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Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048 [J. S. Y., C. J. W., P. M. Z., H. Y., D. N. F., P. K. L., W. H. Y., F. I., R. C. T., M. S. R., W. Z., R. M. P., K. L. B.]; and Department of Neurological Surgery, University of California, Irvine, California 92868-3298 [J. S. Y., P. M. Z., R. C. T., K. L. B.]
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Exclusion criteria included pregnancy, severe pulmonary, cardiac, or other systemic disease associated with an unacceptable anesthetic or operative risk, presence of an acute infection requiring active treatment, and history of an autoimmune disorder or prior history of other malignancies, excluding basal cell carcinoma and benign tumors. Patients were required to use a medically accepted form of birth control during the study.
There were nine patients enrolled in this Phase I study: five women and
four men with an age range from 28 to 77 years of age (mean, 49 years;
see Table 1
). Patients with verified histological diagnoses of newly diagnosed
anaplastic astrocytoma (two patients) or GBM (seven patients) were
eligible for this study. After surgical resection of their tumor,
patients were required to complete a course of external beam radiation
therapy (standard dose, 4500 cGy to tumor with 3-cm margins, 1500 cGy
boost to tumor bed). All of the patients were off steroids at the time
of vaccination. The 7 study patients with GBM were included in a
survival analysis and compared with 42 patients in the control group.
Their mean age was 55.9 ± 14.5 years, and 50% were
male. All of the patients had tumor pathology consistent with GBM, had
undergone surgical resection at our institution within the past 2
years, and had completed a course of radiation therapy (60 Gy as
above).
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Methods for Tumor Antigen PCR.
Total tumor cell RNA was isolated using TriZol RNA isolation kit (Life
Technologies, Inc.) from cultured autologous glioma cells from nine
study patients. For cDNA synthesis, 10 µg of total RNA were digested
with 2 µl of DNase I (Ambion) to remove genomic DNA. The RNA was
transcribed with cDNA synthesis reagents (Life Technologies, Inc.) in
total volume of 50 µl with the use of oligo(dT) (Life Technologies,
Inc.). For PCR, 1 µl/50 µl of the synthesized cDNA was used
with 10 pmol of primers, 1.5 mM
MgCl2, 200 µM deoxynucleotide
triphosphate, and 0.1 µl of Platinum Taq polymerase (Life
Technologies, Inc.). Thermal cycler parameters included 5 min at 95°C
initiation and 35 cycles involving denaturation at 95°C for 30 s, annealing at 58°C (for MAGE-1 and ß-actin) or 52°C (for
gp100 and TRP-2) for 30 s, and extension at 72°C for 1 min.
Primers used for PCR are as follows: primers for MAGE-1, forward,
5'-GCCTGCTGCCCCTGACGAGAG-3', reverse, 5'-AGGAGAGACCTAGGCAGGTG-3';
primers for gp100, forward, 5'-TGGCTCTTGGTCTCAGAAGA-3', reverse,
5'-AGGTGCAGTGCTTATGACTT-3'; primers for TRP-2, forward,
5'-GAGGTGCGAGCCGACACAAG-3', reverse, 5'-TCTGTACACACATCACACTC-3';
primers for ß-actin, forward, 5'-AATCTGGCACCACACCTTCTAC-3', reverse,
5'-CTTCTCCTTAATGTCACGCACG-3'.
Isolation of Tumor-specific MHC-I-associated Peptides.
MHC-I-associated peptides were enriched through acid elution as
described previously (10)
. Briefly,
108 glioma cells were removed from tissue culture
plates by incubation with 2 mM EDTA at room temperature,
followed by three washes with HBSS. The cells were resuspended in 10 ml
of citrate-phosphate buffer (pH 3.2) to dissociate peptides from
surface MHC-I, triturated gently, and centrifuged for 5 min at 1000
rpm. The supernatant was then collected and concentrated by passage
through Sep Pak C18 columns, aliquoted, and frozen at -80°C. Before
patient vaccination, tumor peptide was tested in the Limulus
Amoebocyte Lysate assay (BioWhittaker Inc., Walkersville, MD)
for endotoxin contamination, for aerobic, anaerobic, and fungal
culture, and by Gram’s stain before administration to the patient.
Preparation of Autologous DCs.
Venous blood (20 ml) was drawn from patients on days -7, 7, and 21
(day 0 = first vaccination). The anticipated yield was
106 APCs/20 ml whole blood. In addition, 50 ml of
blood was drawn on day -14 to obtain autologous serum (15 ml) for each
of three APC cultures.
APCs were isolated from whole blood by Ficoll-Hypaque centrifugation, washed three times in PBS, and plated at a concentration of 5 x 106 cells/ml in complete medium consisting of RPMI 1640 (Life Technologies, Inc.) with 10% autologous heat-inactivated serum, 1% gentamicin, and 0.01 M HEPES buffer. After 2 h at 37°C, nonadherent cells were removed by washing with warm complete medium. To generate autologous DCs, adherent APCs were cultured in complete medium for 7 days in the presence of recombinant human GM-CSF (800 units/ml; clinical grade; Immunex Corp., Seattle, WA) and recombinant human IL-4 (500 units/ml; R&D Systems, Inc., Minneapolis, MN).
Preparation and Administration of Autologous DCs Pulsed with
Tumor-specific MHC-I Peptides.
On the days before each of the three DC vaccinations (days -1, 13, and
27), DC cultures were incubated with citrate-phosphate buffer [0.131
M Na2HP04 (pH
3.0)] for 1 min to strip endogenous peptides from MHC-I molecules.
Cells were then washed in RPMI 1640 with 10% autologous patient serum
supplemented with 50 µg/ml autologous tumor-specific MHC-I peptides.
The DCs were cultured overnight with these peptides on a tissue rotator
to facilitate their interaction. Patients received
106 tumor-specific MHC-I peptide-pulsed DCs s.c.
in 0.1–0.2 ml saline in the deltoid region. Three vaccinations at
2-week intervals were administered to each patient.
DC Phenotypic Evaluation.
After 7-day maturation in GM-CSF and IL-4, DCs were harvested from
flasks. Cells were resuspended in RPMI-10% human AB medium and
irradiated with 2500 rad in a Cesium-source irradiator. The
remaining cells were resuspended in PBS containing fetal bovine
serum (2% v/v) and stained with anti-CD14 FITC, anti-HLA-DR
phycoerythin for MHC Class II, and biotinylated anti-CD86
antibodies for B7–1(PharMingen, San Diego, CA). Species and
isotype-matched monoclonal antibodies were used as controls.
DC Functional Assay.
For the functional assay, irradiated DCs were resuspended in RPMI-10%
human AB serum at 2 x 105
cells/ml. Allogeneic PBMC (10,000) were mixed with limiting dilutions
of DCs. PHA (5 µg/ml) was added to separate PBMC cultures as a
positive control. RPMI-10% AB medium alone was added to separate PBMC
cultures as a negative control. All of the cultures were established in
triplicate. PBMC under the above conditions were incubated for 6 days
in a 37°C/5% CO2 incubator.
[3H]thymidine (1 µCi/well) was added
for the final 18 h. Cells were harvested with a 96-well harvester
(Tomtec, Hamden, CT), and cpm were determined on a Microbeta 1450
Trilux liquid scintillation counter (Wallac, Gaithersburg, MD).
CTL Precursor Assay Method.
For stimulation, 50 µl of irradiated tumor cells at 1 x 105/ml were plated in RPMI 1640 with 10%
heat-inactivated autologous serum with autologous 100 ml of PBMC at
1 x 106/ml. IL-2 was added to
give a final concentration of 1000 units/ml, and the plate was
incubated at 37°C in 5% CO2 for 14 days.
Cultures were fed on day 3 by removing 50 µl of supernatant and
replacing it with medium with IL-2 (4000 units/ml), and on day
7, 100 ml of supernatant was removed and replaced with l00 µl
(10,000) autologous irradiated tumor cells at 1 x 105/ml. Autologous tumor cell targets were
labeled for 48 h with [3H]thymidine (2.5
µCi/ml). On day 14, targets were trypsinized, washed twice in
HBSS, and resuspended at 10,000 cells/ml. Cells (100 µl) were
transferred from the coculture plates and added to an empty 96-well
plate. Labeled target cells (1 x 104
/ml) were added on top of the stimulated PBMCs
and resuspended in RPMI-10% human AB serum. The plate was centrifuged
at 1000 x g for 3 min and incubated at
37°C for 5 h. Maximum release was assessed in triplicate wells
containing 10,000 target cells and 5% SDS in H2O
and DNase 1 (Roche, Indianapolis, IN) at 20 units/ml final
concentration for 10 min. The cells were harvested with a cell
harvester (Wallac), and cpm were determined on a Microbeta 1450 Trilux
liquid scintillation counter (Wallac). The first two patients were
analyzed using a CTL precursor assay to quantitate cytotoxic precursor
frequency independent of in vitro stimulation effects. The
inability to grow sufficient numbers of tumor cells to calculate
precursor frequencies necessitated adoption of nonquantitative bulk CTL
assays for the remainder of the patients.
Bulk Cytotoxic T-cell Assay.
CTL activity was tested by JAM assay (11)
. Patients
four through eight grew sufficient numbers of tumor cells (2 x 107 cells) to complete JAM assays and
were evaluated. PBMC for pretreatment and after treatment time points
were thawed, washed twice by centrifugation, and counted. The
concentration was adjusted to 8 x 106/ml in RPMI 1640 medium containing
heat-inactivated human AB serum (10%), nonessential amino acids (1%),
penicillin/streptomycin (1%), and 1 M HEPES buffer (1%).
PBMC were stimulated with allogeneic PBMC (irradiated with 2,000 rad) or with autologous cultured tumor cells (irradiated with 11,000 rad; 1 x 106/ml) for 6 days in RPMI-5 and recombinant human IL-2 (20 units/ml). Tumor or allogeneic PHA blasts (1 x 105/ml) were labeled as targets in 5 µCi/ml [3H]thymidine for 48 h at 37°C in 5% CO2. After incubation, target cells in maximum release wells were lysed with 5% SDS in H2O and incubated in DNase 1 (Roche) at 20 units/ml final concentration for 10 min. PBMC (100 µl; maximum 1 x 107/ml for 100:1 E:T ratio) were added to targets (100 µl; 1 x 105/ml) at various E:T ratios for 6 h. Cells were harvested from plates with a 96-well harvester (Tomtec). CPM were determined using a Microbeta 1450 Trilux liquid scintillation counter (Wallac).
Immunohistochemistry.
Serial 10-µm paraffin sections of surgical intracranial tumor
specimen were stained with mouse antihuman monoclonal antibodies
against CD8 (C8/144B clone M7103 at 1/25 dilution), CD45RO (OPD4 clone
M0834 at 1/50 dilution), CD20 (L26 clone M0755 at 1/200 dilution), and
CD56 (T199 clone M0852 at 1/10 dilution; DAKO Corp., Carpinteria, CA).
Primary antibodies were detected using the biotin-peroxidase system
(DAKO Corp.).
Statistical Analysis.
Continuous variables were compared using Student’s t test,
and categorical variables were compared using
2 or Fisher’s exact test. P <
0.05 was considered statistically significant.
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Results |
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The ß-actin primers were designed to detect genomic DNA
contamination. The PCR product from cDNA is 394 bp. The PCR product
from genomic DNA should be 835 bp. Fig. 1A
suggests that the RNA preparation was free of genomic DNA
contamination. Four out of nine patients expressed MAGE-1 in cultured
glioma cells (Fig. 1B)
. Six out of nine patients
demonstrated gp100 expression (Fig. 1C)
, and three patients
demonstrated TRP-2 expression (Fig. 1D)
. In total, the
cultured glioma cells of eight out of nine patients expressed at least
one tumor-associated antigen. Immunohistochemical staining of
autologous tumor culture cells revealed that in the four out of nine
patients that were PCR positive for the MAGE-1 antigen, nearly every
cell was immunopositive for the MAGE-1 protein (Data not shown).
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and sufficient numbers of functional DCs were isolated in
all of the patients in this clinical trial (106
DCs/vaccination). These DCs were cocultured with autologous tumor
peptide, washed, and administered to patients three times over the
course of 6 weeks.
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. Patient 3
developed a mild fever (100°F) lasting several hours after
vaccination. The same patient also developed nausea and vomiting
several weeks later. Patient 5 developed palpable supraclavicular,
axillary, and inguinal lymph nodes 1 week after the first vaccination,
which persisted for 2 months.
Development of Systemic Cytotoxicity.
One goal of this clinical trial was to determine whether ex
vivo maturation of DCs and exposure of DCs to a MHC-I-associated
tumor antigen from autologous cultured glioma cells could induce an
immune response against malignant gliomas. Cytotoxicity directed toward
autologous tumor cells was assessed in PBMC from patients’
prevaccination, 1 week after each vaccination, and 6 and 12 weeks after
the last vaccination. Of seven patients that were evaluated, four
demonstrated enhanced cytotoxic T-cell activity after DC vaccination.
In all of the patients who developed cytotoxic T-cell activity,
cytotoxicity was sustained through the last time point, 3 months after
the last vaccination (Fig. 2B)
. In two patients (2 and 4),
cytotoxicity developed 12 weeks after the third DC vaccination.
Patients 7 and 8 demonstrated cytotoxicity before and after
vaccination. Patient 1 had no discernible CTL activity before or after
vaccination.
Intracranial Infiltration of T Cells after Vaccination.
Four patients who developed apparent tumor progression as suggested by
new areas of gadolinium enhancement on magnetic resonance imaging scans
underwent reoperation subsequent to the third DC vaccination (Table 1
,
patients 2, 4, 6, and 8). Two of these four patients developed a robust
CD8+ cytotoxic and CD45RO+ memory T-cell infiltration in areas of tumor
(patients 6 and 8) that was not apparent on tumor specimen obtained
before vaccination (Fig. 3, A
-H). There were increased numbers of CD4+
helper T cells after vaccination but significantly less than CD8+ T
cells (data not shown). One of these patients underwent two
reoperations, the first before vaccination and the second at 94 days
after the first vaccination (patient 8). In this patient, the tumor
specimen after the second reoperation (after vaccination) demonstrated
massive intratumoral infiltration by CD8+ cytotoxic T cells and CD45RO+
memory T cells, as compared with tumor specimens before vaccination
(Fig. 3, A
-D). There were no CD20+ B cells or
CD56+ NK cells detectable before or after vaccination in either patient
(data not shown). In contrast, two other patients who underwent
reoperation for a recurrent gadolinium-enhancing mass (patients 2 and
4) displayed few infiltrating CD45RO+, CD8+, CD4+, CD20+, or CD56+
cells in surgical specimens taken before or after vaccination (data not
shown). Both of these patients died from tumor progression. Similarly,
there was no increase in numbers of intratumoral lymphocytes in
specimens from four nonvaccinated GBM patients who underwent
re-resection. All of the four nonvaccinated patients demonstrated few
CD45RO+ and CD8+ T cells from their first surgical specimen, which
diminished in number in reoperation specimens (Fig. 3, I and J)
. There were very few CD20+ B cells in the first and
second specimens, and no CD56+ NK cells were detected in either
specimen. Thus, enhanced cytotoxic (CD8+) T-cell and memory (CD45RO+)
T-cell infiltration appears to be a characteristic of a subset of
vaccinated patients who undergo reoperation.
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Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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One goal of this clinical trial was to determine whether ex vivo maturation of DCs and exposure of DCs to a MHC-I-associated tumor antigen from autologous cultured glioma cells could induce an immune response against glioma tumor cells. That four of seven tested patients in this pilot trial have shown cytotoxic T cell-mediated immunological responses after peptide-pulsed DC vaccination supports the role of DC vaccination in generating specific immunity. The relationship between peripheral CTL activity and tumor rejection has not been unequivocally established by the present or by previous trials (15, 16, 17, 18) .
It was not known whether peripheral cytotoxic T cells would reach their intracranial target after DC vaccination. In some immunotherapy trials, systemic cytotoxic responses have failed to prevent tumor growth in the central nervous system (19 , 20) . We observed a dramatic intratumoral infiltration of CD45RO+ memory and CD8+ cytotoxic T cells after vaccination in two of four patients who had undergone reoperation for gadolinium enhancement on magnetic resonance imaging which is suggestive of recurrent tumor, whereas nonvaccinated patients exhibited no similar infiltration. Thus, we demonstrate that DC vaccination can induce intra-glioma T-cell infiltration despite the immunologically privileged status of the central nervous system. All of the four patients that underwent reoperation demonstrated either preexisting or new systemic cytotoxicity in vitro. The study of tumor expression of immunosuppressive cytokines or cell surface markers may elucidate factors that differentiate patients who will respond to systemic cytotoxicity.
The presence of CD8+ T cells and absence of CD20+ B cells in intracranial tumor of vaccinated patients are consistent with the initiation of a Th1- rather than a Th2-mediated response by peptide-pulsed DCs, although other alternatives include preferential migration/survival of T cells. Intracranial CD8+ infiltration has been associated with vaccination in active immunotherapy models in mice (9 , 21) . The robust intratumoral infiltration of CD45RO+ T cells suggests vaccine-mediated induction of activated T cells with specific homing and/or in situ expansion properties. In a DC immunotherapy trial for melanoma, CD45RO+ memory T cells were shown to strongly infiltrate DTH sites, as well as metastases in regression. In addition, significant CD8+ infiltration was noted in regressing metastases. In a separate clinical trial, vaccination of renal cell carcinoma patients with tumor cell-DC hybrids demonstrated DTH sites that were infiltrated by CD8+ cells. Therefore, the intracranial cellular response of patients with malignant glioma mirrors the peripheral response noted in regressing melanoma tumors and in DTH sites of renal cell carcinoma patients after DC vaccination. The absence of both B and NK cell tumor infiltration in the present trial suggests that such effects are relatively limited to the T-cell compartment. This suggests that DCs in this study may preferentially activate antigen-specific T cells, rather than NK cells, as described in distinct in vitro studies (22) .
DC vaccination of patients with glioma appears to be safe and not associated with autoimmunity. In this Phase I trial, DC vaccinations were well tolerated. Mild toxicities included transient fever, nausea, and vomiting in one patient and the development of palpable lymph nodes in another patient. To date, with a median follow-up of 455 days, no clinical or radiological features of autoimmune disease were detected in our patients. Clinical trials using DC immunotherapy have been published for four other cancers: lymphoma (15) ; melanoma (16) ; prostate cancer (17) ; and renal cell carcinoma (18) . In these DC vaccine studies, mild fever and swelling of an injected lymph node lasting 1–2 days have been reported (16) . No other significant adverse events including autoimmunity were reported in trials using DC immunotherapy (15, 16, 17, 18) or in animal models of brain tumor therapy with DC vaccination (7, 8, 9) . Thus, DC vaccination to tumor has not been associated with significant autoimmunity. On the other hand, induction of lethal experimental allergic encephalomyelitis has been described in primates and guinea pigs after vaccination with human glioblastoma tissue (23) . Continued evaluation will be necessary to determine if autoimmunity develops from cross-reactivity between brain tumor antigens and normal neural antigens.
Patients with GBM treated with DC vaccination appear to have prolonged survival compared with patients who have had conventional treatment. When study patients were compared with GBM patients who underwent craniotomy with radiation and chemotherapy at our institution, there appeared to be a prolongation in survival of study patients. Although there was no difference in these groups with respect to age, gender, or degree of resection, a selection bias could not be ruled out. Although the number of patients in the study group was small, the survival suggests that this form of active immunotherapy may be a promising approach.
Study patients with glioblastoma were divided into Radiation Therapy
Oncology Group (RTOG) recursive partitioning classes
(24)
. This technique allows comparison of series data
based on clinical and histological stratification parameters. Three
patients with GBM in the study were stratified in RTOG Class III with
<50 years of age and Karnofsky performance scores of 
90. These
patients had a median survival of 19.1 months compared with RTOG data
of 18 months for this class of 175 patients. Four patients with GBM in
the study were stratified in RTOG Class V with >50 years of age,
radiotherapy of > 54Gy, and the inability to
return to work. This group of patients had a median survival of 11.6
months compared with the RTOG class V patients (n = 395) with a median survival of 9 months. Because of the small
number of study patients in each of these classes, statistical analysis
could not be performed. The patients in this study, however, exceeded
the expected survival according to this analysis. Despite the
prolongation of survival in this analysis as well as in the survival
analysis compared with GBM patients treated at our institution, the
potential for patient selection bias will only be eliminated by a
randomized trial.
The association of intracranial CD8+ T-cell infiltration and survival has been established in an active immunotherapy model of intracranial metastasis (25) . Active immunotherapy with DCs or tumor vaccines for experimental intracranial glioma have demonstrated an association of CD8+ intratumoral infiltration and prolonged survival (9 , 21) . The enhanced median survival of patients enrolled in this study suggests that tumor-specific T-cell activation, infiltration, and/or function may prolong the survival of glioma patients. Phase II studies using DC immunotherapy are under way to further elucidate the effects of DC vaccination in patients with malignant gliomas and to confirm its effect on survival. This immunotherapy strategy appears promising as an approach to successfully induce an antitumor immune response and to increase survival in patients with gliomas.
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FOOTNOTES |
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1 Supported in part by National Institute of
Health Grant N502232 (to J.S.Y.) 
2 Present address: Department of Anatomy, Medical College
of Virginia, Richmond, Virginia 23298.
3 To whom requests for reprints should be
addressed, at 8631 West Third Street #800E, Los Angeles, CA 90048.
Phone: (310) 423-0815; Fax: (310) 423-0810; E-mail: blackk{at}cshs.org
4 The abbreviations used are: GBM, glioblastoma
multiforme; APC, antigen-presenting cells; DC, dendritic cell; GM-CSF,
granulocyte-macrophage colony stimulating factor; IL, interleukin;
PBMC, peripheral blood mononuclear cells; PHA,
phytohemagglutinin; DTH, delayed type hypersensitivity.
Received 5/15/00. Accepted 12/13/00.
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J. S. Yu, G. Liu, H. Ying, W. H. Yong, K. L. Black, and C. J. Wheeler Vaccination with Tumor Lysate-Pulsed Dendritic Cells Elicits Antigen-Specific, Cytotoxic T-Cells in Patients with Malignant Glioma Cancer Res., July 15, 2004; 64(14): 4973 - 4979. [Abstract] [Full Text] [PDF]
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G. Liu, H. Ying, G. Zeng, C. J. Wheeler, K. L. Black, and J. S. Yu HER-2, gp100, and MAGE-1 Are Expressed in Human Glioblastoma and Recognized by Cytotoxic T Cells Cancer Res., July 15, 2004; 64(14): 4980 - 4986. [Abstract] [Full Text] [PDF]
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D. A. Caruso, L. M. Orme, A. M. Neale, F. J. Radcliff, G. M. Amor, W. Maixner, P. Downie, T. E. Hassall, M. L.K. Tang, and D. M. Ashley Results of a phase 1 study utilizing monocyte-derived dendritic cells pulsed with tumor RNA in children and young adults with brain cancer Neuro-oncol, July 1, 2004; 6(3): 236 - 246. [Abstract] [PDF]
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 S. Paczesny, J. Banchereau, K. M. Wittkowski, G. Saracino, J. Fay, and A. K. Palucka Expansion of Melanoma-specific Cytolytic CD8+ T Cell Precursors in Patients with Metastatic Melanoma Vaccinated with CD34+ Progenitor-derived Dendritic Cells J. Exp. Med., June 7, 2004; 199(11): 1503 - 1511. [Abstract] [Full Text] [PDF]
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C. J. Wheeler, K. L. Black, G. Liu, H. Ying, J. S. Yu, W. Zhang, and P. K. Lee Thymic CD8+ T Cell Production Strongly Influences Tumor Antigen Recognition and Age-Dependent Glioma Mortality J. Immunol., November 1, 2003; 171(9): 4927 - 4933. [Abstract] [Full Text] [PDF]
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T. Tatsumi, C. J. Herrem, W. C. Olson, J. H. Finke, R. M. Bukowski, M. S. Kinch, E. Ranieri, and W. J. Storkus Disease Stage Variation in CD4+ and CD8+ T-Cell Reactivity to the Receptor Tyrosine Kinase EphA2 in Patients with Renal Cell Carcinoma Cancer Res., August 1, 2003; 63(15): 4481 - 4489. [Abstract] [Full Text] [PDF]
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 K. Tschoep, T. C. Manning, H. Harlin, C. George, M. Johnson, and T. F. Gajewski Disparate functions of immature and mature human myeloid dendritic cells: implications for dendritic cell-based vaccines J. Leukoc. Biol., July 1, 2003; 74(1): 69 - 80. [Abstract] [Full Text] [PDF]
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 L. Samady, E. Costigliola, L. MacCormac, Y. McGrath, S. Cleverley, C. E. Lilley, J. Smith, D. S. Latchman, B. Chain, and R. S. Coffin Deletion of the Virion Host Shutoff Protein (vhs) from Herpes Simplex Virus (HSV) Relieves the Viral Block to Dendritic Cell Activation: Potential of vhs- HSV Vectors for Dendritic Cell-Mediated Immunotherapy J. Virol., March 15, 2003; 77(6): 3768 - 3776. [Abstract] [Full Text] [PDF]
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I. D. Davis, M. Jefford, P. Parente, and J. Cebon Rational approaches to human cancer immunotherapy J. Leukoc. Biol., January 1, 2003; 73(1): 3 - 29. [Abstract] [Full Text] [PDF]
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 I. Espinoza-Delgado Cancer Vaccines Oncologist, August 1, 2002; 7(90003): 20 - 33. [Abstract] [Full Text] [PDF]
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T. Yang, T. F. Witham, L. Villa, M. Erff, J. Attanucci, S. Watkins, D. Kondziolka, H. Okada, I. F. Pollack, and W. H. Chambers Glioma-associated Hyaluronan Induces Apoptosis in Dendritic Cells via Inducible Nitric Oxide Synthase: Implications for the Use of Dendritic Cells for Therapy of Gliomas Cancer Res., May 1, 2002; 62(9): 2583 - 2591. [Abstract] [Full Text] [PDF]
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L. M. Liau, E. R. Jensen, T. J. Kremen, S. K. Odesa, S. N. Sykes, M. C. Soung, J. F. Miller, and J. M. Bronstein Tumor Immunity within the Central Nervous System Stimulated by Recombinant Listeria monocytogenes Vaccination Cancer Res., April 1, 2002; 62(8): 2287 - 2293. [Abstract] [Full Text] [PDF]
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) and 12
weeks (
) after the last of three DC/tumor peptide administrations.