15 research outputs found

    Development of effective tumor immunotherapy using a novel dendritic cell–targeting Toll-like receptor ligand

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    <div><p>Although dendritic cell (DC)-based immunotherapy shows little toxicity, improvements should be necessary to obtain satisfactory clinical outcome. Using interferon-gamma injection along with DCs, we previously obtained significant clinical responses against small or early stage malignant tumors in dogs. However, improvement was necessary to be effective to largely developed or metastatic tumors. To obtain effective methods applicable to those tumors, we herein used a DC-targeting Toll-like receptor ligand, h11c, and examined the therapeutic effects in murine subcutaneous and visceral tumor models and also in the clinical treatment of canine cancers. In murine experiments, most and significant inhibition of tumor growth and extended survival was observed in the group treated with the combination of h11c-activated DCs in combination with interferon-gamma and a cyclooxygenase2 inhibitor. Both monocytic and granulocytic myeloid-derived suppressor cells were significantly reduced by the combined treatment. Following the successful results in mice, the combined treatment was examined against canine cancers, which spontaneously generated like as those in human. The combined treatment elicited significant clinical responses against a nonepithelial malignant tumor and a malignant fibrous histiocytoma. The treatment was also successful against a bone-metastasis of squamous cell carcinoma. In the successful cases, the marked increase of tumor-responding T cells and decrease of myeloid-derived suppressor cells and regulatory T cells was observed in their peripheral blood. Although the combined treatment permitted the growth of lung cancer of renal carcinoma-metastasis, the marked elevated and long-term maintaining of the tumor-responding T cells was observed in the patient dog. Overall, the combined treatment gave rise to emphatic amelioration in DC-based cancer therapy.</p></div

    Therapeutic and analytic results for case no. 1.

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    <p>(A) Tumor appearance before and after the 20th treatment (day 176). (B) Volume of the tumor after the start of treatment. The points indicated with arrows are when the analyses of the PB cells were performed. (C) Responses of T cells against tumor antigens. T cells were collected from PB on the days indicated by arrows in Fig 13B. The responses against own tumor lysate are shown in (a), and those against the lysate of an unrelated tumor are shown in (b). The protein concentration of the lysate in culture was 50 μg/ml. (D) Percentage of Treg and MDSC in the PB at the points indicated.</p

    The therapeutic and analytic results of case no. 3.

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    <p>(A) The X-ray image of radial bone before (day 0) and after the 10th treatment (day76). (B) Responses of T cells collected from the PB at the points indicated. (a) and (b), same as <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0188738#pone.0188738.g013" target="_blank">Fig 13C</a>. (C) Percent of Treg and MDSC in the PB at the points indicated.</p

    Therapeutic and analytic results for case no. 4.

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    <p>(A) Tumor appearance before and after the 8th treatment (day 56). (B) Responses of T cells collected from the PB at the points indicated. (a) and (b), same as <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0188738#pone.0188738.g013" target="_blank">Fig 13C</a>. (C) Percent of Treg and MDSC in the PB at the points indicated.</p

    Effect of the treatments on the infiltration of macrophage/DC in the tumor tissue.

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    <p>The treatments indicated were performed against CT26WT cells growing in the lung of BALB/c mice. Treatments were performed 3 times with a 7 day interval. Lungs were collected on the next day of third treatment. The infiltration of the Iba 1<sup>+</sup> macrophages/DCs in the tumor tissue was evaluated by IHC. (A) Representative photo data of the lung tumor of the mice with the indicated treatments are shown. (B) The numbers of the Iba 1<sup>+</sup> cells per 1000 cells in the lung tumor of the mice with the indicated treatments are shown. Experiments were performed using 3 mice in each group. Results are expressed as mean ± SEM. * *<i>p</i> <0.01, *<i>p</i> <0.05.</p
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