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*
Department of Dermatology, University of Erlangen-Nuremberg, Erlangen, Germany;
Department of Dermatology, University of Wurzburg, Wurzburg, Germany;
Department of Dermatology, University of Mainz, Mainz, Germany;
§
Molecular Immunology Group, Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-producing, effector
CD8+ T cells have been reliably observed in patients
vaccinated with melanoma Ags. Therefore, our DC vaccination strategy
performs an adjuvant role and encourages further optimization of this
new immunization approach. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-secreting effectors in fresh blood, our
results stand in contrast to studies in which other melanoma peptides
were administered with non-DC adjuvants. There, long term culture
assays were required to detect evidence of cytokine-secreting
CD8+ T cells (8). The new data
suggest that DCs represent an improved adjuvant for the induction of
melanoma-reactive T cells even in advanced cancer and represent a solid
basis for further optimization of this novel vaccination approach. |
Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Inclusion criteria were stage IV cutaneous melanoma (i.e., distant metastases) progressive despite chemo- or chemoimmunotherapy, HLA-A2.1+, Mage-3 mRNA expression in one or more metastasis, expected survival 4 mo or more, Karnofsky index 60% or more, age 18 years or older, informed consent given, and effective contraception use. Important exclusion criteria were active CNS metastasis, any significant psychiatric abnormality, severely impaired organ function; Abs to HIV-1/2, HTLV-1/2, hepatitis B virus, or hepatitis C virus; active autoimmune disease (except vitiligo); pregnancy; systemic chemo-, radio-, or immunotherapy 4 wk or less before the study.
Clinical protocol, DC generation, and immunization schedule
The study was performed at the Departments of Dermatology in
Erlangen, Wurzburg, and Mainz. It was approved by the local ethics
committees and the protocol review committee of the Ludwig Institute
for Cancer Research (New York, NY) and was performed under the
supervision of its Office of Clinical Trials Management (LUD 97-011).
Five DC vaccinations were administered at 14-day intervals. To explore
the toxicity and efficacy of various routes the first three
vaccinations were administered by superficial s.c. injection (6 x
106 DC total, 1.5 x
106 DC in 500 µl of PBS/site), and the
following two were given i.v. (6 and 12 x
106 DC for vaccinations 4 and 5, respectively).
We pulsed all DC with Mage-3A2.1 tumor peptide (10)
(FLWGPRALV, GMP quality, Clinalfa, Laufelfingen, Switzerland) as well
as the IM A2.1 peptide (GILGFVFTL, Clinalfa); the latter served as a
positive control. DC in half the patients were also pulsed with the
control recall Ag tetanus toxoid (TT; Statens Serum Institute,
Copenhagen, Denmark). The generation of DC was performed exactly as
previously described (6). In short, immature DC were
generated from plastic adherent monocytes in the presence of GM-CSF and
IL-4. On day 6 autologous monocyte-conditioned medium was added to
differentiate mature DC by day 7. A single leukapheresis was performed
at the onset of the study, and cryopreserved PBMC aliquots were then
used to make the DC for the following vaccinations. The recall Ag TT
was added at 10 µg/ml for the last 24 h of culture. Mage-3 and
IM A2.1 peptides (10 µM each) were added together for the last 8
h, and the mature DC were then pulsed once more (1 h at 37°C) on day
7 with Mage-3 and IM A2.1 peptides (30 and 10 µM, respectively). In
pilot experiments we used peptide-specific CTL clones and IFN-
ELISPOT analysis to show that these peptide-loaded DC were efficient
presenting cells and comparable to TAP-deficient T2 cells. Release
criteria and quality control for the DC vaccine included typical
morphology (>95% nonadherent veiled cells), phenotype (>95%
HLA-DR+++, CD86+++,
CD40+, CD25+,
CD14-, and >65% CD83++),
and negative microbial tests of samples taken repetitively from DC
cultures, all as previously described (6).
Measurement of immune responses
Immediately before each vaccination and 14 days after the final fifth vaccination, blood was drawn and used for ELISPOT analysis, which was obligatory according to the trial protocol. In addition, residual PBMC were cryopreserved for additional assays before the first and 14 days after the fifth vaccination.
Recall Ag specific proliferation and cytokine production. PBMC (3 and 10 x 104/well) were cultured with or without TT (at 0.1, 1, and 10 µg/ml) and pulsed on day 5 with [3H]thymidine exactly as previously described (6).
Measurement of CD8+ T cell responses
in uncultured PBMC.
IFN--releasing (i.e., effector) Mage-3 (6) and IM
peptide-specific (11), CD8+ T cells
were quantified with an ELISPOT assay exactly as previously described.
HLA-A2.1-restricted Mage-3, IM, or HIV-1 gag (SLYNTVATL; as negative
control) peptides were used at 10 µM. The number of spot-forming
cells was calculated per 1 x 105
CD8+ T cells to allow comparison of frequencies
at the different time points and with the results of other assays (see
below).
Recall CD8+ T cell responses in tissue culture: binding to HLA class I tetramer complexes. Soluble IM and Mage-3 HLA A2.1 tetramers were prepared, and binding to T cells was analyzed by flow cytometry at 37°C as previously described (12). Frozen aliquots of PBMC were thawed and analyzed following a 7-day culture in the presence of 10 µM Mage-3A2.1 or IM A2.1 peptide (vs no peptide as control), IL-2 (100 IU/ml), and IL-7 (10 ng/ml).
Recall CD8+ T cell responses in tissue culture: semiquantitative assessment of CTL precursors (CTLp). The multiple microculture method developed by Romero et al. (13) was used, as previously described (6), to determine CTLp.
Statistical analysis
A repeated measurement ANOVA model was chosen, because samples were repeatedly taken from the same patients. This model enables adjustment and assessment for covariates that potentially modify the connection between the response and the background. The covariates included in the model were time (i.e., time point of blood sampling), peptide (i.e., IM or Mage-3), and PBMC (i.e., number of PBMC used for the analyses).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Twelve far-advanced stage IV melanoma patients were enrolled. Four died after two or three vaccinations, while the remaining eight patients (five in Erlangen, two in Wurzburg, and one in Mainz) received all five DC vaccinations at 14-day intervals (three vaccinations at 6 million DC s.c. followed by two i.v. ones with 6 and 12 million DC, respectively), and were thus fully evaluable. The DC were pulsed with Mage-3A2.1 and IM A2.1 peptides, and in all but three patients (05, 06, and 07) also with TT. All DC preparations fulfilled the release criteria described in Materials and Methods.
Toxicity
No major (more than grade II) toxicity occurred. However, we observed mild inflammatory reactions at the s.c. vaccination sites (all patients except 05), fever (all except 03), and also slight lymph node enlargements (all except 09) developing 2 days or more after vaccinations 1–3. Due to transient grade II fever (39.9°C) in patient 01, TT pulsing of the DC was omitted after the s.c. vaccinations. Nevertheless, transient grade II fever (in the absence of infection) still occurred after the fourth (first i.v.) DC injection, but was not observed at the final fifth vaccination when IM peptide was also omitted.
Clinical responses
No significant tumor responses were observed at the final evaluation 2–3 wk after the fifth vaccination. All patients showed disease progression except patient 07, whose extensive lymph node metastases appeared stable.
Immune responses
TT specific, CD4+ T cell responses.
In all five patients treated with TT-pulsed DC a significant boost of
recall Ag-specific immunity was evident in proliferation assays (Fig. 1
), indicating that the DC employed were
indeed stimulatory. In sharp contrast, immunity to TT did not increase
in patients 05, 06, and 07, whose DC had not been pulsed with TT (Fig. 1), emphasizing the Ag specificity of the DC vaccine.
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ELISPOT. As it was unlikely that Mage-3-specific CTL would be
induced in the far-advanced melanoma patients, all DC were also loaded
with the IM A2.1 peptide as a positive control. As shown in Fig. 2, the frequency of IM peptide-specific
CD8+ T cells increased in all patients following
DC vaccination, albeit with varying degree and rapidity.
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and Table I). This increase was not caused by
intercurrent influenza infection, as shown by repetitive serological
influenza tests.
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-releasing effector
CD8+ T cells increased in all patients upon
vaccination (except in patient 06, who had significant frequencies of
Mage-3A2.1-specific T cells already at onset; Fig. 2
). Patients 01, 03,
and 07 produced high frequencies of spot-forming cells (
1/1000
CD8+ T cells), while the numbers in all other
patients were 1 log lower (Fig. 2). Peak responses were often reached
after the s.c. vaccinations (patients 03, 04, 05, 07, and 10) and
declined upon successive i.v. injections (Fig. 2). In two patients (01
and 09) an alternative pattern appeared, in that a significant response
was not detectable until the first and second i.v. vaccination (i.e.,
vaccinations 4 and 5, respectively; Fig. 2). The number of
IFN--releasing CD8+ T cells on a few occasions
(sporadic low frequency in patient 04 at the time of vaccination 5, and
significantly decreased frequencies only at the time of vaccinations 2
and 3 in patient 06 despite an interassay variability of <20%) for
unknown reasons did not fit into the two patterns that had become
apparent (i.e., initial increase followed by a decline vs increase
until the end of the study). In the three patients (05, 06, and 07) whose DC were not loaded with TT, varying levels of Mage-3A2.1 peptide-specific T cells were already present at the beginning of the study. Therefore, we do not know whether TT, which was included as a fail-safe internal control for immunization, was also critical in providing tumor-nonspecific help for CTL induction, e.g., by conditioning DC (1, 2).
Recall cultures provided evidence for the expansion of Mage-3 specific
precursors. After one in vitro restimulation, lytic effector cells were
demonstrable in all except patient 10, but due to insufficient numbers
of CD8+ T cells, the CTLp frequency and its
change over time could not be evaluated critically, except in patients
01 (0 vs 30/107 CD8+ T
cells) and 09 (0 vs 50/107
CD8+ T cells). The observed postimmunization
frequency is well above the frequency found in individuals without
cancer (
6/107 CD8+ T
cells) (14). In these two patients sufficient numbers of T
cells were available to allow replication of the recall assay and
confirmation by tetramer analysis of the increase in
Mage-3A2.1-specific memory CD8+ T cells in
patient 1 (0.04 vs 1.70%; see Fig. 3) as well as patient 09 (0.04 vs
0.14%; not shown). Of note is that in both patients despite a
comparable frequency of Mage-3A2.1- and IM peptide-specific,
IFN--producing effector T cells (0.21 vs 0.28% in patient 1, 0.05
vs 0.12% in patient 09), the recall assays revealed a much higher
percentage of IM peptide-specific CTL precursor cells (21.05%
HLA-A2.1/IM-peptide tetramer binding cells vs only 1.7%
HLA-A2.1/Mage-3 peptide tetramer-positive cells in patient 01 and 20.13
vs 1.14% in patient 09). These data indicate that the
Mage-3A2.1-specific precursors proliferated much less in the vitro
assays than the IM peptide-specific CTL precursors.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-producing CD8+ T
cells in blood ex vivo without prolonged in vitro stimulation. Of note
is that the responses to the Mage-3 peptide appear comparable to the
responses to the IM peptide that served as a positive control even
though the Mage-3 specific CTL precursor frequency is very low even in
noncancer patients (14). This has not previously been
reported for either peptide (8, 15) or DC
(3, 4, 5, 6) vaccination. The lack of a significant clinical
response despite induction of Mage-3A2.1-specific effectors could be
explained by the recent finding that this epitope is not well presented
by most melanoma cells (16). Evidence for expansion of
specific memory CD8+ T cells following
vaccination was also obtained by in vitro recall assays using standard
cytotoxicity as well as tetramer binding as a readout. Furthermore,
expansion of TT-specific recall responses was evident in all patients
vaccinated with DC who were pulsed also with TT.
A possible explanation for the effective immunization we observed may
be our use of mature DC and the (superficial) s.c. administration
route, whereas others have employed immature DC and i.v. or intranodal
injection (3, 5). In a recently reported trial we used
mature, Mage-3A1 peptide-loaded DC, but we failed to reliably
demonstrate preactivated Ag-specific CD8+ T
cells, as IFN--producing CD8+ T cells in this
previous study were found only in 2 of 11 patients and merely at a
single time point (6). There are several potential
explanations for this apparent difference. It might, for example,
simply be easier to induce immunity to the Mage-3A2.1 epitope, as the
CTLp frequency for this epitope is at least twice that for the Mage-3A1
peptide (14). Another possibility is that active
CD8+ effectors were sequestered in (regressing)
metastases in the Mage-3A1 trial (6), but not in the
current trial where no regressions occurred. An alternative explanation
is that the kinetics of the Mage-3A2.1-specific immune response are
slower than those of the Mage-3A1 response, so that immunomonitoring 14
days after a preceding vaccination would still pick up elevated
effectors in the case of immunization to Mage-3A2.1 but not following
vaccination with Mage-3A1-pulsed DC. It is currently also unclear
whether the constant detection of IFN--producing Mage-3A2.1-specific
CD8+ T cells directly ex vivo was perhaps
primarily due to the fact that in the current study all 6 x
106 DC were given s.c., while in the previous
trial (6) only half the DC were given s.c. and the other
half were given intradermally. It is indeed noteworthy that a recent
study used DC equivalent to those employed in the current study and
also showed immunogenicity in healthy individuals upon s.c. injection
(17).
We have identified in this study a DC vaccination strategy that clearly
works to some extent, so that it is now much easier to address in
future studies potentially important variables such as maturational
state of DC, cell dose, and route and frequency of injections. Our
observation that responses to Mage-3 or IM peptides (see Fig. 2) can
decline significantly following the two final i.v. administrations of
pulsed DC vaccinations confirms the findings of our previous Mage-3A1
DC vaccination trial (6) and implies that the i.v. route
might indeed be counterproductive. The current finding that in two
patients (01 and 09) a significant response was not detectable until
the first and second i.v. vaccinations (i.e., vaccinations 4 and 5,
respectively; see Fig. 2) points, however, to the alternative
possibility that the biweekly vaccination schedule might be problematic
independently of the route chosen. This concern is underscored by the
recent observation in a murine model that frequent vaccinations after
achieving a peak response can lead to a decrease in immunity
(18). Therefore, it might be particularly critical to
address this variable to exclude that too frequent injections of
Ag-loaded DC induce activation-induced cell death of Ag-specific
CD8+ T cells. Future studies will also require
the use of peptides other than Mage-3 to assess whether the melanoma
reactive cells can recognize and kill autologous tumor
cells. Now that we have initial evidence for potent immunologic
efficacy, we are confident that it will be relatively straightforward
to rationally optimize the DC vaccination approach.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Beatrice Schuler-Thurner, Dermatologische Klinik mit Poliklinik, Hartmannstrasse 14, D-91052 Erlangen, Germany.
3 Abbreviations used in this paper: DC, dendritic cells; ELISPOT, enzyme-linked immunospot; CTLp, CTL precursor; IM, influenza matrix; TT, tetanus toxoid.
Received for publication March 15, 2000. Accepted for publication June 26, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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H. Kobayashi, Y. Song, D. S. B. Hoon, E. Appella, and E. Celis Tumor-reactive T Helper Lymphocytes Recognize a Promiscuous MAGE-A3 Epitope Presented by Various Major Histocompatibility Complex Class II Alleles Cancer Res., June 1, 2001; 61(12): 4773 - 4778. [Abstract] [Full Text] [PDF]
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S. Ebner, G. Ratzinger, B. Krosbacher, M. Schmuth, A. Weiss, D. Reider, R. A. Kroczek, M. Herold, C. Heufler, P. Fritsch, et al. Production of IL-12 by Human Monocyte-Derived Dendritic Cells Is Optimal When the Stimulus Is Given at the Onset of Maturation, and Is Further Enhanced by IL-4 J. Immunol., January 1, 2001; 166(1): 633 - 641. [Abstract] [Full Text] [PDF]
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 J. Baggers, G. Ratzinger, and J. W. Young Dendritic Cells as Immunologic Adjuvants for the Treatment of Cancer J. Clin. Oncol., December 1, 2000; 18(23): 3879 - 3882. [Full Text] [PDF]
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