From: Subject: Clinical Responsiveness of Glioblastoma Multiforme to Chemotherapy after Vaccination -- Wheeler et al. 10 (16): 5316 -- Clinical Cancer Research Date: Sat, 30 Sep 2006 23:56:22 +0200 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_002B_01C6E4EC.08384CC0" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.2962 This is a multi-part message in MIME format. ------=_NextPart_000_002B_01C6E4EC.08384CC0 Content-Type: text/html; charset="Windows-1252" Content-Transfer-Encoding: quoted-printable Content-Location: http://clincancerres.aacrjournals.org/cgi/content/full/10/16/5316 Clinical Responsiveness of Glioblastoma Multiforme to = Chemotherapy after Vaccination -- Wheeler et al. 10 (16): 5316 -- = Clinical Cancer Research 3D"Clinical
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Clinical Cancer Research Vol. 10, 5316-5326, August 15, = 2004
=A9 2004=20 American = Association for Cancer Research

Clinical Trials

Clinical Responsiveness of Glioblastoma Multiforme to Chemotherapy = after=20 Vaccination

Christopher J. Wheeler, = Asha=20 Das, Gentao Liu, John S. Yu and = Keith L.=20 Black

Maxine Dunitz Neurosurgical Institute, Cedars-Sinai = Medical=20 Center, Los Angeles, California

ABSTRACT

Purpose: Although the development of immune-based = therapies=20 for various cancers including malignant glioma has been = heralded=20 with much hope and optimism, objective clinical improvements = in=20 most vaccinated cancer patients have not been realized. To = broaden=20 the search for vaccine-induced benefits, we examined synergy = of=20 vaccines with conventional chemotherapy.

Experimental Design: Survival and progression times were = analyzed=20 retrospectively in 25 vaccinated (13 with and 12 without = subsequent=20 chemotherapy) and 13 nonvaccinated de novo glioblastoma = (GBM)=20 patients receiving chemotherapy. Immune responsiveness and = T-cell=20 receptor excision circle (TREC) content within CD8+ T=20 cells (CD8+ TRECs) was determined in vaccinated=20 patients.

Results: Vaccinated patients receiving subsequent = chemotherapy=20 exhibited significantly longer times to tumor recurrence = after=20 chemotherapy relative to their own previous recurrence times, = as well as significantly longer postchemotherapy recurrence=20 times and survival relative to patients receiving isolated=20 vaccination or chemotherapy. Patients exhibiting objective = (>50%)=20 tumor regression, extremely rare in de novo GBM, were = also=20 confined to the vaccine + chemotherapy group. Prior tumor = behavior,=20 demographic factors, other treatment variables, distribution = of=20 vaccine responders, and patients with high CD8+ = TRECs all=20 failed to account for these differences in clinical outcome. = Within=20 all GBM patients receiving post-vaccine chemotherapy, = however,=20 CD8+ TRECs predicted significantly longer = chemotherapeutic=20 responses, revealing a strong link between the predominant = T-cell=20 effectors in GBM and tumor chemosensitivity.

Conclusions: We propose that therapeutic vaccination = synergizes=20 with subsequent chemotherapy to elicit tangible clinical = benefits=20 for GBM patients.

INTRODUCTION

Malignant brain tumors are among the gravest forms of cancer. = The=20 most common of these incurable tumors, glioblastoma multiforme = (GBM)=20 (grade IV glioma, glioblastoma), carries with it an average = survival=20 between 12 and 18 months (with 90=9695% of patients surviving = less than=20 2 years), without the possibility of spontaneous remission or = effective treatment (1,=20 2,=20 3)=20 . The consistently short survival and absence of effective = treatment=20 that make GBM such a devastating disease also render the = evaluation=20 of new therapies for this disease relatively rapid and=20 unequivocal. Survival from diagnosis represents the most = objective=20 standard for evaluation of GBM therapies, in part because = tumor=20 mass reduction (i.e., surgically) does not necessarily = correlate with prolonged survival (4,=20 5,=20 6)=20 .

Unfortunately, conventional therapies are remarkably ineffective = at improving GBM clinical outcome, despite the ability of=20 conventional therapies to confer significant benefits to = patients=20 with non-glioma tumors (3=20 ,=20 7 ,=20 8) . Even the few treatments effective against GBM = typically=20 either exhibit small increases in survival that are evident = only from=20 large population studies or primarily benefit certain = (i.e.,=20 young) patient subpopulations (9=20 ,=20 10) . Thus, novel therapies for GBM are needed. =

Cancer vaccines represent one novel therapy for GBM (11,=20 12,=20 13)=20 . The therapeutic efficacy of vaccination for any human = tumor,=20 however, remains controversial because tumor destruction or = extended=20 life span is not observed in most vaccinated cancer patients = (14,=20 15,=20 16)=20 . In contrast, current cancer vaccines do reliably elicit=20 tumor-reactive cytotoxic T lymphocytes (CTLs) in most = patients (14=20 ,=20 15 ,=20 17) . The reasons underlying the general clinical failure = of=20 cancer vaccines are unknown, but one possibility is that the = kinetics=20 of tumor killing by effector CTLs in cancer patients may be = too=20 inefficient to keep pace with rapidly growing, mutating = tumors in=20 situ. Consistent with this notion, it was reported = previously=20 that therapeutic vaccination with autologous tumor = antigen-pulsed=20 dendritic cells is sufficient to enhance peripheral = tumor-reactive=20 CTL activity and CD8+ T-cell infiltration into = tumors=20 in situ in GBM patients (13)=20 . Nevertheless, improvements in overall patient survival were = not=20 apparent in this initial study.

Because CTLs induce death in their cellular targets, it is not=20 unreasonable to expect that inefficient CTL killing might = either=20 incompletely trigger death pathways in targeted tumor cells = or=20 select for CTL-resistant tumor variants. In the first case,=20 vaccine-elicited tumor-responsive CTLs might fundamentally = alter=20 tumors by "priming" their apoptotic machinery, much as death=20 receptor ligation (which CTLs can induce) sensitizes cells to = anticancer drug-induced apoptosis (18)=20 . In the second case, CTLs could fundamentally alter tumor = cell=20 physiology and/or genetics through selection of = immune-resistant=20 variants, a demonstrated phenomenon in cancer patients = receiving=20 therapeutic vaccinations (19,=20 20,=20 21)=20 . Either possibility could in theory be exploited by = additional=20 therapeutic modalities. Therefore, the clinical insufficiency = of=20 cancer vaccines encourages the examination of synergy between = vaccination and other therapies and with chemotherapy in=20 particular.

A retrospective examination of the impact of therapeutic = vaccination=20 on the efficacy of conventional GBM chemotherapy was thus = undertaken.=20 Progression rates and overall survival were compared among 12 = vaccine-treated, 13 chemotherapy-treated, and 13 vaccine +=20 chemotherapy-treated de novo GBM patients. The results = suggest=20 that chemotherapy synergizes with previous therapeutic = vaccination to=20 generate a uniquely effective treatment that slows GBM = progression=20 and significantly extends patient survival relative to=20 individual therapies. This represents the first evidence that = a=20 vaccine-based therapeutic approach may extend survival in a = majority=20 of cancer patients and represents a novel treatment strategy = that=20 may substantially prolong GBM survival across a wide age = range=20 relative to standard radiation plus chemotherapy. Additional=20 independent evidence linked levels of the predominant = antitumor=20 effector T cells in GBM patients, CD8+ recent = thymic=20 emigrants (RTEs), to chemotherapeutic responsiveness, = consistent with=20 a direct influence of antitumor immunity on GBM=20 chemosensitivity.

MATERIALS AND METHODS

Patients and Clinical Variables.
All patients = suffered=20 from de novo GBM (average age, 55 years; range, = 32=9678 years)=20 and provided informed consent to treatments and associated=20 monitoring.

Patients in the vaccine group underwent craniotomy (five = patients=20 underwent one craniotomy before receiving vaccine therapy, = six=20 patients underwent two craniotomies, and one patient = underwent=20 four craniotomies before receiving vaccine therapy). All of=20 these patients received a course of radiation before = vaccination.=20 Four patients in this group also received chemotherapy, and = one=20 patient received stereotactic radiosurgery (SRS) before = vaccination.=20 After vaccination, five of these patients underwent another=20 craniotomy, and three received additional SRS. None received=20 chemotherapy after vaccination.

All patients in the chemotherapy group underwent craniotomy,=20 radiation, and chemotherapy. Six of these patients underwent = a=20 second craniotomy, and five patients received additional SRS. = Of=20 note, the longest overall survivor in this group (991 days) = suffered=20 from postoperative intracranial abscess requiring multiple = surgical=20 procedures for drainage. Intracranial infections in malignant = glioma=20 patients are associated with prolonged survival and have been = proposed to initiate an antitumor immune response (22)=20 .

Patients in the vaccine + chemotherapy group underwent = craniotomy=20 (eight patients underwent one craniotomy, and five patients=20 underwent two craniotomies) before receiving the vaccine = therapy.=20 All of these patients received radiation therapy. Five = patients=20 received additional chemotherapy, and three received SRS. = After=20 vaccination, six of these patients underwent another = craniotomy,=20 and five received SRS. All patients received chemotherapy = after=20 vaccination at the time of tumor progression. Notably, a = single=20 patient in this group (surviving >730 days and depicted in = Fig. 3B ) experienced a cutaneous glioblastoma with single = lymph=20 node involvement before vaccination and at the site of = irradiated=20 tumor cell inoculation for delayed type hypersensitivity = testing.=20 These two tumors were removed surgically approximately 1 year = prior to chemotherapy and did not recur.



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  		Fig. 3. A, CTL or type I = cytokine=20 vaccine responders are equally distributed among vaccine and = vaccine=20 + chemotherapy groups. A, all vaccine responders were = separated from nonresponders and plotted against patient = survival,=20 which failed to distinguish them. Responders were also = equally=20 distributed among vaccine (4 of 12; right panel) or = vaccine +=20 chemotherapy groups (4 of 13; left panel; P = =3D 0.45,=20 binomial distribution) and failed to distinguish survival = times=20 within these groups (the indicated probabilities were = derived from=20 two-sided t tests). B, TRECs quantified within = 50,000=20 purified CD8+ T cells from PBMCs collected at the = time of=20 surgery were determined and plotted for five vaccine and = nine=20 vaccine + chemotherapy patients. Purified T cells were = unavailable=20 for TREC assay in all other vaccinated patients. = CD8+=20 TREC ranges were statistically indistinguishable between = vaccine and=20 vaccine + chemotherapy patients (indicated probabilities = were=20 derived from two-sided t tests). =

 = ;
Vaccinated=20 patients were steroid-free during blood collection and = vaccinations=20 as described previously (13)=20 , and they received three vaccines, 2 weeks apart, of 10=9640 = x 106 autologous = dendritic=20 cells loaded with either HLA-eluted peptides from cultured = tumor=20 cells or 150 =B5g/ml autologous tumor freeze-thaw lysate, = starting=20 approximately 15 weeks after surgery. A fourth identical = vaccination=20 followed 6 weeks later only in Phase II trial patients (12 of = 25=20 patients). Serial magnetic resonance imaging (MRI) scans were = performed every 2=963 months for all patients and were = continuously=20 monitored until mid-2003. For all patients, tumor antigens of = uncharacterized composition were obtained from cell cultures = (phase=20 IA; Table 1 ) or lysates (all other trials; Table 1 ) originating from a single surgical tumor = resection=20 preceding vaccination. Newly diagnosed patients (six patients = in the=20 vaccine group and five patients in the vaccine + chemotherapy = group)=20 were vaccinated starting approximately 15 weeks after = diagnosis.=20 Recurrent patients (six patients in the vaccine group and = eight=20 patients in the vaccine + chemotherapy group; P =3D = 0.5,=20 binomial distribution) were vaccinated starting from 3=9619 = months=20 after diagnosis [vaccine group, average, 9.5 =B1 5.5 months = (range,=20 4.4=9619.1 months); vaccine + chemotherapy group, average, = 7.1 =B1 4.1=20 months (range, 3.1=9615 months); P =3D 0.4, two-tailed = t=20 test]. Recurrent patients contributed less to differences in = overall=20 survival between the vaccine + chemotherapy and vaccine = groups than=20 did newly diagnosed patients: overall survival of recurrent=20 patients was 899 =B1 208 days in the vaccine + chemotherapy = group=20 versus 557 =B1 97 days in the vaccine group (P =3D = 0.186,=20 log-rank), whereas overall survival of newly diagnosed = patients=20 was 1046 =B1 246 versus 529 =B1 41 days in the vaccine = +=20 chemotherapy and vaccine groups, respectively (P =3D 0.098,=20 log-rank).


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  		Table 1 Demographic and = treatment=20 parameters of GBM patient groups =

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Cell=20 Isolation and Lysis.
Peripheral blood mononuclear cells = (PBMCs) were=20 prepared with Ficoll from patients=92 blood obtained at the = time of=20 surgery and/or from banked leukaphereses. CD4+ and = CD8+ T cells were purified from PBMCs using MACS = bead=20 separation (Miltenyi Biotec, Auburn, CA). CD4+ or=20 CD8+ cells (107 cells/ml) were prepared = for=20 quantitative real-time PCR (qPCR) by lysis in 100 =B5g/ml = proteinase K=20 (Boehringer, Indianapolis, IN) for 1 h at 56=B0C, with = inactivation at=20 95=B0C for 10 min.

Cytotoxic T Lymphocyte Assays.
Bulk CTL assay was = performed with the JAM assay (23)=20 . Pre-vaccine and post-vaccine PBMCs were harvested and = adjusted to 8=20 x 106 cells/ml = in RPMI=20 1640 containing heat-inactivated human AB serum and = stimulated with=20 irradiated (11,000 rads) autologous cultured tumor cells at 1 = x 106 cells/ml for 6 days in = the presence=20 of 20 units/ml recombinant human interleukin (IL)-2. Tumor = cells=20 were labeled at 1 x = 105=20 cells/ml in 5 =B5Ci/ml [3H]thymidine for 48 h at = 37=B0C in 5%=20 CO2. After incubation, target cells in maximum = release=20 wells were lysed with 5% SDS in H2O and incubated = in DNase=20 I (Roche) at 20 units/ml final concentration for 10 min. = PBMCs (100=20 =B5l; maximum, 1 x 107 = cells/ml for=20 100:1 E:T ratio) were added to targets (100 =B5l; 1 x 105 cells/ml) at = various E:T=20 ratios for 6 h. Cells were harvested from plates with a = 96-well=20 harvester (Tomtec). CPM were determined using a Microbeta = 1450 Trilux=20 liquid scintillation counter (Wallac), and the percentage of = target=20 cell lysis was plotted. Progressive or consistent increases = in target=20 cell lysis with increasing E:T ratio by post-vaccine PBMCs = that was=20 at least 1.5 SDs greater than pre-vaccine lysis was = considered a=20 positive response.

Interferon-3D{gamma}=20=20 Quantification.
Dendritic cells were prepared by incubating = loosely=20 adherent PBMCs in RPMI 1640 +10% human AB serum, 500 units/ml = IL-4,=20 and 800 units/ml granulocyte macrophage colony-stimulating=20 factor for 8 days at 37=B0C in 5% CO2. Dendritic = cells (2=20 x 106 cells/ml) = were=20 pulsed with autologous tumor freeze-thaw lysate (150 =B5g/ml) = for 18 h=20 and irradiated. Autologous pre- and post-vaccine PBMCs (1 = x 106 cells/ml) were stimulated = in 10%=20 human AB serum with 1 x=20 106 irradiated lysate-pulsed dendritic cells/ml, with = IL-2=20 (300 IU/ml) added on day 2 and a 2-h re-stimulation with 150=20 =B5g/ml tumor lysate on day 11. RNA was isolated using Trizol = (GIBCO Invitrogen, San Diego, CA) and transcribed using = random=20 hexamers. Quantified plasmid DNA standards and cDNAs were = amplified=20 using qPCR primers and probes (Qiagen Operon, Alameda, CA) as = described previously (24=20 ,=20 25) . A 3D≥1.5-fold increase in CD8-normalized intereron = (IFN)-=20 production after vaccination indicated a positive response (25)=20 . IFN-3D{gamma} primers were as follows: 5'-AGCTCTGCATCGTTTTGGGTT-3',=20 forward; 5'-GTTCCATTATCCGCTACATCTGAA-3', reverse; and=20 5'-carboxyfluorescein-TCTTGGCTGTTACTGCCAGGACCCA-carboxy-tetramethylrhodam= ine-3',=20 probe. Reference (CD8) primers were as follows:=20 5'-CCCTGAGCAACTCCATCATGT-3', forward; 5'-GTGGGCTTCGCTGGCA-3', = reverse; and 5'-carboxyfluorescein-TCAGCCACTTCGTGCCGGTCTTC-3', = probe.=20 Reactions were amplified in 25 =B5l of 10 mM=20 deoxynucleotide triphosphates, 400 nM = primers,=20 200 nM TaqMan probe, and 0.5 unit of = platinum=20 Taq polymerase at 95=B0C for 5 min, 95=B0C for 30 s, and = 60=B0C for 30 s=20 for 45 cycles and detected on an iCycler (Bio-Rad, Hercules, = CA).=20 Patients responsive to TRP-2, Her-2, MAGE-1, or gp100 were = identified=20 by post-vaccine increases in IFN-3D{gamma}=20 = production by=20 PBMCs to peptide-pulsed T2 cells (1 =B5M = peptide,=20 2 h, 37=B0C) using enzyme-linked immunosorbent assay and/or = ELISPOT=20 kits (R&D Systems, Minneapolis, MN) according to the=20 manufacturer=92s instructions.

T-Cell Receptor Excision Circle = Quantification.
TRECs=20 were quantified in duplicate or triplicate by qPCR using the = 5'=20 nuclease (TaqMan) method, as described previously (26)=20 , and detected on an iCycler system (Bio-Rad). qPCR was=20 performed on 5 =B5l of cell lysate (from 50,000 cells) with=20 primers 5'-CACATCCCTTTCAACCATGCT-3' (forward),=20 5'-GCCAGCTGCAGGGTTTAGG-3' (reverse), and=20 carboxyfluorescein-5'-ACACCTCTGGTTTTTGTAAAGGTGCCCACT-carboxy-tetramethylr= hodamine-3'=20 (probe; MegaBases, Chicago, IL). PCR reactions including 0.5=20 unit of platinum Taq (Gibco, Grand Island, NY), 3.5 mM MgCl2, 0.2 mM=20 deoxynucleotide triphosphates, 500 nM of each = primer,=20 and 150 nM probe were amplified at 95=B0C = for 5 min,=20 95=B0C for 30 s, and 60=B0C for 1 min for 45 cycles. Control = =DF-actin=20 reactions were performed to ensure nucleic acid content, and=20 negative samples were excluded from further analysis. TREC = values=20 were adjusted for T-cell purity.

Statistical Analyses.
Statistical analyses = included=20 two-tailed Mann-Whitney log-rank tests for disease-free and = overall=20 survival, binomial distribution probability, and Pearson=92s=20 correlation coefficients (r values) calculated with = SAS and=20 Excel software. Binomial distributions were determined for 2- = and=20 3-year survival frequencies between vaccine + chemotherapy = group and=20 other (vaccine or chemotherapy) patient groups. Where = indicated,=20 values are included =B1 SE.

RESULTS

De novo GBM patients (GBM did not arise from malignant=20 progression of initially lower-grade gliomas) were enrolled = into one=20 of three vaccine studies conducted from 1998=962001 at a = single=20 institution (Maxine Dunitz Neurological Institute), or were=20 given chemotherapy alone, after surgical tumor resection and=20 standard radiation therapy. Vaccinated (vaccine or vaccine +=20 chemotherapy) patients received at least three vaccinations=20 with autologous tumor antigen-pulsed dendritic cells, = starting=20 approximately 15 weeks after surgery and 5 weeks after = radiation=20 therapy (Tables 1 and 2 ; Fig. 1A ). Patients receiving chemotherapy alone = (chemotherapy=20 patients) were treated (with surgery, radiation, and = chemotherapy)=20 over the same time interval as vaccinated patients (Table = 3) . Serial MRI scans were performed every 2=963 = months in=20 all patients. Tumor progression and overall survival among = vaccine,=20 chemotherapy, and vaccine + chemotherapy groups were = monitored and=20 compared (Figs. 1 and 2 ).


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  		Table 2 Vaccine trial = composition and=20 distinctions =

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  		Fig. 1. A, tumor = progression=20 (recurrence) intervals monitored for each group of GBM = patients.=20 Progression times were monitored over intervals before=20 (Pretreatment Recurrences) or spanning (Initial=20 Recurrences) vaccination or chemotherapy and = subsequently=20 thereafter (Subsequent Recurrences). All patients = (n =3D=20 12 for vaccine group and n =3D 13 for other groups) = experienced=20 initial and subsequent recurrences, whereas only the = indicated=20 subpopulations (n) experienced pretreatment = recurrences.=20 B, initial and subsequent times to tumor progression = in=20 vaccine, chemotherapy, and vaccine + chemotherapy groups. = Tumor=20 progression was defined as the time from first diagnosis of = brain=20 tumor (de novo GBM in all cases) to the first new = scan=20 enhancement, if verified by subsequent scans or by = histology, or=20 time from diagnosis to death due to tumor progression. = Initial=20 recurrence times were identical among all three groups = (P=20 > 0.6). The small difference in subsequent recurrence = times=20 between vaccine and chemotherapy groups and the difference = between=20 pretreatment and initial recurrence times within the vaccine = +=20 chemotherapy group were not statistically significant = (P >=20 0.07). C, pretreatment and initial recurrence times = of=20 recurrent patients in vaccine (n =3D 6) and vaccine + = chemotherapy (n =3D 8) groups. Mean times to tumor = progression=20 =B1 SE are shown for each group over specific inter-vals, as = indicated=20 in B and C. The small difference between = pretreatment=20 and initial recurrence times within the vaccine + = chemotherapy group=20 was not statistically significant (P > 0.62). As = for all=20 (recurrent and nonrecurrent) patients as depicted in = B, the=20 difference in subsequent recurrence times within recurrent = patients=20 in the vaccine + chemotherapy group was significant = (P =3D=20 0.02). Significance (P values) was derived from = double-sided=20 paired t tests (pretreatment or initial recurrence = after=20 vaccine versus subsequent recurrence after = chemotherapy in=20 vaccine + chemotherapy group) or unpaired double-sided = t=20 tests (all other comparisons). =

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  		Table 3 Chemotherapy use =

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  		Fig. 2. A, overall = survival in=20 vaccine, chemotherapy, and vaccine + chemotherapy groups. = Overall=20 survival was defined as the time from first diagnosis of = brain tumor=20 (de novo GBM in all cases) to death due to tumor = progression.=20 Kaplan-Meier survival plots with censored values in open=20 circles are shown for each group. Dashed line,=20 chemotherapy group; thin solid line, vaccine group; = thick=20 solid line, vaccine + chemotherapy group. Survival of = the=20 vaccine group was identical to that of chemotherapy group = (P=20 =3D 0.7, log-rank test). Survival of vaccine + chemotherapy = group was=20 significantly greater relative to survival in the other two = groups=20 together (P =3D 0.048, log-rank test), greater than = survival in=20 the chemotherapy group alone (P =3D 0.028, log-rank = test), and=20 greater than survival in the vaccine group alone (P = =3D 0.048,=20 log-rank test). Two of the three patients exhibiting = objective tumor=20 regression survived for >2 years (730 days) after = diagnosis.=20 B, tumor regression following post-vaccine = chemotherapy.=20 Relative days after diagnosis are represented by the = numbers=20 under individual MRI scans, with individual patient scans in = each=20 row. Patient 11 recurred 82 days after vaccine initiation; = patient 9=20 recurred 147 days after vaccine initiation, was treated = surgically,=20 and recurred 227 additional days (374 days total) after = vaccine=20 initiation. An additional patient (patient 10), the longest = survivor=20 of those exhibiting objective tumor regression, suffered = tumor=20 recurrence 35 days after vaccine initiation and was treated = with=20 subsequent chemotherapy, which was followed by objective = tumor=20 regression. A complete array of images was not available for = this=20 individual, however. All scans except the pre-resection scan = for=20 patient 2 were performed after contrast enhancement with = gadolinium.=20 Patient numbers can be cross-referenced to Table 3 . =

 = ;
Treatment=20 and demographic variables, including proportion of = nonsurvivors,=20 surgery before or after vaccination (where appropriate), = chemotherapy=20 before vaccination (where appropriate), gender, and age, were = not=20 significantly different among the relevant groups (Table 1) . In addition, Karnofsky performance status = (KPS) and=20 inclusion of recurrent versus newly diagnosed (all = de=20 novo GBM) patients did not differ significantly between the=20 vaccine and vaccine + chemotherapy patient groups (Table 1) . Inclusion criteria for vaccinated de = novo GBM=20 patients, the pathological type common among the three = vaccine=20 trials, were identical among these trials (Table 2) . Similarly, antitumor immune response rates = were=20 similar for the three vaccine trials (Table 2) , suggesting that differences in antigen source = and/or=20 vaccine dosing among individual trials did not substantially=20 impact their immunologic efficacy. Moreover, vaccine, vaccine = +=20 chemotherapy, and chemotherapy patients exhibited identical=20 recurrence times after initial treatment (Fig. 1B) , indicating a lack of inherent bias in = clinical tumor=20 behavior among all three patient groups before additional = treatment.=20 For these reasons, and despite the fact that the trials were = not=20 designed to address the issue, we felt that analysis of these = patient groups could reveal testable hypotheses pertaining to = synergy between vaccination and chemotherapy.

Only the extent of surgical resection and the inclusion of = recurrent=20 patients differed significantly between the patient groups. = All=20 vaccinated patients received image-complete resections, and = both=20 vaccinated patient groups included similar numbers of = recurrent=20 patients, whereas a portion of chemotherapy patients received = partial=20 resections and, as a group, contained significantly fewer = recurrent=20 patients than either vaccine group (Table 1 ; data not shown). Both of these biases had = the=20 potential to produce longer survival in both vaccine groups = relative=20 to the chemotherapy group. On the contrary, mean times to = progression=20 of chemotherapy patients were similar to those in previous = reports (8)=20 and did not differ significantly from those before or=20 immediately after initial treatment in either vaccination = group=20 (Table 2 ; Fig. 1, B and C ). Similarly, overall survival (Table 2 ; Fig. 2A ) or survival from therapy initiation for chemotherapy=20 patients was statistically indistinguishable from that of = patients=20 receiving vaccine only (P =3D 0.66 for survival from = therapy=20 initiation; data not shown). Thus, tumor behavior after = initial=20 treatment appeared identical among all three groups, and = therapeutic=20 vaccination by itself failed to significantly slow = progression or=20 prolong survival relative to conventional GBM chemotherapy = (Fig.=20 2A ; P =3D 0.7, log-rank test). Exclusion = or=20 isolation of recurrent patients did not alter the trend = toward=20 increased overall survival in patients receiving post-vaccine = chemotherapy but also resulted in too few patients per group = to=20 discern any statistical differences (nonrecurrent vaccine +=20 chemotherapy versus vaccine, 1046 =B1 246 = versus 529 =B1 41=20 days, respectively, P =3D 0.1; recurrent vaccine + = chemotherapy=20 versus vaccine, 899 =B1 208 versus 557 =B1 97 = days,=20 respectively, P =3D 0.2). Overall survival was also = identical=20 between recurrent and nonrecurrent patients pooled from both = groups=20 of vaccinated patients (P =3D 0.79; data not shown),=20 inconsistent with a survival bias due to their inclusion.

Despite exhibiting initial progression times that were identical = to those of the other two groups, GBM patients receiving = post-vaccine=20 chemotherapy enjoyed significantly longer times to tumor = progression=20 after chemotherapy relative to previous progression times in=20 the same patients or to comparable progression times in = patients=20 receiving vaccination or chemotherapy alone (Fig. 1B) . This pattern is not normally observed in = GBM=20 patients, for whom sequential times to tumor progression = typically=20 decrease (27=20 ,=20 28) . Overall survival (Table 2 ; Fig. 2A ) or survival from treatment initiation (data = not=20 shown) for GBM patients receiving chemotherapy after = vaccination was=20 also significantly prolonged relative to that of patients = receiving=20 either vaccine or chemotherapy alone (P =3D 0.025 and = 0.047 for=20 vaccine + chemotherapy relative to vaccine group and for = vaccine +=20 chemotherapy relative to vaccine and chemotherapy groups = combined,=20 respectively; data not shown). This demonstrates that tumors=20 exhibited the same previous clinical behavior regardless of = their=20 treatment grouping, inconsistent with the possibility that an = inadvertent selection bias resulted in inherently slower = progressing=20 tumors in patients receiving chemotherapy after vaccination. = In=20 addition, progression times after vaccination were not = significantly=20 different from pre-vaccine progression times in recurrent = vaccinated=20 patients (Fig. 1C) . This indicated that increased times to = tumor=20 progression were unique to the period of chemotherapy after=20 vaccination and further refuted the possibility of selection = bias.=20 The two groups of vaccinated patients were also statistically = indistinguishable with respect to all other treatment = variables,=20 including number of craniotomies, proportion of recurrent = patients,=20 radiation, SRS, and chemotherapy before vaccination, and they = exhibited similar KPS values after vaccine therapy (Table = 1) .

Importantly for this rapidly fatal disease, 2-, 3-, and 4-year=20 survival were also unique for patients receiving chemotherapy = after vaccination. Whereas chemotherapy or vaccination alone=20 resulted in a 2-year survival within the established range = for=20 GBM (8%; Table 1 ), postvaccination chemotherapy resulted in a = substantial increase in 2-year survivors (42%; Table 1 ; P < 0.05, binomial distribution). = Similarly, no 3- or 4-year survivors were evident after = chemotherapy=20 or vaccination alone, but such survivors persisted among = post-vaccine=20 chemotherapy patients (Table 1 ; P < 0.01 for 3-year survivors, binomial = distribution).

Finally, objective (>50%) regression of tumor mass was = observed=20 in 3 of 13 vaccine + chemotherapy patients, and this occurred = only after initiation of post-vaccine chemotherapy (Fig. 2,=20 A and B) . A similar regression was also observed in a = single=20 grade III malignant glioma patient receiving chemotherapy = after=20 vaccination (data not shown). Such dramatic regression of = de=20 novo GBM was unique to this group and is extremely = uncommon=20 in the literature, although a single example of partial GBM=20 regression after post-vaccine chemotherapy has recently been=20 reported (29)=20 . In that report, imaging studies suggested either rapid = tumor=20 recurrence after vaccination or vaccinemediated effects (such = as=20 inflammation). In this context, it is significant that tumor=20 recurrence in all vaccinated patients in the current study = was=20 determined by increased tumor imaging on MRI scans. These = increases=20 were probably not related to vaccine-induced inflammation = because 33%=20 (4 of 12) of vaccine patients and 46% (6 of 13) of vaccine +=20 chemotherapy patients were biopsied on observation of = post-vaccine=20 increases in tumor imaging, and all exhibited histologically = verified=20 recurrent tumor (data not shown). This suggests that apparent = increases in tumor imaging in our study were not due to=20 vaccine-induced inflammatory responses and instead generally=20 reflected bona fide tumor recurrence. This suggests = that the=20 specific therapeutic regimen of chemotherapy after = vaccination,=20 rather than vaccination alone, elicited tumor regression. In = any=20 case, this first demonstration of multiple objective = (>50%)=20 regressions of GBM in any adoptive immunotherapy setting, as = well as=20 in the treatment of GBM generally, is significant.

The above-mentioned results allowed us to hypothesize that = antitumor=20 immunity directly impacts GBM chemosensitivity. Although data = refuting inadvertent selection bias were evident, independent = means of testing this hypothesis were sought. It was = particularly=20 important to rule out that the distinct clinical outcomes in=20 vaccine only versus vaccine + chemotherapy groups were not = due=20 to differential induction of antitumor immunity, despite our=20 previous demonstration of efficient antitumor CTL response = induction=20 using similar vaccine methodology (13)=20 .

We initially examined either CTL or type I cytokine (i.e., = IFN-) responsiveness after vaccination, depending on = the=20 particular trial in which patients were enrolled (Table 2) . The incidence of responders of either type = (CTL+) was=20 distributed equally both within individual vaccine clinical = trials=20 (Table 2) and within vaccine and vaccine + chemotherapy = groups=20 (Fig. 3A ; 4 of 11 and 4 of 13 patients tested, = respectively;=20 P =3D 0.5, binomial distribution). Vaccine patients = combined=20 from both vaccine and vaccine + chemotherapy groups who = exhibited=20 enhanced responses to tumor cells or lysate after vaccination = exhibited a nonsignificant tendency toward increased overall=20 survival (Fig. 4A ; P =3D 0.23, log-rank test), which was somewhat = more=20 pronounced when survival from vaccine initiation was examined = (P =3D 0.08; data not shown). Similarly, increased overall=20 survival of CTL-responsive patients receiving vaccine +=20 chemotherapy relative to CTL nonresponders receiving vaccine = alone=20 approached but did not achieve statistical significance (Fig. = 4A ; P =3D 0.05, log-rank test). = Nevertheless,=20 survival time from vaccine initiation of CTL responders in = the=20 vaccine + chemotherapy group was significantly higher than = that of=20 CTL nonresponders in the vaccine group (P =3D 0.022, = log-rank=20 test; data not shown). All other treatment/responder = subgroups=20 exhibited less suggestive survival differences (Fig. = 4A ; P > 0.06, log-rank test). The = average age=20 of CTL responders between groups was also similar (55 =B1 6 = and 50 =B1 17=20 years for vaccine and vaccine + chemotherapy groups, = respectively;=20 P =3D 0.63, two-tailed t test). Thus, although = we cannot=20 rule out a partial influence of vaccine responders on the = most=20 objective measure of GBM outcome (overall survival), neither = distinct=20 frequencies nor ages of vaccine responders alone could = account for=20 the increased overall survival observed between vaccine and = vaccine +=20 chemotherapy groups.



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  		Fig. 4. A, vaccine = responsiveness=20 fails to account for different survival between vaccine and = vaccine=20 + chemotherapy groups. CTL or type I cytokine vaccine = responders=20 were separated from nonresponders, and Kaplan-Meier plots = for=20 patient survival were generated. Responders failed to = exhibit=20 distinct survival in general (top panel) or within = either the=20 vaccine (bottom right panel) or vaccine + = chemotherapy group=20 (bottom left panel). B, all vaccinated = patients were=20 separated based on the median TREC level quantified within = 50,000=20 purified CD8+ T cells from PBMCs collected at the = time of=20 surgery (216 molecules/50,000 CD8+ T cells). = Patients=20 with high CD8+ TRECs failed to exhibit distinct = survival=20 in general (depicted panels) or within vaccine + = chemotherapy=20 groups (data not shown; P =3D 0.9, log-rank). Similar = analysis=20 of patients receiving vaccine only was not meaningful due to = insufficient subgroup sizes (n =3D 3 and n =3D = 2 for low=20 and high CD8+ TREC levels, respectively). = Purified T=20 cells were unavailable for TREC assay in all other = vaccinated=20 patients. All indicated probabilities were derived from = log-rank=20 analysis. =

 = ;
The=20 inability of immunologic vaccine responders to significantly = predict=20 clinical outcome in cancer is common in vaccine trials (14=20 ,=20 15 ,=20 30 ,=20 31) and could stem from the likelihood that conventional = CTL and=20 cytokine response assays may not directly measure activities = of the=20 most clinically relevant immune effectors. In this context, = it is=20 particularly notable that levels of CD8+ RTE T = cells=20 measured by TREC analysis (26=20 ,=20 32 ,=20 33) , which allow accurate prediction of clinical outcome = in=20 vaccinated and unvaccinated GBM patients (34)=20 , largely account for age-dependent GBM clinical outcome and=20 dominantly influence vaccine responses in GBM patients (34)=20 . Moreover, most resting cells capable of binding to any of = several=20 tumor-associated antigens in GBM patients were shown to be=20 CD8+ RTEs, and these cells dominated in = vivo=20 responses to such antigens after therapeutic vaccination (34)=20 . We therefore examined whether differential CD8+ TREC=20 levels, as markers for what are likely the most clinically = relevant=20 immune effectors in GBM, accounted for overall survival = differences=20 between vaccine and vaccine + chemotherapy groups.

Distribution of patients with CD8+ TRECs above the median=20 value (216 molecules/50,000 CD8+ T cells) was = equivalent=20 between vaccine and vaccine + chemotherapy groups (Fig. = 3B ; two of five and five of nine patients = analyzed,=20 respectively; P =3D 0.25, binomial distribution). = Similarly,=20 CD8+ TREC values did not differ between these = groups (Fig.=20 3B ; P =3D 0.44, two-tailed t test). = Patients=20 combined from both vaccine and vaccine + chemotherapy groups=20 (14 patients for whom CD8+ TREC data were available) = who=20 exhibited high CD8+ TREC levels also exhibited = overall=20 survival similar to patients with low CD8+ TREC = levels=20 (Fig. 4B ; P =3D 0.79, log-rank test). = Similarly, high=20 CD8+ TRECs failed to predict longer overall = survival=20 within the vaccine + chemotherapy group (Fig. 4B ; P =3D 0.36, log-rank test). High = CD8+=20 TRECs also failed to predict longer survival from vaccination = in=20 general or within the vaccine + chemotherapy group (P = =3D 0.41=20 and 0.58, respectively; data not shown). Similar analysis = could not=20 be performed for the vaccine only group due to a more limited = set of=20 obtainable CD8+ TREC data. Thus, by these = analyses, there=20 was no evidence of skewing of patients with high = CD8+ TREC=20 levels and no evidence that antitumor activity mediated by=20 CD8+ RTEs or other immune effectors was = responsible for=20 longer survival in patients receiving vaccine + = chemotherapy.=20

Although segregation of patients based on either vaccine = responsiveness=20 or median CD8+ TREC values failed to reveal = statistically=20 different overall survival times, CTL responders receiving=20 post-vaccine chemotherapy did exhibit longer survival from=20 vaccination than nonresponders without subsequent = chemotherapy=20 (P =3D 0.022; data not shown), and both IFN-3D{gamma}=20 = response=20 magnitude and CD8+ TRECs exhibited significant=20 correlations with overall survival times from the combined=20 vaccination group patients (r =3D 0.77 and P = < 0.05=20 and r =3D 0.936 and P < 0.01, respectively, = Pearson=92s=20 correlation; data not shown). Thus, although these aspects of = cellular immunity could not account for significant = differences=20 in overall survival between the vaccine and vaccine + = chemotherapy=20 groups, the involvement of immune processes in = postvaccination=20 chemotherapy responses could not be altogether discounted. = This=20 suggested that more focused analysis of patients receiving=20 post-vaccine chemotherapy might reveal an association between = immune=20 and chemotherapeutic responsiveness.

Because times to recurrence were increased specifically after=20 chemotherapy in vaccine + chemotherapy patients, we = considered=20 the increase in time to recurrence relative to previous = recurrence=20 time (i.e., after vaccination) in the same patient as a=20 quantitative indicator of chemotherapeutic responsiveness. = This=20 parameter was also normalized with respect to prior tumor = behavior=20 in the same patient, obviating the need to compare only de = novo GBM patients and justifying expanding the analysis = to all=20 GBM patients receiving post-vaccine chemotherapy. We thus=20 compared chemotherapeutic responses to quantifiable aspects = of=20 immune responsiveness (IFN-3D{gamma}=20 = response=20 magnitude and CD8+ TREC levels) and to a strong=20 established prognostic factor for GBM, patient age. This = analysis was=20 performed in all patients from whom these data were = available.=20

In all GBM patients receiving post-vaccine chemotherapy, patient = age correlated inversely with chemotherapeutic responsiveness = (r =3D =960.56; P =3D 0.04; Fig. 5A ), confirming that such responsiveness was = age=20 dependent and that this population adhered to established = clinical=20 trends (9)=20 . IFN-3D{gamma} response magnitude, on the other hand, failed to = correlate=20 with chemotherapeutic responsivenss (r =3D 0.44; = P >=20 0.05; Fig. 5B ), whereas CD8+ TRECs correlated = extremely=20 well with GBM chemotherapeutic responsiveness (r =3D = 0.96;=20 P < 0.003; Fig. 5C ). In addition, higher CD8+ TREC = levels, but=20 neither age nor CTL responsiveness, predicted significantly = greater=20 chemotherapeutic responses (Fig. 5, D=96F ; average 12.58 =B1 5.63 month increase = versus=20 1.42 =B1 1.75 month decrease with CD8+ TRECs below = median;=20 P =3D 0.005, log-rank). This relationship was not = simply a=20 function of an independent influence of age on thymic = CD8+=20 RTE production because CD8+ TRECs correlated more = strongly=20 to chemotherapeutic responsiveness than did patient age (Fig. = 5,=20 A and C) and uniquely predicted increased times to = progression=20 (Fig. 5D) , consistent with previous studies (34)=20 .



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  		Fig. 5. CD8+ TRECs = are strongly=20 associated with chemotherapeutic responses after = vaccination.=20 Patient age (A and D), type I cytokine = (IFN-) response magnitude (B and E), or = TRECs=20 quantified within 50,000 purified CD8+ T cells = from PBMCs=20 collected at the time of surgery (C and F) = were=20 correlated with the increase in time to tumor progression = (time to=20 recurrence after chemotherapy minus time to recurrence after = vaccination in the same patient; A=96C). Median = values for=20 these same three variables were used to subdivide the = patient=20 population, and Kaplan-Meier survival analyses were = conducted=20 (D=96F). Data were derived from all vaccinated GBM = patients=20 (de novo and secondary GBM) for whom chemotherapeutic = response and age (n =3D 17), IFN-3D{gamma}=20=20 response magnitude (n =3D 12), or TREC results = (n =3D 12)=20 were available. A related variable, time to tumor = progression after=20 chemotherapy divided by time to tumor progression after = vaccination,=20 also correlated significantly with CD8+ TRECs = (r =3D=20 0.80; P < 0.01) and patient age (r =3D = =960.67;=20 P < 0.05) but failed to do so with IFN-3D{gamma}=20=20 response magnitude (r =3D =960.40; P > = 0.05). =

 = ;
Taken=20 together, these findings suggest that GBM tumors are recognized = and=20 acted on in situ by cellular immune components. Overall, = such=20 activity may result in a fundamental alteration of GBM tumors = that=20 renders them increasingly sensitive to DNA-altering = chemotherapy,=20 despite the inability of vaccination by itself to confer = overt=20 clinical benefits to patients.

DISCUSSION

Although originating from distinct clinical studies not designed = to address synergy between vaccination and chemotherapy, = several=20 criteria help validate comparison among the three patient = treatment=20 groups and, in particular, between the two vaccine patient = groups=20 analyzed here. First, the overwhelming prognostic factors for = glioma clinical outcome are tumor type, tumor grade, and = patient=20 age. All three groups were composed only of patients with = identical=20 types and grades of tumor (grade IV astrocytoma =3D GBM) and = exhibited=20 statistically identical age ranges. In addition, a less = robust=20 and more subjective prognostic factor, KPS, which was not = followed=20 rigorously in chemotherapy patients, was not statistically = different=20 between vaccine and vaccine + chemotherapy patients after=20 vaccination. This suggests that, among vaccinated patients, = there was=20 no bias in a prognostic factor that was obtained near the = time=20 of segregation into vaccine only or vaccine + chemotherapy = subgroups.=20 Finally, and perhaps most convincingly, all three groups = exhibited=20 identical tumor recurrence times after initial therapy = (vaccination=20 or chemotherapy), suggesting that tumors from patients in any = one group behaved clinically like those from any other before = further treatment. Thus, no prognostically or empirically = defined=20 bias in patient composition or tumor behavior among the three = treatment groups was evident before secondary chemotherapy. =

However, a potential bias between chemotherapy and all = vaccinated=20 patients was possible due to a portion of chemotherapy = patients=20 experiencing partial surgical resection of their tumors, = whereas=20 all patients receiving vaccinations had image-complete = resections.=20 In addition, the chemotherapy only group included = significantly=20 fewer recurrent patients than either of the vaccine groups,=20 which included similar proportions of recurrent patients. = Although=20 the clinical benefit of complete surgical resection has not=20 been scientifically addressed by design, it is thought to = provide=20 a statistically significant survival increase (35)=20 . This increase is minimal, however, and has only been = evident from=20 meta-analyses of hundreds of patients in any study. We = therefore do=20 not expect a proportion of incompletely resected patients = within an=20 already limited population to account for the relatively = large=20 difference in survival between chemotherapy and vaccine +=20 chemotherapy patients. This expectation is supported by the = fact that=20 survival was statistically identical between chemotherapy and = vaccine (without subsequent chemotherapy) patient groups, the = latter of which, like the vaccine + chemotherapy group, was=20 composed entirely of patients with image-complete tumor=20 resections.

Both recurrent and nonrecurrent GBM patients are grouped = together=20 in most of our analyses. Because overall survival from = initial=20 diagnosis of de novo GBM, rather than survival from = treatment=20 initiation, was examined, this grouping results primarily in=20 treatment timing differences between recurrent and = nonrecurrent=20 patients. Arguments against a bias due to treatment timing=20 differences, as well as sensitization to vaccination by prior = treatment, include the fact that each vaccine group contained = statistically similar proportions of recurrent patients = (Table 1) and that recurrent patients exhibited = identical overall=20 survival relative to nonrecurrent patients pooled from both=20 vaccinated patient groups (see Patients and Clinical = Variables in=20 "Materials and Methods," and "Results"). The fact that = increased=20 survival or times to recurrence were observed and that this = was=20 confined to only one of the vaccine groups also refute that=20 recurrent patient inclusion meaningfully affected the = clinical=20 outcome data. Thus, the only obvious potential biases in = patient=20 composition among the three treatment groups are = statistically=20 unlikely and directly refuted by empirical clinical data, = although=20 we cannot formally exclude this possibility in a combined,=20 nonrandomized study of so few patients. We nonetheless felt = justified=20 in comparing tumor progression and overall survival among = three=20 treatment groups of de novo GBM patients with = identical=20 prognostic and pretreatment factors.

Vaccinated patients receiving subsequent chemotherapy exhibited=20 significantly delayed tumor progression and longer survival=20 relative to those receiving vaccinations without subsequent=20 chemotherapy or those receiving chemotherapy alone. Improved=20 clinical outcome appeared dependent on the specific = combination=20 of therapeutic vaccination followed by chemotherapy. These=20 observations suggest a substantial therapeutic slowing of GBM = progression and extension of overall survival for GBM = patients. It is=20 impossible to exclude the possibility that vaccination and=20 chemotherapy simply had additive, rather than synergistic, = effects.=20 It is notable, however, that incrementally favorable clinical = outcomes were not evident with vaccination alone, and those = seen=20 following post-vaccine chemotherapy appeared to markedly = surpass=20 those in previous vaccine studies as well as those in even = the=20 most hopeful analyses of GBM chemotherapy, including multiple = regimens in predominantly younger, potentially more = chemosensitive=20 patients (8)=20 . We therefore suspect that vaccination does not simply mimic = a=20 second regimen of chemotherapy but instead contributes unique = benefits to the patient that are not evident with either = vaccination=20 in the absence of subsequent chemotherapy or chemotherapy = alone. As=20 such, this allows us to hypothesize that this specific = treatment=20 combination conferred significantly increased survival to a=20 population of treated cancer patients, a unique outcome for a = vaccine-based therapy. A controlled prospective analysis is = thus=20 warranted to rigorously test the prediction that combinatorial=20 immune/chemotherapy is superior to either vaccine therapy or=20 standard chemotherapy alone and represents the best available = treatment in a larger population of GBM patients.

Both clinical outcome and chemotherapeutic responsiveness are=20 known to be age-dependent processes in gliomas in general (3=20 ,=20 9 ,=20 36) . Age-dependent glioma clinical outcome is critically=20 impacted by the production of CD8+ T cells in the = thymus=20 in mice, and a directly related parameter, TREC concentration = within CD8+ T cells, largely accounts for = agedependent=20 prognosis in GBM patients (34)=20 . This raises the possibility of a similar immune impact on=20 additional agedependent properties of GBM, such as = responsiveness to=20 chemotherapy. In support of this, we observed a stronger = correlation=20 between CD8+ TRECs and chemotherapeutic = responsiveness=20 than between age and chemotherapeutic responsiveness, and=20 CD8+ TREC levels predicted a significant increase in = such=20 responsiveness. This close relationship suggested that = clinical=20 responsiveness to chemotherapy is similarly impacted by the=20 production and/or function of newly emigrated CD8+ T=20 cells. Because levels of such T cells were shown to = predominantly=20 mediate antitumor immune responsiveness after vaccination of = GBM=20 patients (34)=20 , this constitutes evidence favoring the hypothesis that = antitumor=20 immunity impacts GBM chemosensitivity.

Thus, a cellular immune variable related to effector activity=20 appears not only to account for the strongest prognostic = factor=20 in GBM (age; Ref. 34=20 ) but also to be closely linked to chemotherapeutic = responsiveness of=20 these tumors. Because age is the single most dominant factor=20 influencing the outcome of most human tumors, it will be = additionally=20 important to determine whether cellular immune processes = similarly=20 influence clinical outcome and chemotherapeutic efficacy in = distinct=20 human tumors. If so, the clinical expectations associated = with=20 immune-based cancer therapies would be substantially = broadened.=20

It has been unclear whether the failure of therapeutic cancer=20 vaccines for most patients stems from the prevention of=20 vaccine-elicited CTL responsiveness to tumor cells or from = the=20 inability of responding CTLs to counteract net tumor = expansion (17)=20 . In light of this, it is tempting to speculate that = vaccination=20 induces systemic activation of antitumor CTLs that then = infiltrate=20 and attempt to kill tumors. Although such attempts by = tumor-reactive=20 CTLs alone may fail to prevent tumor regrowth, immune = effector=20 activity related to CD8+ RTEs may nonetheless = constrain=20 recurrent tumors by presensitizing them to alternative,=20 drug-inducible apoptotic pathways. In fact, in vitro = studies=20 have documented that sublethal death receptor signaling of = the type=20 elicited by CTLs can enhance the sensitivity of human tumor = cells to=20 multiple anticancer drugs (18)=20 . Thus, the vaccine protocols used here appeared to elicit = immune=20 effector responses that were linked to fundamental = alterations in=20 tumors (manifested as sensitivity to chemotherapy), but these = responses by themselves were insufficient to counteract net = tumor=20 expansion. Although the basis of this insufficiency remains = unknown,=20 these findings justify closer examination of the role of = immune=20 effectors after therapeutic cancer vaccination, as well as = assessment=20 of the molecular consequences of sublethal and lethal immune = effector=20 activity on tumors.

ACKNOWLEDGMENTS

We thank Dr. Julie Korenberg (Cedars-Sinai Research Institute) = for=20 invaluable insight in preparing the manuscript and Dr. Janet = Elashoff=20 and Meenu Sandhu (Cedars-Sinai Research Institute Biostatistics = Core)=20 for statistical analysis and critique.

FOOTNOTES

Grant support: A grant from the = Joseph=20 Drown Foundation (C. Wheeler) and the Maxine Dunitz = Neurosurgical=20 research fund.

The costs of publication of this = article were=20 defrayed in part by the payment of page charges. This article = must=20 therefore be hereby marked advertisement in accordance = with 18=20 U.S.C. Section 1734 solely to indicate this fact.

Requests for reprints: = Christopher J.=20 Wheeler, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai = Medical=20 Center, 8631 West Third Street, Suite 800E, Los Angeles, CA = 90048.=20 Phone: (310) 423-6646; Fax: (310) 423-0302; E-mail: wheelerc{at}cshs.org

Received 3/11/04; revised 5/ 5/04; accepted 5/ 5/04.

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L. M. Liau, R. M. Prins, S. M. Kiertscher, S. K. Odesa, = T. J.=20 Kremen, A. J. Giovannone, J.-W. Lin, D. J. Chute, P. S. Mischel, = T. F.=20 Cloughesy, and M. D. Roth
Dendritic Cell Vaccination in = Glioblastoma Patients Induces Systemic and Intracranial T-cell = Responses=20 Modulated by the Local Central Nervous System Tumor=20 Microenvironment
Clin. Cancer Res., = August 1, 2005;=20 11(15): 5515 - 5525.
[Abstract]=20 [Full=20 Text] [PD= F]=20
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To = view a=0A= copy of this license, visit = http://creativecommons.org/licenses/by-sa/2.5/ or=0A= send a letter to Creative Commons, 559 Nathan Abbott Way, Stanford, = California=0A= 94305, USA.=0A= =0A= Attribution: Leave my name and web address in this script intact.=0A= =0A= Not Supported in Opera=0A= ----------------------=0A= * user/password authentication=0A= * responseXML data member=0A= =0A= Not Fully Supported in Opera=0A= ----------------------------=0A= * async requests=0A= * abort()=0A= * getAllResponseHeaders(), getAllResponseHeader(header)=0A= =0A= */=0A= // IE support=0A= if (window.ActiveXObject && !window.XMLHttpRequest) {=0A= window.XMLHttpRequest =3D function() {=0A= var msxmls =3D new Array(=0A= 'Msxml2.XMLHTTP.5.0',=0A= 'Msxml2.XMLHTTP.4.0',=0A= 'Msxml2.XMLHTTP.3.0',=0A= 'Msxml2.XMLHTTP',=0A= 'Microsoft.XMLHTTP');=0A= for (var i =3D 0; i < msxmls.length; i++) {=0A= try {=0A= return new ActiveXObject(msxmls[i]);=0A= } catch (e) {=0A= }=0A= }=0A= return null;=0A= };=0A= }=0A= // Gecko support=0A= /* ;-) */=0A= // Opera support=0A= if (window.opera && !window.XMLHttpRequest) {=0A= window.XMLHttpRequest =3D function() {=0A= this.readyState =3D 0; 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i < this._headers.length; i++) {=0A= if (header =3D=3D '*' || this._headers[i].h =3D=3D header) {=0A= ret +=3D this._headers[i].h + ': ' + this._headers[i].v + '\n';=0A= }=0A= }=0A= return ret;=0A= };=0A= this.getResponseHeader =3D function(header) {=0A= var ret =3D getAllResponseHeader(header);=0A= var i =3D ret.indexOf('\n');=0A= if (i !=3D -1) {=0A= ret =3D ret.substring(0, i);=0A= }=0A= return ret;=0A= };=0A= this.setRequestHeader =3D function(header, value) {=0A= this._headers[this._headers.length] =3D {h:header, v:value};=0A= };=0A= this.open =3D function(method, url, async, user, password) {=0A= this.method =3D method;=0A= this.url =3D url;=0A= this._async =3D true;=0A= this._aborted =3D false;=0A= this._headers =3D [];=0A= if (arguments.length >=3D 3) {=0A= this._async =3D async;=0A= }=0A= if (arguments.length > 3) {=0A= opera.postError('XMLHttpRequest.open() - user/password not = supported');=0A= }=0A= this.readyState =3D 1;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= };=0A= this.send =3D function(data) {=0A= if (!navigator.javaEnabled()) {=0A= alert("XMLHttpRequest.send() - Java must be installed and = enabled.");=0A= return;=0A= }=0A= if (this._async) {=0A= setTimeout(this._sendasync, 0, this, data);=0A= // this is not really asynchronous and won't execute until the = current=0A= // execution context ends=0A= } else {=0A= this._sendsync(data);=0A= }=0A= }=0A= this._sendasync =3D function(req, data) {=0A= if (!req._aborted) {=0A= req._sendsync(data);=0A= }=0A= };=0A= this._sendsync =3D function(data) {=0A= this.readyState =3D 2;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= // open connection=0A= var url =3D new java.net.URL(new = java.net.URL(window.location.href), this.url);=0A= var conn =3D url.openConnection();=0A= for (var i =3D 0; i < this._headers.length; i++) {=0A= conn.setRequestProperty(this._headers[i].h, this._headers[i].v);=0A= }=0A= this._headers =3D [];=0A= if (this.method =3D=3D 'POST') {=0A= // POST data=0A= conn.setDoOutput(true);=0A= var wr =3D new = java.io.OutputStreamWriter(conn.getOutputStream(), this._getCharset());=0A= wr.write(data);=0A= wr.flush();=0A= wr.close();=0A= }=0A= // read response headers=0A= // NOTE: the getHeaderField() methods always return nulls for me :(=0A= var gotContentEncoding =3D false;=0A= var gotContentLength =3D false;=0A= var gotContentType =3D false;=0A= var gotDate =3D false;=0A= var gotExpiration =3D false;=0A= var gotLastModified =3D false;=0A= for (var i =3D 0; ; i++) {=0A= var hdrName =3D conn.getHeaderFieldKey(i);=0A= var hdrValue =3D conn.getHeaderField(i);=0A= if (hdrName =3D=3D null && hdrValue =3D=3D null) {=0A= break;=0A= }=0A= if (hdrName !=3D null) {=0A= this._headers[this._headers.length] =3D {h:hdrName, = v:hdrValue};=0A= switch (hdrName.toLowerCase()) {=0A= case 'content-encoding': gotContentEncoding =3D true; break;=0A= case 'content-length' : gotContentLength =3D true; break;=0A= case 'content-type' : gotContentType =3D true; break;=0A= case 'date' : gotDate =3D true; break;=0A= case 'expires' : gotExpiration =3D true; break;=0A= case 'last-modified' : gotLastModified =3D true; break;=0A= }=0A= }=0A= }=0A= // try to fill in any missing header information=0A= var val;=0A= val =3D conn.getContentEncoding();=0A= if (val !=3D null && !gotContentEncoding) = this._headers[this._headers.length] =3D {h:'Content-encoding', v:val};=0A= val =3D conn.getContentLength();=0A= if (val !=3D -1 && !gotContentLength) = this._headers[this._headers.length] =3D {h:'Content-length', v:val};=0A= val =3D conn.getContentType();=0A= if (val !=3D null && !gotContentType) = this._headers[this._headers.length] =3D {h:'Content-type', v:val};=0A= val =3D conn.getDate();=0A= if (val !=3D 0 && !gotDate) this._headers[this._headers.length] = =3D {h:'Date', v:(new Date(val)).toUTCString()};=0A= val =3D conn.getExpiration();=0A= if (val !=3D 0 && !gotExpiration) = this._headers[this._headers.length] =3D {h:'Expires', v:(new = Date(val)).toUTCString()};=0A= val =3D conn.getLastModified();=0A= if (val !=3D 0 && !gotLastModified) = this._headers[this._headers.length] =3D {h:'Last-modified', v:(new = Date(val)).toUTCString()};=0A= // read response data=0A= var reqdata =3D '';=0A= var stream =3D conn.getInputStream();=0A= if (stream) {=0A= var reader =3D new java.io.BufferedReader(new = java.io.InputStreamReader(stream, this._getCharset()));=0A= var line;=0A= while ((line =3D reader.readLine()) !=3D null) {=0A= if (this.readyState =3D=3D 2) {=0A= this.readyState =3D 3;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= }=0A= reqdata +=3D line + '\n';=0A= }=0A= reader.close();=0A= this.status =3D 200;=0A= this.statusText =3D 'OK';=0A= this.responseText =3D reqdata;=0A= this.readyState =3D 4;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= if (this.onload) {=0A= this.onload();=0A= }=0A= } else {=0A= // error=0A= this.status =3D 404;=0A= this.statusText =3D 'Not Found';=0A= this.responseText =3D '';=0A= this.readyState =3D 4;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= if (this.onerror) {=0A= this.onerror();=0A= }=0A= }=0A= };=0A= };=0A= }=0A= // ActiveXObject emulation=0A= if (!window.ActiveXObject && window.XMLHttpRequest) {=0A= window.ActiveXObject =3D function(type) {=0A= switch (type.toLowerCase()) {=0A= case 'microsoft.xmlhttp':=0A= case 'msxml2.xmlhttp':=0A= case 'msxml2.xmlhttp.3.0':=0A= case 'msxml2.xmlhttp.4.0':=0A= case 'msxml2.xmlhttp.5.0':=0A= return new XMLHttpRequest();=0A= }=0A= return null;=0A= };=0A= }=0A= ------=_NextPart_000_002B_01C6E4EC.08384CC0 Content-Type: application/octet-stream Content-Transfer-Encoding: quoted-printable Content-Location: http://clincancerres.aacrjournals.org/javascript/ajax/utility.js /************************************************************************= *****=0A= * javascript/ajax/utility.js=0A= *=0A= * Utility functions for working with XMLHttpRequest data.=0A= *=0A= * Copyright 2006 Board of Trustees of the Leland Stanford Junior = University.=0A= = *************************************************************************= ***/=0A= =0A= /*=0A= * Copy XML nodes into an HTMLElement. This effectively=0A= * clones XML markup which uses XHTML naming conventions=0A= * into an HTML DOM.=0A= */=0A= function copy_xml_to_html(src, dst) {=0A= if (src.nodeType =3D=3D 1) { /* Node.ELEMENT_NODE */=0A= var e =3D document.createElement(src.nodeName);=0A= for (var i =3D 0; i < src.childNodes.length; i++) {=0A= copy_xml_to_html(src.childNodes[i], e);=0A= }=0A= for (var i =3D 0; i < src.attributes.length; i++) {=0A= var n =3D src.attributes[i].name;=0A= var v =3D unescape_xml_string(src.attributes[i].value); =0A= e.setAttribute(n, v);=0A= if (n =3D=3D "class") {=0A= e.className =3D v;=0A= }=0A= else if (n =3D=3D "style") {=0A= set_css_style(v, e, "");=0A= }=0A= }=0A= dst.appendChild(e);=0A= }=0A= else if (src.nodeType =3D=3D 3) { /* Node.TEXT_NODE */=0A= dst.appendChild(document.createTextNode(src.nodeValue));=0A= }=0A= }=0A= =0A= /* =0A= * It is unclear that this is the right thing to be calling=0A= * from copy_xml_to_html, but it appears that Safari decides=0A= * to convert & to the NCR #, and then encodes that=0A= * NCR to &%26%2338;. So, I'm going to treat the DOM Attr=0A= * value as a plain string, and run our XML string input=0A= * through the decoding routine below.=0A= */=0A= function unescape_xml_string(s) {=0A= return s.replace(/'/g, "'")=0A= .replace(/'/g, "'")=0A= .replace(/"/g, "\"")=0A= .replace(/"/g, "\"")=0A= .replace(/>/g, ">")=0A= .replace(/>/g, ">")=0A= .replace(/</g, "<")=0A= .replace(/</g, "<")=0A= .replace(/&/g, "&")=0A= .replace(/&/g, "&");=0A= }=0A= =0A= /*=0A= * Parse set of CSS rules and apply them to an element.=0A= * This is quite horrifying, but I'm unable to determine=0A= * how else to handle this with IE 6. FireFox and other=0A= * sane browsers let you simply set the style attribute=0A= * or use e.style.setProperty(rule, value, priority),=0A= * IE 6 appears to have neither of these capabilities..=0A= */=0A= function set_css_style(css, e, priority) {=0A= var rules =3D css.split(";");=0A= for (var i =3D 0; i < rules.length; i++) {=0A= var nvpair =3D rules[i].split(":");=0A= if (nvpair.length =3D=3D 2) {=0A= try {=0A= var name =3D nvpair[0]; /* style attribute */=0A= var value =3D nvpair[1]; /* attribute value */=0A= =0A= /*=0A= * For each possible style attribute, set the=0A= * appropriate style property in the element.=0A= */=0A= if (name =3D=3D "background") {=0A= e.style.background =3D value;=0A= }=0A= else if (name =3D=3D "background-attachment") {=0A= e.style.backgroundAttachment =3D value;=0A= }=0A= else if (name =3D=3D "background-color") {=0A= e.style.backgroundColor =3D value;=0A= }=0A= else if (name =3D=3D "background-image") {=0A= e.style.backgroundImage =3D value;=0A= }=0A= else if (name =3D=3D "background-position") {=0A= e.style.backgroundPosition =3D value;=0A= }=0A= else if (name =3D=3D "background-position-x") {=0A= e.style.backgroundPositionX =3D value;=0A= }=0A= else if (name =3D=3D "background-position-y") {=0A= e.style.backgroundPositionY =3D value;=0A= }=0A= else if (name =3D=3D "background-repeat") {=0A= e.style.backgroundRepeat =3D value;=0A= }=0A= else if (name =3D=3D "behavior") {=0A= e.style.behavior =3D value;=0A= }=0A= else if (name =3D=3D "border") {=0A= e.style.border =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom") {=0A= e.style.borderBottom =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-color") {=0A= e.style.borderBottomColor =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-style") {=0A= e.style.borderBottomStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-width") {=0A= e.style.borderBottomWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-collapse") {=0A= e.style.borderCollapse =3D value;=0A= }=0A= else if (name =3D=3D "border-color") {=0A= e.style.borderColor =3D value;=0A= }=0A= else if (name =3D=3D "border-left") {=0A= e.style.borderLeft =3D value;=0A= }=0A= else if (name =3D=3D "border-left-color") {=0A= e.style.borderLeftColor =3D value;=0A= }=0A= else if (name =3D=3D "border-left-style") {=0A= e.style.borderLeftStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-left-width") {=0A= e.style.borderLeftWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-right") {=0A= e.style.borderRight =3D value;=0A= }=0A= else if (name =3D=3D "border-right-color") {=0A= e.style.borderRightColor =3D value;=0A= }=0A= else if (name =3D=3D "border-right-style") {=0A= e.style.borderRightStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-right-width") {=0A= e.style.borderRightWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-style") {=0A= e.style.borderStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-top") {=0A= e.style.borderTop =3D value;=0A= }=0A= else if (name =3D=3D "border-top-color") {=0A= e.style.borderTopColor =3D value;=0A= }=0A= else if (name =3D=3D "border-top-style") {=0A= e.style.borderTopStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-top-width") {=0A= e.style.borderTopWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-width") {=0A= e.style.borderWidth =3D value;=0A= }=0A= else if (name =3D=3D "bottom") {=0A= e.style.bottom =3D value;=0A= }=0A= else if (name =3D=3D "clear") {=0A= e.style.clear =3D value;=0A= }=0A= else if (name =3D=3D "clip") {=0A= e.style.clip =3D value;=0A= }=0A= else if (name =3D=3D "color") {=0A= e.style.color =3D value;=0A= }=0A= else if (name =3D=3D "cssText") {=0A= e.style.Sets =3D value;=0A= }=0A= else if (name =3D=3D "cursor") {=0A= e.style.cursor =3D value;=0A= }=0A= else if (name =3D=3D "direction") {=0A= e.style.direction =3D value;=0A= }=0A= else if (name =3D=3D "display") {=0A= e.style.display =3D value;=0A= }=0A= else if (name =3D=3D "font") {=0A= e.style.font =3D value;=0A= }=0A= else if (name =3D=3D "font-family") {=0A= e.style.fontFamily =3D value;=0A= }=0A= else if (name =3D=3D "font-size") {=0A= e.style.fontSize =3D value;=0A= }=0A= else if (name =3D=3D "font-style") {=0A= e.style.fontStyle =3D value;=0A= }=0A= else if (name =3D=3D "font-variant") {=0A= e.style.fontVariant =3D value;=0A= }=0A= else if (name =3D=3D "font-weight") {=0A= e.style.fontWeight =3D value;=0A= }=0A= else if (name =3D=3D "height") {=0A= e.style.height =3D value;=0A= }=0A= else if (name =3D=3D "ime-mode") {=0A= e.style.imeMode =3D value;=0A= }=0A= else if (name =3D=3D "layout-flow") {=0A= e.style.layoutFlow =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid") {=0A= e.style.layoutGrid =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-char") {=0A= e.style.layoutGridChar =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-line") {=0A= e.style.layoutGridLine =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-mode") {=0A= e.style.layoutGridMode =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-type") {=0A= e.style.layoutGridType =3D value;=0A= }=0A= else if (name =3D=3D "left") {=0A= e.style.left =3D value;=0A= }=0A= else if (name =3D=3D "letter-spacing") {=0A= e.style.letterSpacing =3D value;=0A= }=0A= else if (name =3D=3D "line-break") {=0A= e.style.lineBreak =3D value;=0A= }=0A= else if (name =3D=3D "line-height") {=0A= e.style.lineHeight =3D value;=0A= }=0A= else if (name =3D=3D "list-style") {=0A= e.style.listStyle =3D value;=0A= }=0A= else if (name =3D=3D "list-style-image") {=0A= e.style.listStyleImage =3D value;=0A= }=0A= else if (name =3D=3D "list-style-position") {=0A= e.style.listStylePosition =3D value;=0A= }=0A= else if (name =3D=3D "list-style-type") {=0A= e.style.listStyleType =3D value;=0A= }=0A= else if (name =3D=3D "margin") {=0A= e.style.margin =3D value;=0A= }=0A= else if (name =3D=3D "margin-bottom") {=0A= e.style.marginBottom =3D value;=0A= }=0A= else if (name =3D=3D "margin-left") {=0A= e.style.marginLeft =3D value;=0A= }=0A= else 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quoted-printable Content-Location: http://clincancerres.aacrjournals.org/javascript/entrez/callback.js /************************************************************************= *****=0A= * javascript/entrez/callback.js=0A= *=0A= * Entrez Linking callback to populate content box.=0A= *=0A= * Copyright 2006 Board of Trustees of the Leland Stanford Junior = University.=0A= = *************************************************************************= ***/=0A= =0A= /*=0A= * Execute callback to fill content box with Entrez Linking information.=0A= */=0A= function entrez_callback(pmid, callback_url) {=0A= /*=0A= * MSIE 5.5 and below have issues with the JavaScript=0A= * used for Entrez Linking. 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