Glioblastoma Patients Exhibit Circulating Tumor-Specific CD8+ T Cells

Tang, Jie; Flomenberg, Phyllis; Harshyne, Larry A.; Kenyon, Lawrence C.; Andrews, David W.

doi:10.1158/1078-0432.ccr-05-0545

Cited by 48 publications

(31 citation statements)

References 34 publications

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“…Nine of 21 patients had a positive test before any vaccination. This result might reflect the presence of an ongoing, indolent immune responsiveness in some patients as has been described recently (43). Overall, the clinical outcome of our patients was not linked to the presence of a positive DTH response at diagnosis or during vaccination, which underscores the importance of developing a more elaborated immunomonitoring.…”

Section: Discussionsupporting

confidence: 73%

Postoperative Adjuvant Dendritic Cell–Based Immunotherapy in Patients with Relapsed Glioblastoma Multiforme

Vleeschouwer¹,

Fieuws²,

Rutkowski

et al. 2008

Clinical Cancer Research

236

166

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Purpose:To investigate the therapeutic role of adjuvant vaccination with autologous mature dendritic cells (DC) loaded with tumor lysates derived from autologous, resected glioblastoma multiforme (GBM) at time of relapse. Experimental Design: Fifty-six patients with relapsed GBM (WHO grade IV) were treated with at least three vaccinations. Children and adults were treated similarly in three consecutive cohorts, with progressively shorter vaccination intervals per cohort. Feasibility and toxicity were assessed as well as effect of age, extent of resection, Karnofsky Performance Score, and treatment cohort on the progression-free (PFS) and overall survival (OS) using univariable and multivariable analysis. Results: Since the prevaccine reoperation, the median PFS and OS of the total group was 3 and 9.6 months, respectively, with a 2-year OS of 14.8%. Total resection was a predictor for better PFS both in univariable analysis and after correction for the other covariates. For OS, younger age and total resection were predictors of a better outcome in univariable analysis but not in multivariable analysis. A trend to improved PFS was observed in favor of the faster DC vaccination schedule with tumor lysate boosting. Vaccine-related edema in one patient with gross residual disease before vaccination was the only serious adverse event. Conclusion: Adjuvant DC-based immunotherapy for patients with relapsed GBM is safe and can induce long-term survival. A trend to PFS improvement was shown in the faster vaccination schedule. The importance of age and a minimal residual disease status at the start of the vaccination is underscored.In spite of multimodal therapy, including maximal safe neurosurgical resection followed by radiochemotherapy and maintenance chemotherapy, malignant or high-grade gliomas (HGG) continue to have a dismal prognosis (1). Prognosis after relapse is even worse (2, 3), with a median progression-free survival (PFS) of 2 months, and virtually all patients being dead 18 months after the relapse. Even in pediatric patients with relapsed HGG, the prognosis is poor (4).The rationale, the preclinical, and the early clinical evidence to develop dendritic cell (DC)-based immunotherapy for HGG has been reviewed by our research group (5, 6) and by others (7 -14). Vaccination is done with autologous mature monocyte-derived ex vivo generated DC loaded with autologous tumor lysate. The characteristics and in vitro function of the vaccine have been analyzed (15, 16). We described some early clinical experience on feasibility and toxicity that we obtained in a small group of patients (17,18).For the implementation of immunotherapy in clinical practice for patients with relapsed HGG, an observational prospective cohort comparison trial, HGG-IMMUNO, was designed, in which adjuvant autologous DC vaccination is done in patients with relapsed HGG after maximal new resection of the relapsed tumor. Except for the time window in cohort A, which was the

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Section: Discussionsupporting

confidence: 73%

Postoperative Adjuvant Dendritic Cell–Based Immunotherapy in Patients with Relapsed Glioblastoma Multiforme

Vleeschouwer¹,

Fieuws²,

Rutkowski

et al. 2008

Clinical Cancer Research

236

166

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“…Kenyon) and graded according to 2007 WHO criteria as oligodendrogliomas, grade II astrocytomas, grade III anaplastic astrocytomas, and grade IV glioblastoma. Tissues were harvested in bulk or by the Myriad tissue removal device (NICO Corporation), snap-frozen, and stored at À130 C or processed for cell culture as previously described (32).…”

Section: Methodsmentioning

confidence: 99%

Glioma Grade Is Associated with the Accumulation and Activity of Cells Bearing M2 Monocyte Markers

Prosniak

Harshyne

Andrews

et al. 2013

Clinical Cancer Research

Self Cite

173

128

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Purpose: This study is directed at identifying the cell source(s) of immunomodulatory cytokines in highgrade gliomas and establishing whether the analysis of associated markers has implications for tumor grading.Experimental Design: Glioma specimens classified as WHO grade II-IV by histopathology were assessed by gene expression analysis and immunohistochemistry to identify the cells producing interleukin (IL)-10, which was confirmed by flow cytometry and factor secretion in culture. Finally, principal component analysis (PCA) and mixture discriminant analysis (MDA) were used to investigate associations between expressed genes and glioma grade.Results: The principle source of glioma-associated IL-10 is a cell type that bears phenotype markers consistent with M2 monocytes but does not express all M2-associated genes. Measures of expression of the M2 cell markers CD14, CD68, CD163, and CD204, which are elevated in high-grade gliomas, and the neutrophil/myeloid-derived suppressor cell (MDSC) subset marker CD15, which is reduced, provide the best index of glioma grade.Conclusions: Grade II and IV astrocytomas can be clearly differentiated on the basis of the expression of certain M2 markers in tumor tissues, whereas grade III astrocytomas exhibit a range of expression between the lower and higher grade specimens. The content of CD163 þ cells distinguishes grade III astrocytoma subsets with different prognosis.

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“…PBMC were also tested against autologous DC electroporated with mRNA for B5 and A27 VACV proteins and GFP (negative control). TCLs were incubated with or without peptide (10 M) for 6 h. CD4 ϩ and CD8 ϩ T-cell responses were detected by measurements of intracellular IFN-␥ and cell surface markers CD69, CD3, and CD8 by four-color staining, as previously described (38).…”

Section: Methodsmentioning

confidence: 99%

Human T-Cell Responses to Vaccinia Virus Envelope Proteins

Tang¹,

Murtadha²,

Schnell

et al. 2006

J Virol

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One approach for a safer smallpox vaccine is to utilize recombinant subunits rather than live vaccinia virus (VACV). The products of the VACV envelope genes A27L, L1R, B5R, and A33R induce protective antibodies in animal models. We propose that proteins that elicit T-cell responses, as well as neutralizing antibodies, will be important to include in a molecular vaccine. To evaluate VACV-specific memory T-cell responses, peripheral blood mononuclear cells (PBMC) from four VACV vaccinees were tested against whole VACV and the individual envelope proteins A27, B5, L1, and A33, using gamma interferon enzyme-linked immunospot and cytokine flow cytometry assays. PBMC were stimulated with autologous dendritic cells infected with VACV or electroporated with individual VACV protein mRNAs. T-cell lines from all donors, vaccinated from 1 month to over 20 years ago, recognized all four VACV envelope proteins. Both CD4؉ and CD8 ؉ T-cell responses to each protein were detected. Further analysis focused on representative proteins B5 and A27. PBMC from a recent vaccinee exhibited high frequencies of CD4 ؉ and CD8 ؉ T-cell precursors to both B5 (19.8 and 20%, respectively) and A27 (6.8 and 3.7%). In comparison, B5-and A27-specific T-cell frequencies ranged from 0.4 to 1.3% in a donor vaccinated 3 years ago. Multiple CD4؉ and CD8 ؉ T-cell epitopes were identified from both A27 and B5, using overlapping 15-mer peptides. These data suggest that all four VACV envelope proteins may contribute to protective immunity, not only by inducing antibody responses, but also by eliciting T-cell responses.

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Glioblastoma Patients Exhibit Circulating Tumor-Specific CD8+ T Cells

Cited by 48 publications

References 34 publications

Postoperative Adjuvant Dendritic Cell–Based Immunotherapy in Patients with Relapsed Glioblastoma Multiforme

Postoperative Adjuvant Dendritic Cell–Based Immunotherapy in Patients with Relapsed Glioblastoma Multiforme

Glioma Grade Is Associated with the Accumulation and Activity of Cells Bearing M2 Monocyte Markers

Human T-Cell Responses to Vaccinia Virus Envelope Proteins

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