In Vivo Vaccination With Tumor Cell Lysate Plus CpG Oligodeoxynucleotides Eradicates Murine Glioblastoma

Department of Neurosurgery, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
Journla of Immunotherapy (Impact Factor: 4.01). 11/2007; 30(8):789-97. DOI: 10.1097/CJI.0b013e318155a0f6
Source: PubMed


Dendritic cell (DC) vaccines have shown antitumor activity in experimental glioma models and in human glioma patients. The typical approach has been to generate the vaccine ex vivo, by pulsing DCs with tumor lysate or peptides, then administering the DCs back into the patient. This process requires significant expertise and expenses in DC generation. Immature DCs which present antigens to T cells in the absence of appropriate costimulatory signals can lead to induction of immune tolerance. Recent studies have shown that coadministration of toll-like receptor 9 agonists, CpG oligodeoxynucleotides, can promote DC vaccines to break immune tolerance to tumor antigens. We investigated the therapeutic efficacy of in vivo DC activation, by directly administering glioma cell lysate with CpG oligodeoxynucleotides (CpG/lysate), in glioma-bearing mice. Subcutaneous vaccination with CpG/lysate induced a significant increase (P<0.05) in the number of total T cells and activated DCs in lymph nodes draining the vaccination site as compared to mice treated with CpG or tumor lysate alone. Mice vaccinated with CpG/lysate exhibited over 2 times greater median survival than mice in the control groups (P<0.05). Up to 55% of mice vaccinated with CpG/lysate were rendered tumor-free as assessed by survival and bioluminescent imaging. Splenocytes taken from mice vaccinated with CpG/lysate elaborated significantly more IFN-gamma production and displayed greater tumor cell lysis activity compared with the control groups (P<0.05). These results suggest direct vaccination with CpG/lysate provides an alternative and effective approach to induce host antitumor immunity and warrants clinical investigation in the immunotherapy of cancer.

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    • "Cancer immunotherapy aims to activate or enhance the patient's adaptive immune system to kill tumor cells with antigen specificity [1]. A number of strategies have been described, including delivering vaccines comprised of particular tumor antigens (or tumor lysate) together with a strong dendritic cell (DC) adjuvant such as CpG oligonucleotide or PolyI:C [2] [3] or adoptive T cell therapy using the patient's own T cells that are transfected to express a chimeric antigen receptor against a tumor antigen [4]. However, tumors progress in part by exploiting a variety of immune evasion and suppression mechanisms, including attracting a highly suppressive cell and cytokine repertoire in the tumor stroma [5] and inducing anergy, exhaustion or deletion of tumor antigen-specific T cells [6e 8], even when anti-tumor effector T cells are circulating systemically . "
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    ABSTRACT: Accumulating evidence implicates the tumor-draining lymph node (TDLN) in tumor-induced immune escape, as it drains regulatory molecules and leukocytes from the tumor microenvironment. We asked whether targeted delivery of adjuvant to the TDLN, presumably already bathed in tumor antigens, could promote anti-tumor immunity and hinder tumor growth. To this end, we used 30 nm polymeric nanoparticles (NPs) that effectively target dendritic cells (DCs, CD11c(+)) within the lymph node (LN) after intradermal administration. These NPs accumulated within the TDLN when administered in the limb ipsilateral (i.l.) to the tumor or in the non-TDLN when administered in the contralateral (c.l.) limb. Incorporating the adjuvants CpG or paclitaxel into the NPs (CpG-NP and PXL-NP) induced DC maturation in vitro. When administered daily i.l. and thus targeting the TDLN of a B16-F10 melanoma, adjuvanted NPs induced DC maturation within the TDLN and reshaped the CD4(+) T cell distribution within the tumor towards a Th1 (CXCR3(+)) phenotype. Importantly, this also led to an increase in the frequency of antigen-specific CD8(+) T cells within the tumor. This correlated with slowed tumor growth, in contrast to unhindered tumor growth after c.l. delivery of adjuvanted NPs (targeting a non-TDLN) or i.l. delivery of free adjuvant. CpG-NP treatment in the i.l. limb also was associated with an increase in CD8(+)/CD4(+) T cell ratios and frequencies of activated (CD25(+)) CD8(+) T cells within the TDLN whereas PXL-NP treatment reduced the frequency of regulatory T (FoxP3(+) CD4(+)) cells in the TDLN. Together, these data implicate the TDLN as a delivery target for adjuvant therapy of solid tumors.
    Full-text · Article · Oct 2013 · Biomaterials
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    • "However, the direct effects of CpG-ODNs on efficiency of transferred TILs remain unclear. It was reported that CpG-ODNs could elevate the activity capacity of T cells in tumor mass [18, 19]. We extended previous finding by demonstrating that the CpG-ODNs could enhance the antitumor efficacy of adoptive transferred TILs, which was correlated to enhanced activity and proliferation of tumor infiltrating CD4+ T cells and CD8+ T cells. "
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    ABSTRACT: Adoptive cell transfer immunotherapy using tumor infiltrating lymphocytes (TILs) was an important therapeutic strategy against tumors. But the efficacy remains limited and development of new strategies is urgent. Recent evidence suggested that CpG-ODNs might be a potent candidate for tumor immunotherapy. Here we firstly reported that CpG-ODNs could significantly enhance the antitumor efficacy of adoptively transferred TILs in vivo accompanied by enhanced activity capacity and proliferation of CD8(+) T cells and CD8(+) T cells, as well as a Th1 polarization immune response. Most importantly, we found that CpG-ODNs could significantly elevate the infiltration of Th17 cells in tumor mass, which contributed to anti-tumor efficacy of TILs in vivo. Our findings suggested that CpG ODNs could enhance the anti-tumor efficacy of adoptively transferred TILs through modifying Th1 polarization and local infiltration of Th17 cells, which might provide a clue for developing a new strategy for ACT based on TILs.
    Full-text · Article · Oct 2010 · Clinical and Developmental Immunology
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    • "However its precise role in glioma remains unclear with studies supporting both glioma promotion and glioma inhibition results, there is report that local CpG immunotherapy can prolong the survival of mouse with glioma[13,14]. In contrast, Ginzkey et al[15] found increase in tumor size following intratumoral injection of immunostimulatory CpG ODN in a rat glioma model, this was consistent with our previous finding that the intratumoral injection of CpG ODN do not increase the survival time in GL261 glioma animal model[16], and these results indicated that directly local injection of CpG may not yield beneficial effects in glioma patients. "
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    ABSTRACT: Our study aims to evaluate the expression of TLR9 in glioma tissues, examine the association between TLR9 expression, clinicopathological variables, and glioma patient outcome, we further characterized the direct effects of TLR9 agonist CpG ODN upon the proliferation and invasion of glioma cells in vitro. RT-PCR and immunofluorescence were used to determine the expression of TLR9 in glioma cell lines and clinical glioma samples. Tissue microarry and immunohistochemistry were applied to evaluated TLR9 expression in 292 newly diagnosed glioma and 13 non-neoplastic brain tissues. We further investigated the effect of CpG ODN on the proliferation and invasion of glioma cells in vitro with MTT assays and matrigel transwell assay respectively. RT-PCR showed that TLR9 expressed in all the glioma samples and glioma cell lines we examined. The tissue array analysis indicated that TLR9 expression is correlated with malignancy of glioma (p < 0.01). Multivariate Cox regression analysis revealed that TLR9 expression is an independent prognostic factor for PFS of GBM patients (P = 0.026). TLR9 agonist CpG ODN has no significant effect on glioma proliferation, but matrigel transwell analysis showed that TLR9 agonist CpG ODN can significantly enhance glioma invasion in vitro. Our data indicated that TLR9 expression increases according to the histopathological grade of glioma, and the TLR9 expression level is related to the PFS of GBM patients. In addition, our findings warrant caution in the directly injection of TLR9 agonist CpG ODN into glioma tissues for the glioma immunotherapy.
    Full-text · Article · Aug 2010 · BMC Cancer
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