Class C CpG oligodeoxynucleotides as a single agent and in combination with radiotherapy efficiently delayed growth of subcutaneous B16F1 tumors

Cerkovnik, Petra; Novaković, Barbara Jezeršek; Stegel, Vida; Novaković, Srdjan

doi:10.1177/1753425909105581

Cited by 7 publications

(7 citation statements)

References 31 publications

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“…Treatment with CpG ODN and radiation-induced tumor remission in two-thirds of rats inoculated with 9L glioma (Meng et al, 2005). The combination treatment also enhanced tumor growth delay of s.c. B16F1 tumors (Cerkovnik et al, 2009). CpG ODN 1826 enhanced radiation-induced growth delay of Lewis lung cancer in mice and enhanced the apoptotic index in tumors given combined treatments compared to either treatment alone (Yuan et al, 2011).…”

Section: Bugs To Drugs: Cpg Oligodeoxynucleotide and Radiotherapymentioning

confidence: 99%

CpG plus radiotherapy: a review of preclinical works leading to clinical trial

Mason¹,

Hunter²

2012

Front. Oncol.

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Studies performed three decades ago in our laboratory supported the hypothesis that radiation efficacy may be augmented by bacterial extracts that stimulate non-specific systemic antitumor immune responses. Application to the clinic was halted by unacceptable side effects and toxicities resulting from exposure to whole bacterial pathogens. Later scientific advances demonstrated that DNA isolated from bacteria was immunostimulatory and could be reproduced with synthetic oligodeoxynucleotides (ODNs), thus fueling the transition from bugs to drugs. Unmethylated CpG motifs within bacterial DNA induce activation of Toll-like receptor 9 and subsequently activate antigen-specific cellular immune responses. CpG ODNs have demonstrated favorable toxicity profiles in phase I clinical trials. We showed that this potent immunoadjuvant can be used in combination with radiation therapy to enhance local and systemic responses of several murine tumors. Studies demonstrated that enhanced tumor response is mediated in part by the host immune system. Antitumor efficacy was diminished in immunocompromised mice. Animals cured by combination of radiation and CpG ODN were resistant to subsequent tumor rechallenge. This body of work contributes to our understanding of the dynamic interplay between tumor irradiation and the host immune system and may facilitate translation to clinical trials.

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Section: Bugs To Drugs: Cpg Oligodeoxynucleotide and Radiotherapymentioning

confidence: 99%

CpG plus radiotherapy: a review of preclinical works leading to clinical trial

Mason¹,

Hunter²

2012

Front. Oncol.

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“…Additionally, in more than 80% of survivors, a long-lasting immunity has been triggered [19]. Class C CpG ODNs were also shown to suppress the growth of s.c. B16F1 tumors when applied as a single agent and to remarkably enhance the anti-tumor effect of tumor irradiation in combined therapy [20]. …”

Section: Introductionmentioning

confidence: 99%

Tumor vaccine composed of C-class CpG oligodeoxynucleotides and irradiated tumor cells induces long-term antitumor immunity

et al. 2010

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BackgroundAn ideal tumor vaccine should activate both effector and memory immune response against tumor-specific antigens. Beside the CD8+ T cells that play a central role in the generation of a protective immune response and of long-term memory, dendritic cells (DCs) are important for the induction, coordination and regulation of the adaptive immune response. The DCs can conduct all of the elements of the immune orchestra and are therefore a fundamental target and tool for vaccination. The present study was aimed at assessing the ability of tumor vaccine composed of C-class CpG ODNs and irradiated melanoma tumor cells B16F1 followed by two additional injections of CpG ODNs to induce the generation of a functional long-term memory response in experimental tumor model in mice (i.p. B16F1).ResultsIt has been shown that the functional memory response in vaccinated mice persists for at least 60 days after the last vaccination. Repeated vaccination also improves the survival of experimental animals compared to single vaccination, whereas the proportion of animals totally protected from the development of aggressive i.p. B16F1 tumors after vaccination repeated three times varies between 88.9%-100.0%. Additionally, the long-term immune memory and tumor protection is maintained over a prolonged period of time of at least 8 months. Finally, it has been demonstrated that following the vaccination the tumor-specific memory cells predominantly reside in bone marrow and peritoneal tissue and are in a more active state than their splenic counterparts.ConclusionsIn this study we demonstrated that tumor vaccine composed of C-class CpG ODNs and irradiated tumor cells followed by two additional injections of CpG ODNs induces a long-term immunity against aggressive B16F1 tumors.

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“…It is obvious from the results of various studies in humans and in experimental animals that only properly maturated DCs in the presence of tumor antigens are efficient for the induction of antitumor immunity network (1,27,(30)(31)(32)(33).…”

Section: Discussionmentioning

confidence: 99%

“…In our previous studies (27,33,34) we have demonstrated that the DCs could be efficiently maturated in vivo through vaccination of mice with irradiated tumor cells in combination with Cpg ODN class C (tumor vaccine). We have also confirmed that processes triggered by this vaccination included the activation of the effectors of native immunity (phagocytes) as well as the activation of CTL.…”

Section: Discussionmentioning

confidence: 99%

Tumor vaccine composed of CpG ODN class C and irradiated tumor cells up-regulates the expression of genes characteristic of mature dendritic cells and of memory cells

Novaković

2011

Int J Oncol

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Abstract. Only properly mature dendritic cells (DCs) in the presence of tumor antigens accomplish to activate all of the elements of the immune network and have the potential to induce tumor-specific effectors and memory T cells. In the current study, we firstly aimed to investigate the in vivo maturation of antigen presenting cells (APCs) at the molecular level by following the expression of CD11c, CD86 and MyD88 genes in the mixture of mononuclear cells after treatment of mice with a tumor vaccine composed of C-class CpG oligodeoxynucletides (CpG ODN) and irradiated melanoma B16F1 tumor cells. The second objective was to define whether the tumor vaccine induces generation of memory T cells (CD44 hi CD62L lo/hi CD27 hi ). Finally, based on gene expression pattern we aimed to determine the tissue distribution and homing of the (mature) APCs and memory cells after vaccination. We demonstrated that by tumor vaccine the APCs (including DCs) are manipulated in vivo. By this kind of vaccine, the differentiation and maturation of APCs is triggered primarily in the spleen and is subsequently followed by the migration of these APCs to the bone marrow. Once in the bone marrow, these APCs play a crucial role in the development and maintenance of long-lived memory T cells capable of preventing a relapse of malignant disease. In conclusion, our results provide insight into the nature and scope of the antitumor immune response elicited by this kind of tumor vaccine in vivo. We showed that the maturation of APCs is a prerequisite for the generation of effective longterm antitumor immunity.

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Class C CpG oligodeoxynucleotides as a single agent and in combination with radiotherapy efficiently delayed growth of subcutaneous B16F1 tumors

Cited by 7 publications

References 31 publications

CpG plus radiotherapy: a review of preclinical works leading to clinical trial

CpG plus radiotherapy: a review of preclinical works leading to clinical trial

Tumor vaccine composed of C-class CpG oligodeoxynucleotides and irradiated tumor cells induces long-term antitumor immunity

Tumor vaccine composed of CpG ODN class C and irradiated tumor cells up-regulates the expression of genes characteristic of mature dendritic cells and of memory cells

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