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

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.

Effective CpG Immunotherapy of Breast Carcinoma Prevents but Fails to Eradicate Established Brain Metastasis

“…We previously reported that depletion of CD4 + , CD8 + , and NK1.1 + cells abolished cure of brain tumors in mice that were vaccinated with tumor lysate plus CpG ODN s.c. (33). In this study, we found a dramatic increase in these three populations of BILs in mice treated by CpG ODN, consistent with their putative role in immune surveillance of brain tumors that is exacerbated by CpG ODN.…”

Toll-like receptor 9 signaling by CpG-B oligodeoxynucleotides induces an apoptotic pathway in human chronic lymphocytic leukemia B cells

“…Our studies in murine leukemia and brain glioma models have shown that administration of CpG ODNs induced in vivo activation of DCs to activate NK and T cell-mediated antitumor responses with potent therapeutic efficacy. 45,46 Adding CpG ODN to PBMCs from lymphoma patients induced activation of blood DCs to enhance T-cell and NK-cell function. 47 Besides the immune-enhancing effects, CpG ODNs are stable, chemically well defined, inexpensive, and safe agents with clinical drugs available for studies.…”

A simple, clinically relevant therapeutic vaccine shows long-term protection in an aggressive, delayed-treatment B lymphoma model

“…The majority of TAA-based approaches have been reported for DC-based vaccines (20)(21)(22)29), which are very expensive, time consuming, and process intensive. Recently, easy-to-make and inexpensive vaccines using irradiated whole tumor cells or tumor lysate combined with adjuvants have been reported to be promising for various cancers (16,30,31). Here, we report a tumor lysate-based, directly injectable, personalized therapeutic vaccine for B cell lymphoma.…”

“…However, this comes with a cost, an increased probability of autoimmune cross-reactivity: i.e., the chance that in the presence of potent adjuvants, DCs can get sensitized to other, nontumorigenic self-proteins and cause autoimmune reactions. Nevertheless, lysatebased vaccines are being investigated as a viable immunotherapy approach for a variety of tumors (15)(16)(17)(18), and in several clinical trials no significant autoimmune reactions were observed (15,19). For lymphoma, there are few reports on tumor lysate-pulsed DC vaccines (20)(21)(22).…”