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

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.

尽管基于树突状细胞（dendritic cell, DC）的免疫疗法几乎无毒性，但为获得满意的临床疗效，仍需进一步优化改进。此前我们联合干扰素-γ（interferon-gamma）与DC疗法，在犬类小型或早期恶性肿瘤的治疗中取得了显著临床应答。但该方案对进展期或转移性肿瘤的疗效仍有待提升。
为开发适用于此类肿瘤的有效疗法，本研究采用靶向树突状细胞的Toll样受体配体（Toll-like receptor ligand）h11c，并在小鼠皮下与内脏肿瘤模型、犬类癌症的临床治疗中考察其治疗效果。小鼠实验结果显示，联合h11c活化的DC、干扰素-γ与一种环氧合酶2（cyclooxygenase2）抑制剂的治疗组，可对肿瘤生长产生极为显著的抑制作用并延长小鼠生存期。联合疗法还可显著减少单核细胞系与粒细胞系两种髓系来源抑制细胞（myeloid-derived suppressor cells）的数量。
基于小鼠实验的阳性结果，我们针对自发产生且与人类癌症特征相似的犬类癌症开展了联合疗法的临床研究。该联合疗法对非上皮源性恶性肿瘤及恶性纤维组织细胞瘤均诱导产生了显著临床应答，同时也成功治疗了1例鳞状细胞癌（squamous cell carcinoma）骨转移病例。在治疗有效的病例中，患犬外周血中肿瘤反应性T细胞显著增多，而髓系来源抑制细胞与调节性T细胞（regulatory T cells）水平明显下降。
尽管该联合疗法未能抑制肾癌转移性肺癌的生长，但患犬体内肿瘤反应性T细胞仍出现了显著升高且可长期维持。总体而言，该联合疗法显著改善了基于树突状细胞的癌症治疗效果。