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Systemic administration of platelets incorporating inactivated Sendai virus eradicates melanoma in mice.

ABSTRACT: Tumor microenvironments include a number of fibrin clots due to the microbleeding caused by cancer cell invasion into blood vessels, which suggests the potential utility of a platelet vector for systemic cancer treatment. We previously reported that inactivated Sendai virus (hemagglutinating virus of Japan; HVJ) envelope (HVJ-E) activates anti-tumor immunity and induces cancer cell-selective apoptosis. The hemagglutination activity that blocks the systemic administration of HVJ-E was dramatically attenuated by incorporation into platelets. Platelets incorporating HVJ-E (PH complex) were then injected into the tail veins of B16F10 melanoma-bearing mice. The PH complex primarily accumulated in tumor tissues and caused the significant accumulation of various immune cells in the tumor bed. Injections of the PH complex to the melanoma-bearing mouse significantly reduced the tumor size, and the tumor growth was ultimately arrested. Secretion of the chemokine regulated upon activation normal T-expressed and presumably secreted (RANTES) was upregulated following PH stimulation. The RANTES-depletion in melanoma-bearing mice significantly attenuated the cytotoxic T lymphocyte activity and led to a dramatic abrogation of the mouse melanoma suppression induced by the PH complex. Thus, a platelet vector incorporating viral particles, a Trojan horse for cancer treatment, will provide a new approach for cancer therapy using oncolytic viruses.

SUBMITTER: Nishikawa T

PROVIDER: S-EPMC4429689 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Systemic administration of platelets incorporating inactivated Sendai virus eradicates melanoma in mice.

Nishikawa Tomoyuki T Tung Li Yu LY Kaneda Yasufumi Y

Molecular therapy : the journal of the American Society of Gene Therapy 20140715 12

Tumor microenvironments include a number of fibrin clots due to the microbleeding caused by cancer cell invasion into blood vessels, which suggests the potential utility of a platelet vector for systemic cancer treatment. We previously reported that inactivated Sendai virus (hemagglutinating virus of Japan; HVJ) envelope (HVJ-E) activates anti-tumor immunity and induces cancer cell-selective apoptosis. The hemagglutination activity that blocks the systemic administration of HVJ-E was dramaticall ...[more]

PMID: 25023327

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Project description:Aim:The need for non-parenteral administration of inactivated avian influenza virus of H5N1 subtype (AIV-H5N1) vaccine is paramount. Here, we provide preliminary data on the immune response of chicken and mice after intranasal administration of AIV-H5N1-inactivated vaccine with ISCOMS, Inmunair (INM), and combined ISCOMS and INM as an adjuvant. Materials and Methods:The AIV isolate of A/Chicken/Denpasar/01/2004 (H5N1) was cultivated in specific pathogen-free chicken eggs and inactivated with formaldehyde. The vaccine preparation was added with those adjuvants for intranasal administration and aluminum hydroxide for subcutaneous injection. The chicken and mouse were vaccinated at the age of 3 weeks or 1 month and repeated 2 weeks thereafter. In one experiment, chicken was injected with Newcastle disease virus (NDV) at the same time with AIV vaccine. The sera were collected at one (serum 1) and 2 w (serum 2) after booster vaccination. The anti-AIV-H5 and NDV antibodies in chicken sera were detected using hemagglutination inhibition (HI) assay. Mouse IgG anti-AIV-H5N1 antibody was detected using ELISA. Results:The result shows that the geometric mean titers (GMTs) of chicken sera of intranasal vaccinated with inactivated AIV-H5N1 vaccine with mixed ISCOM- INM as adjuvant were <20.0 and 22.7 unit HI-unit (HIU) in serum 1 and serum 2, respectively. The GMTs of the positive control group were 23.7 and 25.7 HIU in serum 1 and serum 2, respectively. The result of the second experiment shows that IgG anti-AIV-H5N1 was detected in mouse sera. In the third experiment, the GMTs of anti-NDV in chicken vaccinated subsequently with inactivated NDV vaccine and AIV-H5N1 with mixed ISCOMS-INM administrated intranasally and aluminum hydroxide adjuvant administrated through subcutaneous injection as well as positive control group receiving NDV vaccine only were 28.0, 28.0, and 27.4 HIU in serum 1 while were 29.6, 29.2, and 28.2 HIU in serum 2, respectively. Conclusion:Intranasal administration of inactivated AIV-H5N1 vaccine-induced a systemic immune response in chicken and mice after adding ISCOMS and/or INM as adjuvants. The adjuvant and the intranasal administration caused no immunosuppressive effect on the chicken immune response to NDV vaccine.

Project description:BACKGROUND: Ultraviolet-inactivated, replication-defective Sendai virus particles (Z strain) have displayed antitumor effect through enhancing the immune responses or inducing apoptosis in a variety of carcinomas. Sendai virus strain Tianjin was isolated from the lungs of marmoset and proved to be a novel genotype of Sendai virus. In this study, we explored the antitumor effect and its mechanism of ultraviolet-inactivated, replication-defective Sendai virus strain Tianjin (UV-Tianjin) in mice bearing CT26 colon carcinoma. METHODS: Three injections of UV-Tianjin were delivered into CT26 tumors growing on the back of BALB/c mice. Tumor size was measured in a blinded manner and survival rate of mice was calculated. In order to make clear antitumor mechanism of UV-Tianjin, the maturation and interleukin-6 (IL-6) release from murine myeloid dendritic cells (DCs) was examined by flow cytometry or ELISA assay after induced by UV-Tianjin and compared with those of live virus. Moreover, real-time RT-PCR and immunohistochemistry was performed to identify whether UV-Tianjin could induce infiltration of DCs, CD4? and CD8? T cells into tumors. The TUNEL assay was done to observe the apoptosis of CT26 tumor cells after UV-Tianjin injection. RESULTS: In animal model, UV-Tianjin could obviously inhibit the growth of CT26 tumors and prolong the survival of the tumor-bearing mice compared with control group (P < 0.01). In vitro murine DCs stimulated by UV-Tianjin underwent dose-dependent maturation, similar to that elicited by live virus. And the secretion amount of IL-6 from DCs induced by UV-Tianjin was a little lower than that released in the presence of live virus. Real-time RT-PCR and immunohistochemistry revealed that UV-Tianjin induced a remarkable infiltration of DCs, CD4? and CD8? T cells into tumors. The TUNEL assay showed that the apoptosis index of tumor tissues injected with UV-Tianjin was significantly higher than that of control group (P < 0.01). CONCLUSIONS: Our results have demonstrated that UV-Tianjin alone could inhibit the growth of CT26 tumor in mice through enhancing host antitumor immunity and inducing apoptosis of tumor cells. Therefore, UV-Tianjin shows its prospect as a novel drug for carcinoma therapy.

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Systemic administration of platelets incorporating inactivated Sendai virus eradicates melanoma in mice.

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Systemic administration of platelets incorporating inactivated Sendai virus eradicates melanoma in mice.

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