Song Guang-Yun, Gibson Glen, Haq Wahajul, Huang Eric C C, Srivasta Tumul, Hollstein Monica, Daftarian Pirouz, Wang Zhongde, Diamond Don, Ellenhorn Joshua D I
Department of General and Oncologic Surgery, City of Hope National Medical Center, Duarte, CA, USA.
Cancer Immunol Immunother. 2007 Aug;56(8):1193-205. doi: 10.1007/s00262-006-0270-3. Epub 2007 Jan 12.
The cellular regulatory protein p53 is overexpressed by almost 50% of all malignancies making it an attractive target for a vaccine approach to cancer. A number of immunotherapy approaches targeting p53 have been evaluated successfully in murine models, but translation of these preclinical findings to the clinic has been unsuccessful. Prior studies in our laboratory employing murine models demonstrated that a modified vaccinia virus Ankara (MVA) vaccine expressing murine p53 could stimulate p53 specific immunity. Systemic administration of the MVA vaccine was able to effect the rejection of established tumors. To better understand the immunologic mechanisms that underlie the vaccine function of human p53, we utilized a murine model in which the murine germ line copy of p53 was replaced with a modified human one. These mice, referred to as Hupki, were evaluated as a tolerant model to explore the capacity of MVA expressing human p53 to overcome tolerance and reject human p53-expressing tumors.
MVAp53 immunization of Hupki mice resulted in the generation of p53-specific CD8(+) T cells and the rejection of a highly aggressive murine mammary carcinoma cell line 4T1(H-2d) transfected with human p53 (4T1p53). An immunologic correlate of tumor protection was evaluated utilizing an overlapping peptide library spanning the full length of human p53. This reagent was also used in combination with MVAp53 to stimulate p53-specific CD8(+) T cell responses in cancer patients.
These studies demonstrate the potential of MVAp53 to overcome tolerance to p53 for cancer immunotherapy.
细胞调节蛋白p53在几乎50%的所有恶性肿瘤中过度表达，这使其成为癌症疫苗治疗方法的一个有吸引力的靶点。许多针对p53的免疫治疗方法已在小鼠模型中成功评估，但这些临床前研究结果向临床的转化却未成功。我们实验室先前使用小鼠模型的研究表明，表达小鼠p53的改良安卡拉痘苗病毒（MVA）疫苗可刺激p53特异性免疫。MVA疫苗的全身给药能够影响已建立肿瘤的排斥反应。为了更好地理解人类p53疫苗功能背后的免疫机制，我们利用了一种小鼠模型，其中小鼠p53的种系拷贝被一种改良的人类p53所取代。这些小鼠被称为Hupki，被评估为一种耐受模型，以探索表达人类p53的MVA克服耐受并排斥表达人类p53肿瘤的能力。
用MVAp53免疫Hupki小鼠导致产生p53特异性CD8(+) T细胞，并排斥转染了人类p53的高侵袭性小鼠乳腺癌细胞系4T1(H-2d)（4T1p53）。利用跨越人类p53全长的重叠肽库评估了肿瘤保护的免疫相关性。该试剂还与MVAp53联合使用，以刺激癌症患者的p53特异性CD8(+) T细胞反应。
这些研究证明了MVAp53在癌症免疫治疗中克服对p53耐受的潜力。
