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*
Department of Pathology, Stanford University School of Medicine, Palo Alto, CA 94304; and
Dendreon, Seattle, WA 98121
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and/or TNF-
secretion, but not IL-4, consistent with induction of
Th1 immunity. Finally, 6 of 21 patients had clinical stabilization of
their previously progressing prostate cancer. All six of these patients
developed T cell immunity to human PAP following vaccination. These
results demonstrate that xenoantigen immunization can break tolerance
to a self-Ag in humans, resulting in a clinically significant antitumor
effect. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Because PAP represents a self-Ag, it is not inherently immunogenic. T cells that recognize self-Ags with high avidity are believed to undergo negative selection through clonal deletion in the thymus or anergy in the periphery (15). We have demonstrated that PAP can be immunogenic in a rodent model (16). However, only immunization with a xenogeneic PAP (hPAP into rat) generated cytotoxic T lymphocytes and prostate-specific autoimmunity, suggesting that xenoantigens may be capable of overcoming tolerance against the homologous self-Ag. Other groups have made similar observations with melanoma Ags (17, 18). Therefore, we wished to examine the use of xenogeneic PAP immunization in humans as a potential cancer vaccine.
One way to potentially immunize patients against PAP is to isolate their dendritic cells (DC), load them with Ag, and then reinfuse these cells as the vaccine. DC represent the most potent APC of the immune system, uniquely capable of sensitizing naive T cells to new Ags. Moreover, when Ag-loaded DC are administered systemically, they home to lymphoid organs where they activate Ag-specific T cells, thereby inducing an immune response. This approach has been used successfully to vaccinate cancer patients, resulting in antitumor immunity and clinical response (19). In the described clinical trial, we examined the ability of DC loaded with the xenogeneic homolog of hPAP derived from mice, mPAP, to generate immune responses in patients with advanced prostate cancer.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Men (n = 21) enrolled in this clinical study
were required to have histologically documented prostate adenocarcinoma
with rising serum PSA levels as well as measurable serum PAP. Patients
could be hormone refractory or hormone sensitive so long as no hormonal
manipulations were performed within the 4 wk before enrolling in the
trial to control for antiandrogen withdrawal effects (6 wk if the
patient had received bicalutamide). Other eligibility requirements
included Karnofsky performance status >70; negative serological tests
for HIV, human T cell leukemia virus-1, hepatitis B, and
hepatitis C; white blood cell count 
2,000/mm3;
absolute neutrophil count 1,000/mm3; platelets
100,000/mm3; creatinine 
2.0 mg/dl; total
bilirubin equal to or less than twice the upper limit of normal; and
liver transaminases equal to or less than five times the upper
limit of normal. The protocol was approved by the Stanford University
School of Medicine (Palo Alto, CA) institutional review board,
and trial subjects provided signed informed consent before completing
the screening process.
Clinical monitoring
Patients were monitored by interval histories, physical
examinations, blood counts, serum chemistries, and measurements of PSA
and PAP monthly during vaccination and then monthly until evidence of
disease progression. Patients were evaluated for toxicity by the
National Cancer Institute common toxicity criteria. Patients were
assessed for antinuclear Abs and rheumatoid factor before and following
vaccination. HLA typing was performed at the Stanford Blood Center.
Tumor burden was evaluated by computed tomography and bone scans
prevaccination, 4 mo following vaccination, and then every 6 mo until
clinical progression. Unless accompanied by clinical progression,
increasing levels of PSA or PAP before completion of the vaccination
were not taken as reasons for discontinuation. Following vaccination,
clinical progression was defined by rising serum PSA levels >50%
above baseline and/or new or enlarged lesions on computerized
tomography or bone scans. Stable disease was defined as a
clinical course that met criteria for neither progressive disease nor
partial response (50% reduction of measurable or evaluable
disease).
PAP Ags
cDNA encoding mPAP was cloned into the pBacPAK8 baculovirus recombination vector (Clontech Laboratories, Palo Alto, CA) to generate recombinant baculovirus. rmPAP was expressed as a His6 fusion protein. Recombinant baculovirus was then cloned by plaque purification and propagated in Sf21 cells adapted to growth in protein-free suspension. mPAP was purified from culture supernatants with Ni-NTA chromatography (Qiagen, Hilden, Germany) to >95% purity by SDS-PAGE. hPAP used for in vitro assays was purified from human seminal fluid (Biodesign International, Kennebunk, ME).
DC vaccine preparation
The patients underwent unmobilized peripheral blood leukapheresis, with two total body blood volumes (8–14 L of blood) processed with a Cobe cell separator (Gambro, Lakewood, CO). PBMC were obtained by centrifugation over Ficoll-Hypaque (Amersham Biosciences, Uppsala, Sweden), and then monocytes were depleted by density centrifugation through Percoll (Amersham Biosciences) density 1.065 as previously described (20, 21, 22). Monocyte-depleted PBMC were incubated with mPAP (2 µg/ml) in RPMI 1640 (BioWhittaker, Walkersville, MD) with 10% pooled human AB serum without the addition of exogenous cytokines. After a 24-h culture in a humidified incubator at 37°C with 10% CO2, DC were further enriched from lymphocytes by centrifugation through a 15% (w/v) metrizamide gradient (Sigma-Aldrich, St. Louis, MO). The enriched DC were cultured overnight in medium containing 50 µg/ml mPAP, washed free of Ag, resuspended in normal saline with 5% autologous serum, and infused. The DC dose was calculated by determining the percentage of DC in the vaccine by flow cytometric analysis assessing lineage-negative (CD3, -14, -19, -56), HLA-DR-positive, and CD11c-positive cells performed using a FACSCalibur (BD Biosciences, Mountain View, CA). The mean DC purity in the administered vaccination was 30%. While the enriched DC product contained some contaminating T cells, the number of T cells transferred (<5 x 107) is less than the sizeable dose required to produce any systemically measurable immune response (23, 24). The DC product also contained some B cells and monocytes, although these cell types have not been demonstrated to prime immunity in vivo in humans. Nevertheless, their potential contribution to the immune response cannot be excluded.
DC vaccination
Twenty-one prostate cancer patients were immunized twice with mPAP-loaded DC 4 wk apart. Patients were sequentially assigned to three cohorts to receive both DC immunizations via i.v., intradermal (i.d.), or intralymphatic (i.l.) injections. For i.v. administration, DC were suspended in 100 ml of normal saline with 5% autologous serum and infused by a peripheral i.v. catheter following premedication with acetaminophen and diphenhydramine. For i.d. administration, DC were suspended in 4 ml of normal saline with 5% autologous serum and were administered 12–20 i.d. injections into the medial thighs following application of topical anesthetic. For i.l. administration, DC were also suspended in a volume of 4 ml, but were infused via a catheter cannulating a lymphatic channel in the dorsum of the foot that was identified through a small incision. This volume is a typical volume for i.l. injection of radiographic contrast for lymphangiography. All adverse events were evaluated for their possible relationship to treatment with DC injections, and the severity was scored according to the National Cancer Institute common toxicity criteria.
T cell functional assays
Blood was obtained from patients before immunization, 1 mo following the DC immunizations, monthly for the initial 6 mo following vaccination, and then every 3 mo thereafter until clinical progression. PBMC were obtained by centrifugation over Ficoll-Hypaque (Amersham Biosciences) and were cultured at 100,000 cells/well in triplicate in 96-well U-bottom plates (Costar, Cambridge, MA) in medium containing 10–50 µg/ml mPAP or hPAP. Other T cell stimulators used for in vitro assays included influenza protein (Aventis Pasteur Connaught, Swiftwater, PA) and PMA with ionomycin (Sigma-Aldrich). T cell proliferation was assessed on the basis of 18-h [3H]thymidine incorporation after 6 days of culture as measured in a Microbeta counter (Wallac, Turku, Finland). The results are expressed as stimulation indexes representing counts per minute relative to baseline counts without Ag. To establish the background for the proliferation assays, a control population of 20 volunteer blood donors was assessed with the same methodology and had average stimulation indexes of 1.15 ± 0.34 and 0.86 ± 0.46 to mPAP and hPAP, respectively. A stimulation index >2 was therefore defined as a positive response. Supernatants were also collected from cell cultures, frozen, and assessed for cytokine secretion by ELISA as described below.
Cytokine ELISA
Ninety-six-well Immulon-4 plates (Dynatech Laboratories,
Chantilly, VA) were coated overnight at 4°C with 50 µl of the
primary Ab to IL-4, IL-10, IFN-, and TNF- (BD PharMingen, San
Diego, CA) in 0.1 M carbonate-bicarbonate buffer, pH 9.5. Wells were
blocked with Blotto (5% nonfat dry milk in 0.05% Tween 20) for 2
h at room temperature. Frozen cell supernatants were added to the wells
and incubated at room temperature for 3 h, after which the
appropriate biotinylated secondary Ab resuspended in Blotto was added
and incubated for 1 h at room temperature. Following washing with
0.05% Tween 20, HRP-conjugated rabbit anti-mouse Ab was added and
incubated for 30 min at room temperature. The plates were washed and
developed with the substrate tetramethyl benzidine (Zymed Laboratories,
South San Francisco, CA). The reaction was stopped with 1 N HCl, and
the OD was read at 450 nm on a microplate reader (Bio-Rad, Hercules,
CA). The limit of detection for the three cytokines assayed was 25
pg/ml. To establish the background levels of cytokine production, a
control population of 20 healthy volunteer adult blood donors was
assessed with the same methodology to mPAP and hPAP. The average
cytokine levels measured in these cultures were 1.0 ± 3.0,
13.6 ± 37.9, and 16.7 ± 24.7 pg/ml for IL-4, IFN-, and
TNF-, respectively. Cytokine production >100 pg/ml was defined as a
positive response.
Cytokine ELISPOT
Ninety-six-well polyvinylidene difluoride-backed plates (MAHA S
45; Millipore, Bedford, MA) were coated with primary Ab to IFN- or
IL-4 (Mabtech, Stockholm, Sweden) overnight at 4°C. Plates were then
washed six times with PBS and blocked with RPMI 1640
supplemented with L-glutamine, penicillin, and 10%
heat-inactivated pooled human AB serum (complete medium (CM))
for 1 h. PBMC (105) were added in 100
µl/well CM to the precoated plates. Ag was resuspended in CM, and 100
µl was added to the cells in duplicate or triplicate wells. The cells
were incubated for 72 h at 37°C in 5% CO2
and washed six times with PBS, and the appropriate biotinylated
detection Ab (Mabtech) was then added. After 2 h of incubation
plates were washed with PBS, and a streptavidin-alkaline
phosphatase conjugate (Mabtech) was added to the wells. The plates were
then incubated for 2 h at room temperature. Wells were washed and
chromogenic alkaline phosphatase substrate (Bio-Rad) was added. After
30–60 min, the colorimetric reaction was terminated by washing with
water, and plates were air-dried. Spots were counted at x20 with a
stereomicroscope (Leitz GZ6; Leitz, Wetzlar, Germany).
Anti-PAP ELISA
Sera collected simultaneously with the PBMC were frozen and analyzed in batches. Ninety-six-well Immulon-4 plates were coated overnight at 4°C with either mPAP or hPAP, blocked with 5% dehydrated nonfat milk in 50 mM TBS and 0.05% Tween 20, and washed with 0.05% Tween 20. Patient sera were diluted in PBS, added to wells, and incubated for 1 h at room temperature. Plates were washed and incubated with goat anti-human total Ig Ab labeled with HRP (Kirkegaard & Perry Laboratories, Gaithersburg, MD) for an additional hour at room temperature. The plates were washed and developed with the substrate tetramethyl benzidine (Zymed Laboratories). The reaction was stopped with 1 N HCl, and the OD was read at 450 nm on a microplate reader (Bio-Rad).
Statistical analyses
T cell proliferative responses before and after DC vaccination were analyzed with the paired sign test (StatView; SAS Institute, Cary, NC). Correlations among baseline absolute lymphocyte count, PSA, PAP, DC route of administration, and DC doses with T cell proliferation and clinical response were analyzed with two-tailed ANOVA. PSA slope and confidence intervals were calculated with a simple linear regression. The Kaplan-Meier plot for progression-free survival was assessed for significance with the Breslow-Gehan-Wilcoxon test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Twenty-one patients with recurrent and/or metastatic disease
completed the phase I clinical trial (Table I
). Seven of these patients had hormone
refractory disease. Eleven had measurable metastases, predominantly in
bone and lymph nodes, while the remainder had prostate cancer evaluable
by serum PSA levels. Four and 15 patients were previously treated with
chemotherapy and/or radiation therapy (XRT), respectively. While the
patients had essentially normal total white counts on study entry,
seven patients had persistent lymphopenia presumably stemming from
prior myelosuppressive treatments or bone involvement of their cancer.
In fact, all lymphopenic patients had received prior XRT
(p = 0.0284). As another general measure of
immune competence, patients were also tested for delayed-type
hypersensitivity to tetanus toxoid, candida, and mumps. Seven patients
did not react to any of these recall Ags and therefore would be deemed
clinically anergic. Skin test unresponsiveness did not correlate with
lymphopenia or prior XRT.
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Patients received two monthly vaccinations with autologous enriched DC obtained from peripheral blood via density gradient centrifugation. Patients underwent leukapheresis preceding each of the vaccinations to obtain PBMC. Committed DC precursors were enriched based upon the change in their buoyant density that occurs as they mature, a process that does not require exogenous cytokines. Cells were cocultured with mPAP during this 2-day ex vivo enrichment. The enriched DC were then administered to the patients as an autologous cellular vaccine with a mean DC dose of 11.2 x 106 per vaccination (range, 0.3–40.4 x 106). All patients tolerated the vaccinations without significant toxicity. Two patients developed grade 2 transfusion reactions at the time of the DC infusions manifesting as self-limited fever and rigors. Three other patients developed grade 1 erythema at the injection sites. Finally, one patient developed a transiently swollen, painful inguinal lymph node following vaccination. Five patients developed elevated antinuclear Abs following vaccination (titers of 1/20–640), and another patient developed an elevated rheumatoid factor following vaccination. None of the patients developed clinically evident autoimmune disease.
Induction of PAP-specific immunity
To assess the induction of T cell immunity with the vaccination
approach, PBMC obtained before and following DC vaccination were
assessed for T cell proliferation in response to mPAP (Fig. 1A). Following vaccination,
all subjects developed T cell proliferative responses to this Ag that
was delivered by the vaccine. More importantly, 11 of the 21 patients
developed T cell proliferation in response to the homologous self-Ag
hPAP (Fig. 1B). Curiously, there was no correlation among
baseline serum PSA, serum PAP, absolute lymphocyte count, or DC dose to
hPAP-specific T cell proliferation following vaccination (data not
shown). Also, there was no difference in T cell proliferation in
response to hPAP between patients who were vaccinated by the different
routes (data not shown). T cell proliferation could be measured for
months following vaccination, consistent with the induction of T cell
memory (Fig. 1C).
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, IFN-, IL-4, and
IL-10 production in response to mPAP and hPAP before and following
vaccination. Seven of 16 evaluated patients produced IFN- and one of
16 patients produced TNF- in response to mPAP (Fig. 2A). Six of 16 evaluated
patients produced only IFN-, one of 16 patients produced TNF-,
and four of 16 patients produced both cytokines in response to hPAP
(Fig. 2B). No patients produced IL-4 or IL-10 (data not
shown) in response to either Ag, consistent with the induction of Th1
immunity. To assess the frequency of PAP-reactive T cells induced with
the vaccination, IFN- and IL-4 secretion was also measured with
cytokine ELISPOT assays in a subset of the patients. In the three
patients who had IFN- responses to both mPAP and hPAP, the frequency
of IFN--producing cells was consistently less in response to hPAP
compared with mPAP (Fig. 3; mean, 51%;
range, 40–64%). Consistent with the cytokine ELISA results, no IL-4
production was detected with the ELISPOT assay (data not shown).
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). Four patients
developed Abs to both mPAP and hPAP, although only one patient
developed Abs at high titer (>1/1000). Four other patients developed
low titers of Abs to mPAP, and another two patients developed Abs
to hPAP.
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While the primary goal in this trial was to assess the
feasibility, safety, and immunogenicity of the DC vaccine, patients
participating in the trial were also assessed for evidence of clinical
response. At study entry candidates were required to have evidence of
progressive prostate cancer based primarily on rising serum PSA levels.
Study subjects did not receive other therapies during the vaccine study
unless they had further clinical progression, at which point they were
taken off the protocol. Six of the 21 patients had evidence of disease
stabilization following completion of the vaccinations as determined by
serum PSA monitoring and confirmed by computed tomography and bone
scans. Serial PSA measurements in a representative patient (patient 21)
are shown in Fig. 4A. Before
vaccination, the patient had a log-linear rising serum PSA (PSA slope,
0.149 ± 0.015). Following vaccination, the patient’s PSA
stabilized (PSA slope, 0.035 ± 0.019) without any other therapy
for well beyond a year. Fig. 4B shows serial PSA
measurements in another patient (patient 12), who also had a
progressive rise in PSA before vaccination (PSA slope, 0.023 ±
0.001) and then had stabilization of his serum PSA (slope, 0.005
± 0.001) for over a year. However, this patient eventually went on to
develop progressive disease, as shown by the abrupt rise in serum PSA.
Interestingly, the patient had lost measurable T cell responses to mPAP
and hPAP by this time.
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C). By contrast, only five of the 15 patients whose disease
progressed immediately following vaccination had measurable T cell
proliferative responses to hPAP. Moreover, the induction of T cell
proliferative responses to hPAP correlated with progression
(p = 0.0087). There was no correlation between
clinical stabilization and the development of anti-PAP Abs.
Finally, there was no correlation between clinical stabilization and
baseline serum PSA, PAP, lymphocyte count, prior treatment, or route of
DC administration (data not shown). |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Despite the advanced disease and immunocompromised state of the
patients in our trial, all patients developed xenoantigen-specific CD4
T cell immunity following immunization. DC used in this trial were
enriched directly from the blood in contrast to other trials that use
monocyte-derived precursors. Patients received DC via i.v., i.d., or
i.l. routes of administration. As we have previously reported
(33), all three routes of DC administration generated T
cell proliferation to mPAP, although there was a difference in the rate
of effector cytokine induction. However, no statistically significant
difference in the induction of T cell proliferation to hPAP or clinical
responses were seen between the different routes. This lack of
correlation may stem from the limited number of patients developing
responses to hPAP, and additional study patients would be required to
clarify this. Nevertheless, hPAP responses were also associated with
IFN- and TNF-, but not IL-4, production and are consistent with a
Th1 phenotype. More importantly, 11 of the patients developed T cell
proliferation in response to the homologous self-Ag, hPAP. Following
vaccination, the frequency of T cells reactive to mPAP as measured by
ELISPOT was similar in magnitude to the frequency of memory T cells
against influenza in this population of patients (data not shown). In
contrast, the frequency of hPAP-reactive T cells was about half that
for mPAP. This would be expected given the negative selection of
self-reactive T cells during thymic development. The induction of
hPAP-specific T cells potentially represents the induction of T cells
with primary specificity for epitopes in the xenoantigen, but that
possess sufficient TCR plasticity to recognize the self-Ag
(34). Xenogeneic homologs may also give rise to altered
peptide ligands that possess agonistic properties to reactive T cells
remaining in the repertoire (35, 36). Alternatively, T
cells recognizing cryptic self-determinants may be expanded with such a
vaccination (37, 38).
Following DC immunization, six of the 21 patients experienced stabilization of disease as assessed by serum PSA and confirmed with radiographic imaging. This stable disease was maintained without any other therapeutic intervention. These results are intriguing given the patient population studied, the progressive nature of metastatic prostate cancer, and the minimal toxicity associated with the vaccination. A rise in serum PSA associated with progressive prostate cancer has an exponential growth rate (log-linear) (39), which was seen in all patients at study entry. Patients whose disease stabilized had statistically significant reductions in the rate of PSA rise, consistent with a change in the growth rate of the cancer (40). In fact, all patients who developed clinical stabilization following vaccination had serum PSA doubling times of 1–4 mo before vaccination. Moreover, clinical stabilization correlated quite strikingly with the development of T cell responses to the relevant self-Ag. Thus, all six of the clinical responders developed T cell immunity to hPAP compared with only five of 15 nonresponders (p = 0.0087). While the induction of predominantly low-titer PAP-specific Abs was detected, no correlation was seen between the presence of anti-PAP Abs and the induction of T cell immunity or clinical stabilization. Therefore, Abs do not appear to be playing a role in the clinical effect.
Patients participating in this trial were not restricted to particular HLA alleles. As a result there was considerable allelic diversity (data not shown), making detection of CD8 T cell immunity difficult. Nevertheless, induction of CD4 T cell help is required for the generation and maintenance of effective CD8 immunity (41, 42) and would serve as a surrogate for detecting patients with a relevant immune response. There was no clear correlation between clinical or immune responses and HLA alleles, although the study size is too small to exclude such a relationship (data not shown). Ultimately, responses to hPAP and clinical responses may be reliant not only on the ability of immunogenic epitopes to be presented by various HLA haplotypes, but also the presence of T cells with relevant TCR specificities. An expanded trial would be required to clarify any potential correlation between HLA alleles and the capacity to present relevant epitopes.
While our results demonstrate that patients with lymphopenia, delayed-type hypersensitivity anergy, and advanced disease can respond to vaccination, treating patients with earlier stages of disease may prove even more successful. Possibilities would include immunizing patients in an adjuvant setting following primary treatment for prostate cancer or following a course of hormonal therapy in hormone-sensitive patients (4). The latter setting offers an opportunity to induce a minimal disease activity state in patients without myelosuppression. Combining a vaccine approach with other treatments may also be promising. For example, preclinical data demonstrate that the addition of cytokines such as IL-2 can increase the efficacy of DC vaccination (43).
This study represents the first demonstration that immunization with xenogeneic Ags can be used to immunize against poorly immunogenic self-Ags in humans. Ultimately, it will be interesting to determine how broadly applicable xenoantigen vaccination will be. Xenoantigens may potentially represent an "altered self," with sufficient differences from self-Ags to render them immunogenic, but with sufficient similarities to allow reactive T cells to maintain recognition of self, as our study demonstrates. Therefore, trials with other xenogeneic Ags would be warranted.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Lawrence Fong, Stanford University School of Medicine, Stanford Blood Center, 800 Welch Road, Palo Alto, CA 94304. E-mail address: lfong{at}stanford.edu
3 Current address: Aventis Gencell, Hayward, CA 94545.
4 Abbreviations used in this paper: PSA, prostate-specific Ag; CM, complete medium; DC, dendritic cell; PAP, prostatic acid phosphatase; hPAP, human PAP; i.d., intradermal; i.l., intralymphatic; mPAP, mouse PAP; XRT, radiation therapy.
Received for publication May 14, 2001. Accepted for publication October 4, 2001.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B activation in hemopoietic progenitor cells. J. Immunol. 160:1224.This article has been cited by other articles:
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), hPAP (
), and influenza
(
) were measured serially following completion of the vaccination.
Results are shown for one patient but are representative of other
patients with proliferative responses to mPAP and hPAP. T cell
proliferation was assessed by [3H]thymidine incorporation
over 18 h following 6 days of culture. Results are expressed as
stimulation indexes (counts with Ag/baseline counts without Ag) ±
SEM.
