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*
Department of Pathology, Stanford University School of Medicine, Palo Alto, CA 94304; and
Millennium Pharmaceuticals, Cambridge, MA 02139
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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production,
however, was seen only with i.d. and i.l. routes of administration, and
no IL-4 responses were seen regardless of route, consistent with the
induction of Th1-type immunity. Five of nine patients who were
immunized by the i.v. route developed Ag-specific Abs compared with one
of six for i.d. and two of six for i.l. routes. These results suggest
that while activated DC can prime T cell immunity regardless of route,
the quality of this response and induction of Ag-specific Abs may be
affected by the route of administration. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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DC presumably must home to secondary lymphoid organs to prime T cell responses. The extent to which DC cultured and loaded with Ag ex vivo are able to migrate to relevant lymphoid organs in humans is unknown. Labeling studies with radioactive tracers have demonstrated that there are significant differences in the distribution of DC-containing cell products that are administered by different routes (13, 14). Although cells injected i.v. collect in the lung and liver, cells injected s.c. or intradermally (i.d.) can migrate to draining lymph nodes with varying efficiencies, although a significant number of cells remain at the injection site. These experiments, however, were limited by their sensitivity and did not resolve whether sufficient DC are capable of reaching lymphoid organs and priming an immune response. Moreover, the capacity of DC to migrate to secondary lymphoid organs may be dependent on their state of activation. Immature DC are believed to preferentially migrate to peripheral tissues, while activated DC are thought to emigrate from peripheral tissues via lymphatics. Clearly, the optimal route of DC administration must be established for such an immunotherapeutic approach to be maximally immunogenic in humans.
In the study discussed in this report, we loaded DC with a recombinant protein Ag, prostatic acid phosphatase (PAP), in vitro and administered the cells via different routes to patients with prostate cancer. In addition to the i.v. route, we explored the i.d. and intralymphatic (i.l.) routes of administration. In humans, i.d. administration of visual dyes or radioactive tracers can be detected within draining lymph nodes, a technique that is clinically used for sentinel lymph node biopsies (15, 16). Intralymphatic administration involves cannulating lymphatic vessels in the feet as a means of delivering the cells directly into lymph nodes via the afferent lymphatics. This approach is performed clinically for lymphangiography and would presumably represent the most efficient means for delivering DC to secondary lymphoid organs where generation of the immune response is known to occur.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Patients (n = 21) enrolled in the study were required to have histologically documented prostate cancer with recurrent or metastatic disease measurable by an abnormal and/or rising serum prostate-specific Ag level as well as detectable serum PAP levels. Patients were hormone refractory or hormone sensitive so long as no hormonal manipulations or other therapies, including immunosuppressive radiation or chemotherapy, were performed during the study. Trial subjects provided signed informed consent that fulfilled institutional review board guidelines before completing the screening process.
Ag production
cDNA encoding mouse PAP was cloned into the pBacPAK8 baculovirus recombination vector (Clontech, Palo Alto, CA) to generate recombinant baculovirus. Recombinant murine PAP (mPAP) was expressed as a His6 fusion protein. Insect SF21 cells were infected with recombinant baculovirus, and PAP was purified from culture supernatants with a nickel-nitrilotriacetic acid column (Qiagen, Hilden, Germany) to >90% purity by SDS-PAGE.
DC preparation
The patients underwent unmobilized peripheral blood leukapheresis, with two total body blood volumes (8–14 liter of blood) processed with a COBE cell separator. PBMC were obtained by centrifugation over Ficoll-Hypaque (Pharmacia, Uppsala, Sweden), and then monocytes were depleted by density centrifugation through Percoll (Pharmacia) as previously described (7). Monocyte-depleted PBMC were incubated with recombinant PAP (2 µg/ml) in RPMI 1640 (BioWhittaker, Walkersville, MD) supplemented 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, St. Louis, MO). The enriched DC were then cultured again overnight in medium containing 50 µg/ml recombinant PAP, washed free of Ag, resuspended in normal saline with 5% autologous serum, and infused. The DC dose was determined from the percentage of total cellular dose that expressed HLA-DR and lacked expression of CD3, CD14, CD19, and CD56 by flow cytometry. The average total cell dose was 112 x 106 cells/injection, with an average DC purity of 30%.
Flow cytometric analysis
Four-color flow cytometry was performed using a Becton Dickinson FACSCalibur (Mountain View, CA). APC-conjugated Abs to CD3, CD14, and CD19; PerCP-conjugated Abs to HLA-DR; and isotype-matched control Abs were obtained from Becton Dickinson. APC-conjugated Ab to CD56, PE-conjugated Ab to CD80, and FITC-conjugated Ab to cutaneous lymphocyte-associated Ag (CLA) were obtained from BD PharMingen (San Diego, CA). PE-conjugated Ab to CD83 was obtained from Immunotech (Westbrook, ME). FITC-conjugated Abs to CD44 and CD49d (very late Ag-4 (VLA-4)) were obtained from Serotec (Raleigh, NC). PE-conjugated Ab to CCR5 was obtained from R&D Systems (Minneapolis, MN). Unconjugated Ab to CCR7 was supplied by Dr. Lijun Wu (Leukosite, Cambridge, MA). FITC-conjugated goat anti-mouse Ab was obtained from Caltag (Burlingame, CA). PE-conjugated Ab to CD62 ligand (CD62L) and CD11a (LFA-1) were produced in our laboratory. Cells (1 x 106) were suspended in staining buffer (Dulbecco’s PBS with 1% FCS and 0.1% sodium azide) with human IgG at 1 mg/ml (Sigma) for 10 min at 4°C to block the Fc receptors. Samples were then stained with the described Abs at the recommended concentrations for 30 min at 4°C, washed three times with staining buffer, and analyzed. Data were evaluated and presented using FlowJo software (Tree Star, San Carlos, CA).
Allogeneic MLR
PBMC from random donors were used as responders in allogeneic MLR for all of the patients. Stimulators in the assays represent PBMC or enriched DC from the patients. Fifty thousand responders were cocultured with varying numbers of irradiated (3000 rad) stimulators in triplicate in 96-well U-bottom plates (Costar, Cambridge, MA) in RPMI 1640 containing 10% pooled human serum. 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).
DC vaccination
Twenty-one prostate cancer patients were immunized twice with recombinant PAP-loaded DC, 4 wk apart. Patients were sequentially assigned to three cohorts to receive both DC immunizations via i.v. (n = 9), i.d. (n = 6), or i.l. (n = 6) 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 administered by 16–24 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. Patients were evaluated for treatment related toxicity by the National Cancer Institute common toxicity criteria during and following vaccination as well as for the induction of anti-DNA Ab and rheumatoid factor following the vaccination.
T cell functional assays
Blood was obtained from patients before immunization, 1 mo following the DC immunizations, and then every 1–3 mo thereafter until clinical progression. PBMC were obtained by centrifugation over Ficoll-Hypaque (Pharmacia) and were cultured at 100,000 cells/well in triplicate in 96-well U-bottom plates (Costar) in medium containing 10–50 µg/ml of mPAP. Other T cell stimulators used for in vitro assays included influenza protein (Connaught, Swiftwater, PA) and PMA with ionomycin (Sigma) as positive recall controls. 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). The results are expressed as stimulation indexes representing counts per minute relative to baseline counts without Ag. A stimulation index >2 was defined as a 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, Chantilly, VA)
were coated overnight at 4°C with 50 µl of the primary Ab to IL-4,
IFN-, and TNF-
(BD PharMingen) in 0.1 M carbonate-bicarbonate
buffer (pH 9.5). Wells were blocked with Blotto (5% nonfat dry milk in
0.05% Tween 20 (TT)) 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. After washing with TT, 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, 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 ELISA sensitivity for the three
cytokines assayed was 25 pg/ml.
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 mPAP, blocked with 5% dehydrated nonfat milk in 50 mM TBS and TT, and washed with TT. Patient sera were diluted in PBS, added to wells, and incubated for 1 h at room temperature. Plates were then 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). 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, cytokine ELISA, and Ab titers before and after DC vaccination were analyzed with the paired sign test (StatView; SAS Institute, Cary, NC).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1% of the PBMC, and a subset expressed CD86 (Fig. 1
A). Following enrichment, DC
possessed an activated phenotype as evidenced by their increased
expression of MHC class II, and costimulatory molecules CD80 and CD86,
as well as DC activation marker CD83 (Fig. 1B). Enriched DC
were significantly more potent than PBMC in stimulating an allogeneic
MLR (Fig. 1C).
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A), DC
following enrichment maintained their expression of LFA-1, CD44, VLA-4,
and CLA (Fig. 2B). They, however, lost their expression of
CD62L and CCR5, but up-regulated surface expression of CCR7.
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).
Self-limited transfusion reactions manifesting as National Cancer
Institute common toxicity grade 2 fever and rigors were seen in two of
18 i.v. infusions. Self-limited skin erythema was seen following 3
of 12 i.d. injections. Tender adenopathy in a draining inguinal
lymph node developed following 1 of 12 i.l. injections. Patients
were also assessed for the development of autoimmunity. Induction of
anti-DNA Abs was seen in three of nine patients receiving i.v.
injections and one of six patients receiving i.l. injections. One of
six patients who received his cell via i.l. injection also developed an
elevated rheumatoid factor following vaccination. Despite these
findings, no patients developed clinical signs of autoimmunity
following vaccination.
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). Although no patients had an
mPAP-specific proliferative response before vaccination, six of nine
(66.7%), five of six (83.2%), and four of six (66.7%) patients
developed PAP-specific T cell proliferation with stimulation indexes
(SI) >2 following a single DC vaccination administered i.v., i.d., and
i.l., respectively. Nevertheless, all vaccinated patients developed T
cell responses following two DC vaccinations. There was no
statistically significant difference in SI following vaccination among
the groups.
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). One of six
patients developed a weak TNF- response in the i.v. group, while no
patients from the other groups developed TNF- responses. However,
when IFN- production was assessed, four of six patients in the i.d.
and three of six patients in the i.l. groups had induction of
responses, and the responses in these groups were statistically
significant. Curiously, no patients from the i.v. group had induction
of IFN- production following immunization. Finally, none of the
patients had measurable IL-4 in the culture supernatants at any
point.
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). Five
of nine patients (55.6%) vaccinated i.v. developed Abs to mPAP, while
one of six (16.7%) patients and two of six patients (33.3%) developed
Abs following immunization via i.d. and i.l. routes of injection,
respectively. Moreover, although the titers of Ab were low in the i.d.
and i.l. cohorts (1/40), the titers seen in the i.v. cohort were
significantly higher (1/80 to 1/3560).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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During their life cycle, DC vary in their expression of a variety of
molecules and receptors to coordinate their migration to particular
target tissues (17). DC precursors that circulate in the
blood migrate to the various tissues through interactions with their
selectins, including CD62L; adhesion molecules including LFA-1, VLA-4,
CD44, and CLA; and chemokine receptors including CCR1, CCR5, and CCR6
(18, 19, 20, 21, 22). Once DC become activated, a process that would
usually occur within the tissues, DC emigrate from tissues via the
draining lymphatics and are drawn by chemokines such as macrophage
inflammatory protein-3
through CCR7 to lymphoid organs, such as
lymph nodes, where they interact with naive T cells (22, 23). DC generated by our enrichment process, which includes 2
days of ex vivo culture in Ag, possessed an activated phenotype. The
cells maintained their expression of adhesion molecules important for
migrating to tissues, but lost their expression of CD62L. Following
i.v. administration, these DC would be unable to home directly to
lymphoid organs via high endothelial venules. Enriched DC also
down-regulated their expression of CCR5 while up-regulating their
expression of CCR7. This pattern would allow the activated DC to
migrate to secondary lymphoid organs via afferent lymphatics.
The extent to which immunity was primed was not statistically different among the different routes despite the higher efficiency by which DC are presumably delivered into lymph nodes with i.l. injection. DC injected i.d. and i.v. should be capable of accessing lymphoid organs sufficiently to prime naive T cells such that an expanded pool of memory T cells can be measured in the blood. Because activated DC lack CD62L but express CCR7, DC administered i.v. may access the secondary lymphoid organs via lymphatics within tissues, rather than directly through high endothelial venules.
To our knowledge, this study represents the first to examine the immune-priming capacity of ex vivo activated human DC administered via different routes. Our results indicate that DC can prime CD4 T cell responses when administered by any of the studied routes. These results indicate that relatively small doses of activated DC are capable of priming immunity regardless of the tissue compartment where they are initially located, demonstrating their potency. Although 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 (24, 25). 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.
In contrast to the T cell proliferative response, the cytokine
profile of the T cells generated by the immunization procedure differed
with route of administration. Mouse studies examining the capacity of
DC to immunize when given through i.v. and s.c. routes have
demonstrated superiority of s.c. injection over i.v. injection in the
induction of CTL (26, 27). Our study in humans
demonstrates that i.d. and i.l. administrations of DC induce Th1
immunity with greater frequency than i.v. administration. In contrast,
i.v. administration was associated with a significantly higher
frequency and titer of Ag-specific Abs. Generation of Abs in addition
to cellular immunity may be desirable in some clinical situations. Abs
specific for certain Ags (e.g., lymphoma Id, CD20, and
her2-neu) have demonstrated efficacy in treating
malignancies expressing these Ags (28). Induction of Abs
such as these in vivo would represent an alternative or additive
approach as an immunotherapy. On the other hand, the simplicity, lack
of transfusion reactions, and frequency of IFN- responses seen with
i.d. administration are potential advantages with this latter route,
especially in the setting where induction of Th1 immunity is
desired.
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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, 800 Welch Road, Palo Alto, CA 94304.
3 Abbreviations used in this paper: DC, dendritic cell; i.d., intradermal; PAP, prostatic acid phosphatase; mPAP, murine PAP; i.l., intralymphatic; CLA, cutaneous lymphocyte-associated Ag; VLA-4, very late Ag-4; TT, 5% nonfat dry milk in 0.05% Tween 20; CD62L, CD62 ligand; SI, stimulation index.
Received for publication September 26, 2000. Accepted for publication January 16, 2001.
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References |
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L. Fong, D. Brockstedt, C. Benike, J. K. Breen, G. Strang, C. L. Ruegg, and E. G. Engleman Dendritic Cell-Based Xenoantigen Vaccination for Prostate Cancer Immunotherapy J. Immunol., December 15, 2001; 167(12): 7150 - 7156. [Abstract] [Full Text] [PDF]
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) and PBMC (
) were compared. Fifty thousand PBMC from
random donors were cocultured in triplicate in wells with the DC or
PBMC at the indicated cell numbers. Proliferation was assessed after 6
days of culture by [3H]thymidine incorporation over
18 h. The results shown were obtained from the same patient, but
are representative of data from three different patients.
) for each time point are also
represented. *, Induced proliferative responses were statistically
significant from preimmunization levels following two vaccinations
(p > 0.05, paired sign test) regardless of
route.
