Eradication of Ovarian Tumor Xenografts by Locoregional Administration of Targeted Immunotherapy

Cesare, Michelandrea De; Calcaterra, Claudia; Pratesi, Graziella; Gatti, Laura; Zunino, Franco; Ménard, Sylvie; Balsari, Andrea

doi:10.1158/1078-0432.ccr-08-0445

Cited by 22 publications

(23 citation statements)

References 39 publications

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“…[6][7][8][9] Our results indicate that this is not true for tumors growing in the lung, where both tumor immunogenicity and the tumor-induced immunosuppressive environment are critical factors in the success of CpG therapy. Thus, different administration routes might be required for different tumors.…”

Section: Tumor Immunologymentioning

confidence: 99%

“…The anti-tumor effect of CpG has been optimized by direct injection into the tumor to enable increased local concentrations in the tumor microenvironment and to ensure effective local activation of both innate and adaptive immune responses. [6][7][8][9] Thus, local instead of systemic administration of the TLR9 agonist might represent an option to improve the efficacy of CpG as adjuvant in protecting against lung cancer or in treating and/or preventing lung metastases derived from different primary tumors. Bronchial and bronchoalveolar tumors are accessible via the endobronchial space.…”

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confidence: 99%

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Anti‐tumor activity of CpG‐ODN aerosol in mouse lung metastases

Sfondrini

Sommariva

Tortoreto

et al. 2013

Intl Journal of Cancer

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Studies in preclinical models have demonstrated the superior anti-tumor effect of CpG oligodeoxynucleotides (CpG-ODN) when administered at the tumor site rather than systemically. We evaluated the effect of aerosolized CpG-ODN on lung metastases in mice injected with immunogenic N202.1A mammary carcinoma cells or weakly immunogenic B16 melanoma cells. Upon reaching the bronchoalveolar space, aerosolized CpG-ODN activated a local immune response, as indicated by production of IL-12p40, IFN-c and IL-1b and by recruitment and maturation of DC cells in bronchoalveolar lavage fluid of mice. Treatment with aerosolized CpG-ODN induced an expansion of CD41 cells in lung and was more efficacious than systemic i.p. administration against experimental lung metastases of immunogenic N202.1A mammary carcinoma cells, whereas only i.p. delivery of CpG-ODN provided anti-tumor activity, which correlated with NK cell expansion in the lung, against lung metastases of the poorly immunogenic B16 melanoma. The inefficacy of aerosol therapy to induce NK expansion was related to the presence of immunosuppressive macrophages in B16 tumor-bearing lungs, as mice depleted of these cells by clodronate treatment responded to aerosol CpG-ODN through expansion of the NK cell population and significantly reduced numbers of lung metastases. Our results indicate that tumor immunogenicity and the tumor-induced immunosuppressive environment are critical factors to the success of CpG therapy in the lung, and point to the value of routine sampling of the lung immune environment in defining an optimal immunotherapeutic strategy.

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Section: Tumor Immunologymentioning

confidence: 99%

mentioning

confidence: 99%

Anti‐tumor activity of CpG‐ODN aerosol in mouse lung metastases

Sfondrini

Sommariva

Tortoreto

et al. 2013

Intl Journal of Cancer

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“…Synthetic oligodeoxynucleotides (ODN) expressing CpG motifs mimic the immunostimulatory activity of bacterial DNA and are commonly used to activate TLR9 for therapeutic applications (3). CpG-ODN has shown antitumor activity in different animal models (7,8) and in patients with malignant melanoma, renal carcinoma, and recurrent or refractory lymphoma (9)(10)(11)(12); however, experimental studies suggest that CpG-ODN may be more useful as a component of multiagent therapy for cancer rather than as a single agent (13). Because chemotherapy is known to be immunosuppressive, it may seem counterintuitive to combine it with TLR9 stimulation.…”

Section: Introductionmentioning

confidence: 99%

TLR9 Agonists Oppositely Modulate DNA Repair Genes in Tumor versus Immune Cells and Enhance Chemotherapy Effects

et al. 2011

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Synthetic oligodeoxynucleotides expressing CpG motifs (CpG-ODN) are a Toll-like receptor 9 (TLR9) agonist that can enhance the antitumor activity of DNA-damaging chemotherapy and radiation therapy in preclinical mouse models. We hypothesized that the success of these combinations is related to the ability of CpG-ODN to modulate genes involved in DNA repair. We conducted an in silico analysis of genes implicated in DNA repair in data sets obtained from murine colon carcinoma cells in mice injected intratumorally with CpG-ODN and from splenocytes in mice treated intraperitoneally with CpG-ODN. CpG-ODN treatment caused downregulation of DNA repair genes in tumors. Microarray analyses of human IGROV-1 ovarian carcinoma xenografts in mice treated intraperitoneally with CpG-ODN confirmed in silico findings. When combined with the DNA-damaging drug cisplatin, CpG-ODN significantly increased the life span of mice compared with individual treatments. In contrast, CpG-ODN led to an upregulation of genes involved in DNA repair in immune cells. Cisplatin-treated patients with ovarian carcinoma as well as anthracycline-treated patients with breast cancer who are classified as "CpG-like" for the level of expression of CpG-ODN modulated DNA repair genes have a better outcome than patients classified as "CpG-untreated-like," indicating the relevance of these genes in the tumor cell response to DNA-damaging drugs. Taken together, the findings provide evidence that the tumor microenvironment can sensitize cancer cells to DNA-damaging chemotherapy, thereby expanding the benefits of CpG-ODN therapy beyond induction of a strong immune response. Cancer Res; 71(20); 6382-90. Ó2011 AACR.

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“…19 Intraperitoneal administration was selected because this route has been demonstrated to be an effective and well tolerated systemic route as compared with intravenous administration to treat neuroblastoma. [23][24][25][26] Tumor volume was calculated as height × weight × length. Body weight was measured every other day until 21 days.…”

Section: In Vivo Neuroblastoma Modelmentioning

confidence: 99%

Enhancement of anticancer efficacy using modified lipophilic nanoparticle drug encapsulation

Wong¹,

Lee²,

Zhang³

et al. 2012

IJN

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Background: Development of anticancer drugs is challenging. Indeed, much research effort has been spent in the development of new drugs to improve clinical outcomes with minimal toxicity. We have previously reported that a formulation of lipid gold porphyrin nanoparticles reduced systemic drug toxicity when compared with free gold porphyrin. In this study, we investigated the delivery and treatment efficiency of PEG surface-modified lipid nanoparticles as a carrier platform. Methods: We encapsulated antitumor drugs into PEG-modified lipid nanoparticles and these were characterized by size, zeta potential, and encapsulation efficiency. The delivery efficiency into tumor tissue was evaluated using a biodistribution study. To evaluate antitumor efficacy, gold porphyrin or camptothecin (a DNA topoisomerase I inhibitor) were encapsulated and compared using an in vivo neuroblastoma (N2A) model. Results: We showed that drug encapsulation into PEG-modified lipid nanoparticles enhanced the preferential uptake in tumor tissue. Furthermore, higher tumor killing efficiency was observed in response to treatment with PEG-modified lipid nanoparticles encapsulating gold porphyrin or camptothecin when compared with free gold porphyrin or free camptothecin. The in vivo antitumor effect was further confirmed by study of tumor inhibition and positive apoptosis activity. Surface modification of lipophilic nanoparticles with PEG increased the efficiency of drug delivery into tumor tissue and subsequently more effective antitumor activity. Conclusion: This specific design of a chemotherapeutic agent using nanotechnology is important in the development of a safe and effective drug in cancer therapy.

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Eradication of Ovarian Tumor Xenografts by Locoregional Administration of Targeted Immunotherapy

Cited by 22 publications

References 39 publications

Anti‐tumor activity of CpG‐ODN aerosol in mouse lung metastases

Anti‐tumor activity of CpG‐ODN aerosol in mouse lung metastases

TLR9 Agonists Oppositely Modulate DNA Repair Genes in Tumor versus Immune Cells and Enhance Chemotherapy Effects

Enhancement of anticancer efficacy using modified lipophilic nanoparticle drug encapsulation

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