observed previously in similar studies (18) . s.c. injections of PA2024 were generally harmless, with six patients experiencing mild (grade 1–2) systemic toxicity and four patients having a local grade 1 reaction at the site of s.c. injection. Interestingly, at the time of these reactions, two patients (4 and 10) demonstrated high levels of T-cell reactions to PA2024 and its components in vitro. This indicates the possibility that the s.c. administration of PA2024 induced a delayed-type hypersensitivity-like reaction.
PA2024, the fusion protein used for "pulsing" dendritic cells, contains full-length PAP and GM-CSF. The fusion molecule is endowed with the enzyme function of acid phosphatase and can stimulate growth in GM-CSF–dependent cell lines. Exposure to PA2024 allows dendritic cells to process, edit, and present antigen in the context of HLA class I and class II restriction characteristic for each individual. Consequently, we did not select patients on the basis of their HLA makeup; this decision is supported by an analysis of the ability of different HLA class I molecules to present PAP-derived peptides, which showed that most can present one or more peptides derived from PAP.5 Such peptides can elicit cytotoxic T cells that can effectively lyse PAP-secreting prostate tumor cells in vitro (21) .
Murphy and colleagues treated prostate cancer patients with autologous dendritic cells pulsed with HLA-A0201-specific peptides derived from prostate-specific membrane antigen (11) . In contrast to our experience, no patient developed immunity to these peptides. In a pilot study of dendritic cells for treatment of HIV infection, we pulsed the cells with either HIV-derived HLA-A2–restricted peptides or with the whole HIV GP160 protein (8) . Although dendritic cells pulsed with either the protein or the peptides elicited HIV-specific cytotoxic T cells, the protein-pulsed dendritic cells were significantly more potent. Similarly, dendritic cells pulsed with whole immunoglobulin protein elicited cytotoxic T cells in the patients with B-cell lymphoma (5) and, possibly, in multiple myeloma (22) . Dendritic cells pulsed with peptides or tumor lysates resulted in T-cell immune responses in the patients suffering from melanoma (7) . These studies did not compare immunogenicity of dendritic cells pulsed with peptides with immunogenicity of the cells pulsed with whole proteins, but it is highly probable that tumor-cell lysates contained both HLA class I- and class II-restricted peptides.
Development of an effective immune response requires complex interactions between CD4-positive class II-restricted T cells and C8-positive class I-restricted T cells. Possibly, protein-pulsed dendritic cells can stimulate both CD4- and CD8-positive T cells, whereas peptide-pulsed dendritic cells are designed to stimulate CD8-positive T cells only. The limited clinical data with antigen-pulsed dendritic cells suggest that breaking tolerance to hitherto unrecognized antigens such as PAP and prostate-specific membrane antigen requires stimulation of both CD4- and CD8-positive T cells (23) . Under some circumstances, targeting CD8-positive T cells alone with class I-restricted peptides may suffice for stimulation of immunity, but the concurrent targeting of CD4-positive T cells may augment the response.
Although APC8015 raised T cells specific for GM-CSF and PAP with similar efficacy, the combined treatment (APC8015 and PA2024) had a different effect on raising antibodies against GM-CSF and PAP: (a) after 16–20 weeks, antibodies against GM-CSF were observed in most patients. Interestingly, antibodies against PAP were detected in only 5 (of 11) patients, invariably at low titers; (b) the titer of antibodies to GM-CSF was inversely proportional to the administered dose of PA2024; and (c) it is noteworthy that some patients harbored spontaneous antibodies to GM-CSF; however, this condition did not predict a high-antibody response to GM-CSF after treatment. In contrast to these results, we observed a higher rate of antibody responses to PAP and higher titers of anti-PAP antibodies in a study of APC8015 alone given on a schedule similar to the one used in the current trial (weeks 0, 4, and 8; Ref. 18 ). Comparison of the two trials of APC8015 suggests that administration of soluble antigen PA2024 in the dose and schedule used in this trial actually suppressed antibody generation. The administration of soluble antigen without adjuvant can suppresses B-cell immune responses (24) . However, GM-CSF is an immune adjuvant; our data and those of others demonstrate that fusion proteins containing GM-CSF elicit potent antibody responses in the absence of exogenous adjuvant.
Development of anti-GM-CSF antibodies after parenteral administration has been well documented (25 , 26) , but these antibodies appear to have no apparent clinical consequences. It is unlikely that antibodies to GM-CSF would affect the potency of APC8015 because dendritic cells display peptide fragments of GM-CSF and antibodies cannot recognize such peptides. Antibodies to GM-CSF could, however, limit the adjuvant effect of GM-CSF administered either as a fusion protein such as PA2024 or as a soluble protein boost.
In the reduction of the levels of circulating PSA and PAP, we found preliminary evidence of activity of this immunotherapy protocol. In one patient (5) , however, PSA dropped to less than one-half of the pretreatment value at the time when the disease actively progressed; his PAP remained unchanged. This observation is in line with the concerns about the use of PSA as the sole end point for measuring the response of prostate cancer to novel treatments (27) .
We did not observe any objective radiographic response to treatment. The time to disease progression after diagnosis was in the range of values reported for cytotoxic treatments for hormone-refractory prostate cancer, where progression was determined by means other than changes in PSA (28 , 29) . However, the treatment was well tolerated and elicited few side effects compared with chemotherapy. It raised PAP-specific immunity effectively. In addition, we observed sporadic treatment-induced decreases of circulating PSA and PAP. Consequently, we have initiated a Phase II trial with the highest dose of PA2024; the goal of the trial is to define better the response, time to progression, and survival in a cohort of men with hormone-refractory prostate cancer treated with APC8015 followed by PA2024.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by Mrs. Adelyn L. Luther, Singer
Island, Florida, and the Mayo Clinic Cancer Center. 
2 To whom requests for reprints should be
addressed, at Mayo Clinic, Guggenheim 1311A, Rochester, MN
55905. Phone: 507-284-2814; Fax: 507-266-5146; E-mail: vukpavlovic.stanimir{at}mayo.edu
3 The abbreviations used are: PAP, prostatic acid
phosphatase; GM-CSF, granulocyte/macrophage-colony stimulating factor;
PBMC, peripheral blood mononuclear cell; PSA, prostate-specific
antigen; HLA, human leukocyte antigen.
4 G. Strang, W. G. Haag, B. Smits, J. Breen, P.
Sopapan, and W. C. A. van Schooten. Quantitation of cellular immune
response after immunotherapy for prostate cancer, manuscript in
preparation.
5 S. Vuk-Pavlovi, unpublished data.
Received 12/11/99; revised 2/ 1/00; accepted 2/ 2/00.
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