異體骨髓來源樹突狀細胞與犬隻腫瘤細胞融合癌症疫苗在臨床應用上的評估

樹突狀細胞/腫瘤細胞融合型癌症疫苗是一種新型且具有腫瘤專一性的免疫療法。然而在臨床治療上由於樹突狀細胞的生產不易，常導致治療上的限制。在本篇研究中，我們成功的使用體外培養的方式誘導骨髓單核球細胞分化成樹突狀細胞，其生產量較周邊血液來源的生產方式達20倍之多。我們首先利用異體骨髓來源之樹突狀細胞與腫瘤細胞(犬傳染性花柳性腫瘤，CTVT)融合，進而製備癌症疫苗。在臨床評估上，我們將此疫苗施打在帶有CTVT腫瘤(長至兩公分直徑大小時)的實驗犬隻，施打部位為近局部淋巴結的皮下。此疫苗重複施打三次、每次間隔兩星期，以評估疫苗的治療效果。施打兩次後即發現此疫苗已具有抑制腫瘤的生長的能力，三次後腫瘤的生長則受到嚴重的抑制。此外，此疫苗成功的引起抗腫瘤的免疫相關反應(包括增加腫瘤內浸潤的淋巴球、腫瘤專一性毒殺型T細胞的活化、以及增加腫瘤的組織相容性複合物分子的表現)。進一步發現自然殺手型細胞的免疫反應也在治療後被加強。由於在CTVT的實驗模式中得到良好的效果，我們將此疫苗之原理應用在犬隻口腔惡性黑色素瘤病畜的臨床治療實驗上。此治療乃結合外科手術切除與癌症疫苗的施打。超過半數的病例成功的引起抗腫瘤的相關免疫反應，且相較於只接受手術治療的病畜而言，具有延長其存活率的作用。綜合上述，本研究研發出一個有效生產異體骨髓來源之樹突狀細胞，且經過與腫瘤細胞融合制成癌症疫苗後，成功的引起宿主的免疫反應並抑制腫瘤的生長或延長其存活率。因此本融合型疫苗在癌症治療上有其潛力。

關鍵字

骨髓來源樹突狀細胞；犬傳染性花柳病；黑色素瘤；融合型疫苗

並列摘要

Dendritic cell (DC)/cancer cell hybrid vaccine has been emphasized as a new and cancer cell-specific therapeutics. However, the relatively low yield efficiency of the DC generation from peripheral blood limits its clinical application. In this study, we have generated over 20 times more DC from bone marrow (BMDC)/mononuclear leucocytes than the peripheral blood source. The allogeneic BMDC were fused with canine transmissible venereal tumor (CTVT) cells to produce the hybrid vaccine, which was injected subcutaneously (SQ) three times with a two-weeks interval near the draining lymph nodes into beagles with CTVTs of 2 cm in diameter. The CTVT-fusion hybrid vaccination program inhibited the tumor growth as early as at the second vaccination. It significantly increased the host immune responses including the increased lymphocytic infiltrations, CTL responses, and MHC I/II expressions on the tumor. It was interesting to find that the NK activity was also enhanced. We then generated the fusion hybrids of allogeneic BMDC/canine oral malignant melanomas from individual canine patients. The melanoma fusion hybrids were given SQ to the original canine patients but after a surgical removal of the melanoma. After the vaccinations, more than half of the cases have shown increased specific immune responses and the survival time were significantly prolonged in comparing to the dogs with the surgery removal only. To conclude, the canine allogeneic BMDC provided us an efficient way to generate the fusion hybrid vaccines that augmented the host immune responses and demonstrated its clinical potentials in treating cancers.

並列關鍵字

BMDC ； CTVT ； Melanoma ； Hybrid vaccines

參考文獻

[1] Steinman RM, Cohn ZA. Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution. J Exp Med 1973 May 1;137(5):1142-62.

[2] Wu L, Liu YJ. Development of dendritic-cell lineages. Immunity 2007 Jun;26(6):741-50.

[3] Benko S, Magyarics Z, Szabo A, Rajnavolgyi E. Dendritic cell subtypes as primary targets of vaccines: the emerging role and cross-talk of pattern recognition receptors. Biol Chem 2008 May;389(5):469-85.

[4] Valladeau J, Saeland S. Cutaneous dendritic cells. Semin Immunol 2005 Aug;17(4):273-83.

[5] von Bubnoff D, Bausinger H, Matz H, Koch S, Hacker G, Takikawa O, et al. Human epidermal langerhans cells express the immunoregulatory enzyme indoleamine 2,3-dioxygenase. J Invest Dermatol 2004 Aug;123(2):298-304.

國際替代計量

異體骨髓來源樹突狀細胞與犬隻腫瘤細胞融合癌症疫苗在臨床應用上的評估

全文下載

主題瀏覽