Article

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: 3.35). 11/2007; 30(8):789-97. DOI: 10.1097/CJI.0b013e318155a0f6
Source: PubMed

ABSTRACT 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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    • "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.
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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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