Dendritic Cell Vaccination in Glioblastoma Patients Induces Systemic and Intracranial T-cell Responses Modulated by the Local Central Nervous System Tumor Microenvironment

Liau, Linda M.; Prins, Robert M.; Kiertscher, Sylvia M.; Odesa, Sylvia K.; Kremen, Thomas J.; Giovannone, Adrian J.; Lin, Jia‐Wei; Chute, Dennis J.; Mischel, Paul S.; Cloughesy, Timothy F.; Roth, Michael D.

doi:10.1158/1078-0432.ccr-05-0464

Cited by 481 publications

(395 citation statements)

References 45 publications

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“…In recent years, we have examined the applicability of a series of tumor cellbased immunization approaches for patients with gliomas [9][10][11][12][13][14][15]. Although promising results have been achieved [9,16,17], a limitation of this strategy is the need for autologous tumor and the time delay involved in generating a patient-specific vaccine. In contrast, vaccines in the form of synthetic peptides encoding T-cell epitopes in GAA would eliminate the need for autologous fresh glioma explants to generate clinical grade vaccines, facilitate timely vaccine production, and potentially reduce the risk of autoimmune encephalitis.…”

Section: Introductionmentioning

confidence: 99%

Expression of glioma-associated antigens in pediatric brain stem and non-brain stem gliomas

et al. 2008

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We investigated the protein expression of three glioma-associated antigens (GAAs) in pediatric brain stem glioma (BSG) and non-brain stem glioma (NBSG) cases with a view to their possible use in immunotherapy. Expression of EphA2, IL-13Rα2 and Survivin were studied by immunohistochemistry on paraffin-embedded tissues using a series of 15 BSG cases and 12 NBSG cases. Thirteen of 15 BSGs and all 12 NBSGs expressed at least one of GAAs; and 7 BSGs and 9 NBSGs expressed at least two of these GAAs at higher levels than non-neoplastic brain. There was no association between the tumor grade and levels of GAA expression. Although many cases demonstrated diffuse expression of GAAs throughout specimens, partial or patchy expression was noted in a small number of cases, suggesting a need for targeting multiple GAAs in immunotherapy. These results suggest that EphA2, IL-13Ralpha2 and Survivin are suitable targets for developing vaccine strategies for pediatric glioma.

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Section: Introductionmentioning

confidence: 99%

Expression of glioma-associated antigens in pediatric brain stem and non-brain stem gliomas

et al. 2008

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“…Although all studies led to the induction of antitumor CTLs and lymphocyte infiltration into tumors in situ, survival benefit remained low. Objective tumor regressions appeared to relate to the absence of a bulky tumor mass secreting TGF-␤2 and, importantly, on the maturation status of DCs inside and around the tumor (7,8). Therapeutic strategies combining abrogation of local immunosuppression with potent immune stimulation are therefore of particular interest in the search for efficient treatments of malignant gliomas.…”

mentioning

confidence: 99%

TLR Ligands in the Local Treatment of Established Intracerebral Murine Gliomas

Grauer

Molling

Bennink

et al. 2008

The Journal of Immunology

120

102

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Local TLR stimulation is an attractive approach to induce antitumor immunity. In this study, we compared various TLR ligands for their ability to affect murine GL261 cells in vitro and to eradicate established intracerebral murine gliomas in vivo. Our data show that GL261 cells express TLR2, TLR3, and TLR4 and respond to the corresponding TLR ligands with increasing MHC class I expression and inducing IL-6 secretion in vitro, while TLR5, TLR7, and TLR9 are essentially absent. Remarkably, CpG-oligonucleotides (CpG-ODN, TLR9) appeared to inhibit GL261 cell proliferation in a cell-type specific, but CpG-motif and TLR9-independent manner. A single intratumoral injection of CpG-ODN most effectively inhibited glioma growth in vivo and cured 80% of glioma-bearing C57BL/6 mice. Intratumoral injection of Pam3Cys-SK4 (TLR1/2) or R848 (TLR7) also produced a significant survival benefit, whereas poly(I:C) (TLR3) or purified LPS (TLR4) stimulation alone was not effective. Additional studies using TLR9+/+ wild-type and TLR9−/− knockout mice revealed that the efficacy of local CpG-ODN treatment in vivo required TLR9 expression on nontumor cells. Additional experiments demonstrated increased frequencies of tumor-infiltrating IFN-γ producing CD4+ and CD8+ effector T cells and a marked increase in the ratio of CD4+ effector T cells to CD4+FoxP3+ regulatory T cells upon CpG-ODN treatment. Surviving CpG-ODN treated mice were also protected from a subsequent tumor challenge without further addition of CpG-ODN. In summary, this study underlines the potency of local TLR treatment in antiglioma therapy and demonstrates that local CpG-ODN treatment most effectively restores antitumor immunity in a therapeutic murine glioma model.

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“…DC vaccine trials especially those in glioma patients report massive intra tumoral infiltration of CD8+ T cells in several patients who received multiple DC vaccines (Liau et al, 2005). As we could not obtain a post vaccination biopsy from all our patients, it was not possible to ascertain the infiltration status in most of them especially, the patient who responded, but a biopsy from another patient who received lysate primed DC showed significant infiltration post vaccination.…”

Section: Discussionmentioning

confidence: 82%

Development and Clinical Evaluation of Dendritic Cell Vaccines for HPV Related Cervical Cancer - a Feasibility Study

Ramanathan¹,

Ganesarajah²,

Raghanvan³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Human papillomavirus infection (HPV) and HPV related immune perturbation play important roles in the development of cervical cancer. Since mature dendritic cells (DCs) are potent antigen-presenting cells (APC), they could be primed by HPV antigens against cervical cancers. In this study we were able to generate, maintain and characterize, both phenotypically and functionally, patient specific dendritic cells in vitro. A randomized Phase I trial with three arms -saline control (arm I), unprimed mature DC (arm II) and autologous tumor lysate primed mature DC (arm III) and fourteen patients was conducted. According to WHO criteria, grade 0 or grade one toxicity was observed in three patients. One patient who received tumor lysate primed dendritic cells and later cis-platin chemotherapy showed a complete clinical response of her large metastatic disease and remained disease free for more than 72 months. Our findings indicate that DC vaccines hold promise as adjuvant sfor cervical cancer treatment and further studies to improve their efficacy need to be conducted.

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Dendritic Cell Vaccination in Glioblastoma Patients Induces Systemic and Intracranial T-cell Responses Modulated by the Local Central Nervous System Tumor Microenvironment

Cited by 481 publications

References 45 publications

Expression of glioma-associated antigens in pediatric brain stem and non-brain stem gliomas

Expression of glioma-associated antigens in pediatric brain stem and non-brain stem gliomas

TLR Ligands in the Local Treatment of Established Intracerebral Murine Gliomas

Development and Clinical Evaluation of Dendritic Cell Vaccines for HPV Related Cervical Cancer - a Feasibility Study

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