Vaccine Clinical Trials

一项临床研究已经完成，以评估含有多种肿瘤抗原和共刺激分子的疫苗在转移性癌患者中的安全性和临床结果。痘病毒载体具有被证实的安全记录，可用于合并多种转基因。先前的痘病毒疫苗临床试验表明，对自身抗原的免疫耐受可以被打破。癌胚抗原（CEA）和MUC-1在相当比例的常见实体癌中过表达。这项研究的主要终点是评估安全性，免疫和临床反应是这种新型疫苗方案的次要终点。25例患者接受痘病毒疫苗方案治疗，该方案包括CEA和MUC-1基因，以及三组共刺激分子（TRICOM，由B7.1、ICAM-1和LFA-3组成），这些共刺激分子被改造成牛痘（PANVAC-V）作为原疫苗，而鸡痘（PANVAC-F）作为加强疫苗。这种疫苗耐受性良好。除了注射部位的反应外，在超过2%的循环中未见II级或更大的毒性。8例患者中有3例发生了cd8介导的cea特异性免疫应答，9例患者中有6例发生了cd4介导的cea特异性免疫应答。一名透明细胞卵巢癌合并症状性腹水的患者在放射学和生化方面有持久的临床反应（18个月），一名乳腺癌患者证实大肝转移灶的大小减少了20%。这种疫苗策略似乎是安全的，与CD8和CD4免疫反应相关，并已显示出临床活性的证据。这种新型疫苗的进一步试验，无论是单独使用还是与免疫增强剂和其他治疗剂联合使用，都有必要用于一系列人类癌症。其他研究成果在以下出版物中有描述：Aragon-Ching B， Williams K, Gulley J.雄激素剥夺治疗对免疫系统的影响：前列腺癌联合治疗的意义。生物科学进展，2009,31(4):559 - 567。[J]张建军，张建军，张建军，等。小儿麻痹性脑脊髓炎疫苗治疗效果的研究进展。疫苗。2007。在出版社。[J]张建军，张建军，张建军，等。肿瘤疫苗的研究进展。中国。巨蟹座学报，2007。[J]张建军，李建军，李建军，李建军，李建军，李建军，李建军，李建军，李建军，李建军，李建军，李建军，李建军，李建军，李建军，李建军，李建军，李建军，李建军，李建军。[J] .北京。2007。在出版社。[J]张建军，张建军，张建军，等。前列腺特异性抗原疫苗在前列腺癌患者中的临床应用。泌尿生殖系统癌症杂志。5:347- 50,2007。[j]吴淑娟，王晓华，王晓华，等。双膦酸盐在肿瘤治疗中的应用。肿瘤学报，581- 91,2007。[J]张丽娟，张丽娟，张丽娟，等。低剂量酮康唑治疗非转移性雄激素非依赖型前列腺癌（AIPC）的临床意义及临床意义。中华医学杂志。14(3):331 - 331,2007。[J]刘建军，刘建军，刘建军，刘建军，刘建军。鉴定细胞毒性t淋巴细胞表位(s)及其激动剂表位(s)的新靶标疫苗治疗（PAGE4）。Int。[j] .中国医学杂志，2007,31(2):595- 595。[j]李建平，李建平。肿瘤免疫治疗的未来方向：CTLA4阻断。自然临床实践。中国生物医学工程杂志，2007,31(4):391 - 397。[J] O'Mahony D, Morris JC, Quinn C, Gao W, Wilson WH, Gause B, Pittaluga S, Neelapu S, Brown M, Fleisher TA, Gulley JL, Schlom J, Nussenblatt R, Albert P, Davis TA, Lowy I, Petrus M, Waldmann TA, Janik JE。晚期恶性肿瘤患者肿瘤疫苗失败后CTLA-4阻断的初步研究中国。癌症杂志，13:958- 664,2007。[j]吴绍林，张志强，李建军，陈春林，陈文辉。对于雄激素不依赖型前列腺癌和仅骨转移的患者，常规间歇计算机断层扫描检测新的软组织疾病可能是不必要的。中国生物医学工程学报，2009,31(2):526 - 531。[j]李建平，李建平，李建平。PANVAC-VF：针对癌中CEA和MUC1的痘病毒疫苗治疗。生物疗法的专家意见。7: 543- 54,2007。[j]李建军，张建军，李建军，等。多西他赛单独或联合PANVAC-V（牛痘）和PANVAC-F（鸡痘）治疗转移性乳腺癌（NCI 05-C-0229）的随机II期研究。中国。中华医学杂志，2006,31(2):379 - 379。[j]李建军，李建军，李建军，等。基于癌胚抗原/ tricom的疫苗和辐射治疗癌胚抗原阳性实体瘤患者肝转移的试点试验临床结直肠癌。[6]: 72-5, 2006。[j]张建军，张建军，张建军。前列腺癌治疗性疫苗。肿瘤学杂志。11:451-62,2006。[j]李建平，李建平，李建平。用于治疗前列腺癌的基于psa的疫苗。疫苗专家审查。[5] [j], 2006。[j]李建平，李建平。前列腺癌的免疫治疗：未来如何？内科杂志。肿瘤防治杂志。中国。中国地质大学学报（自然科学版），2006。[J]张建军，张建军，张建军，张建军，张建军，张建军，张建军，张建军，张建军，张建军，等。电离辐射暴露患者血清蛋白质组学研究进展。巨蟹座，66:1844- 50,2006。[J]李建平，李建平，李建平，等。中华医学杂志，25(2),2006。[j]张建军，张建军，李建军，等。前列腺内前列腺特异性抗原疫苗在前列腺癌放射治疗后局部失败或在缺乏局部决定性治疗的情况下雄激素剥夺治疗的临床进展患者中的I期可行性研究临床泌尿生殖系统癌。5: 89-92, 2006。[J]张建军，李建军，李建军，等。早期治疗有好处[字母]。j .中国。杂志24:5172-3；作者回复5173,2006。[J]张晓东，李晓东，李晓东，李晓东，杨晓东，杨晓东，杨晓东，杨晓东，杨晓东，杨晓东，杨晓东。多西紫杉醇联合疫苗治疗雄激素非依赖性前列腺癌的临床研究。中国。巨蟹座，12:1260-9,2006。[J]郭志强，郭志强，郭志强，郭志强，郭志强，郭志强，郭志强。基于TRICOM载体的癌症疫苗。咕咕叫。制药。中国生物医学工程学报，2006,12:351-61。[J] Dahut WL, Lakhani NJ, Gulley JL, Arlen PM, Kohn EC, Kotz H, McNally D, Parr A, Nguyen D, Yang sxy, Steinberg SM, Venitz J, Sparreboom A, fig WD。口服2-甲氧基雌二醇（一种抗血管生成和细胞凋亡的药物）在实体瘤患者中的I期临床试验。癌症医学杂志。[j] . 2006: 22-7。[j]何志强，郭志强，郭志强，郭志强，郭志强，郭志强，郭志强，郭志强，郭志强，张志强，等。免疫辅助佐剂的研究进展。前面。生物工程学报，2006,31(2):589 - 593。(杂志

A clinical study has been completed to evaluate safety and clinical outcomes of a vaccine containing multiple tumor antigens and costimulatory molecules in patients with metastatic carcinoma. Poxviral vectors have a proven safety record and can be used to incorporate multiple transgenes. Prior clinical trials with poxviral vaccines have shown that immunologic tolerance to self-antigens can be broken. Carcinoembryonic antigen (CEA) and MUC-1 are overexpressed in a substantial proportion of common solid carcinomas. The primary endpoint of this study was to evaluate safety, with immunologic and clinical responses as secondary endpoints of this novel vaccine regimen. Twenty-five patients were treated with a poxviral vaccine regimen consisting of the genes for CEA and MUC-1, along with a triad of costimulatory molecules (TRICOM, composed of B7.1, ICAM-1, and LFA-3) engineered into vaccinia (PANVAC-V) as a prime and fowlpox (PANVAC-F) as booster vaccinations. The vaccine was well-tolerated. Apart from injection-site reaction, no grade II or greater toxicity was seen in more than 2% of the cycles. Three of 8 patients tested developed a CD8-mediated CEA-specific immune response, and 6 of 9 patients developed a CD4-mediated CEA-specific immune response. A patient with clear cell ovarian cancer and symptomatic ascites had a durable (18-month) clinical response radiographically and biochemically, and one breast cancer patient had a confirmed decrease of > 20% in the size of large liver metastasis. This vaccine strategy appears to be safe, is associated with both CD8 and CD4 immune responses, and has shown evidence of clinical activity. Further trials with this novel vaccine, either alone or in combination with immunopotentiating and other therapeutic agents, are warranted for a range of human carcinomas. Other accomplishments are described in the following publications: Aragon-Ching B, Williams K, Gulley J. Impact of androgen-deprivation therapy on the immune system: implications for combination therapy of prostate cancer. Front Biosci. 4957-71, 2007. [Journal] Gulley J, Madan R, Arlen P. Enhancing efficacy of therapeutic vaccinations by combination with other modalities. Vaccine. 2007. In Press. [Journal] Schlom J, Arlen P, Gulley J. Cancer vaccines: moving beyond current paradigms. Clin. Cancer Res. 3776-82, 2007. [Journal] Arlen P, Skarupa L, Pazdur M, Seetharam M, Tsang K, Grosenbach D, Feldman J, Poole D, Litzinger M, Steinberg S, Jones E, Chen C, Marte J, Parnes H, Wright J, Dahut W, Schlom J, Gulley J. Clinical safety of a viral vector-based prostate cancer vaccine strategy. J Urol. 2007. In Press. [Journal] Theoret M, Arlen P, Pazdur M, Dahut W, Schlom J, Gulley J. Phase I trial of an enhanced prostate-specific antigen-based vaccine with anti-CTLA-4 antibody in patients with metastatic androgen-independent prostate cancer. Clin Genitourinary Cancer. 5: 347-50, 2007. [Journal] Wu S, Dahut W, Gulley J. The use of bisphosphonates in cancer patients. Acta Oncologica. 581-91, 2007. [Journal] Madan R, Lieberman R, Gulley J, Dahut W, Arlen P. A significant PSA response to low dose ketoconazole in a patient with non-metastatic androgen independent prostate cancer (AIPC) and a review of the literature. Amer J Therapeutics. 14: 310-3, 2007. [Journal] Yokokawa J, Bera TK, Palena C, Cereda V, Remondo C, Gulley JL, Arlen PM, Pastan I, Schlom J, Tsang KY. Identification of cytotoxic T-lymphocyte epitope(s) and its agonist epitope(s) of a novel target for vaccine therapy (PAGE4). Int. J. Cancer. 121: 595-605, 2007. [Journal] Gulley JL, Dahut WL. Future directions in tumor immunotherapy: CTLA4 blockade. Nature clinical practice. Oncology. 4: 136-7, 2007. [Journal] O'Mahony D, Morris JC, Quinn C, Gao W, Wilson WH, Gause B, Pittaluga S, Neelapu S, Brown M, Fleisher TA, Gulley JL, Schlom J, Nussenblatt R, Albert P, Davis TA, Lowy I, Petrus M, Waldmann TA, Janik JE. A pilot study of CTLA-4 blockade after cancer vaccine failure in patients with advanced malignancy. Clin. Cancer Res. 13: 958-64, 2007. [Journal] Wu SL, Jones E, Gulley JL, Arlen PM, Chen CC, Figg WD, Dahut WL. Routine interval computed tomography to detect new soft-tissue disease might be unnecessary in patients with androgen-independent prostate cancer and metastasis only to bone. BJU Int. 99: 525-8, 2007. [Journal] Madan RA, Arlen PM, Gulley JL. PANVAC-VF: poxviral-based vaccine therapy targeting CEA and MUC1 in carcinoma. Expert opinion on biological therapy. 7: 543-54, 2007. [Journal] Arlen PM, Pazdur M, Skarupa L, Rauckhorst M, Gulley JL. A randomized phase II study of docetaxel alone or in combination with PANVAC-V (vaccinia) and PANVAC-F (fowlpox) in patients with metastatic breast cancer (NCI 05-C-0229). Clin. Breast Cancer. 7: 176-9, 2006. [Journal] Ahlers CM, Camphausen K, Citrin D, Arlen PM, Gulley JL. A pilot trial of a carcinoembryonic antigen/ TRICOM-based vaccine and radiation to liver metastases in patients with carcinoembryonic antigen-positive solid tumors. Clinical colorectal cancer. 6: 72-5, 2006. [Journal] Tarassoff CP, Arlen PM, Gulley JL. Therapeutic vaccines for prostate cancer. Oncologist. 11: 451-62, 2006. [Journal] Madan RA, Gulley JL, Arlen PM. PSA-based vaccines for the treatment of prostate cancer. Expert review of vaccines. 5: 199-209, 2006. [Journal] Arlen PM, Dahut WL, Gulley JL. Immunotherapy for prostate cancer: what's the future?. Hematol. Oncol. Clin. North Am. 20: 965-83, xi, 2006. [Journal] Menard C, Johann D, Lowenthal M, Muanza T, Sproull M, Ross S, Gulley J, Petricoin E, Coleman C, Whiteley G, Liotta L, Camphausen K. Discovering clinical biomarkers of ionizing radiation exposure with serum proteomic analysis. Cancer Res. 66: 1844-50, 2006. [Journal] Gulley J, Figg W, Dahut W. Even more cost savings?. J Oncol Pract. 25: 202, 2006. [Journal] Lattouf JB, Arlen PM, Pinto PA, Gulley JL. A phase I feasibility study of an intraprostatic prostate-specific antigen-based vaccine in patients with prostate cancer with local failure after radiation therapy or clinical progression on androgen-deprivation therapy in the absence of local definitive therapy. Clinical genitourinary cancer. 5: 89-92, 2006. [Journal] Gulley JL, Parnes HL, Wright J, Dahut WL. Early treatment gets the benefit [letter]. J. Clin. Oncol. 24: 5172-3; author reply 5173, 2006. [Journal] Arlen PM, Gulley JL, Parker C, Skarupa L, Pazdur M, Panicali D, Beetham P, Tsang KY, Grosenbach DW, Feldman J, Steinberg SM, Jones E, Chen C, Marte J, Schlom J, Dahut W. A randomized phase II study of concurrent docetaxel plus vaccine versus vaccine alone in metastatic androgen-independent prostate cancer. Clin. Cancer Res. 12: 1260-9, 2006. [Journal] Garnett CT, Greiner JW, Tsang KY, Kudo-Saito C, Grosenbach DW, Chakraborty M, Gulley JL, Arlen PM, Schlom J, Hodge JW. TRICOM vector based cancer vaccines. Curr. Pharm. Des. 12: 351-61, 2006. [Journal] Dahut WL, Lakhani NJ, Gulley JL, Arlen PM, Kohn EC, Kotz H, McNally D, Parr A, Nguyen D, Yang SX, Steinberg SM, Venitz J, Sparreboom A, Figg WD. Phase I clinical trial of oral 2-methoxyestradiol, an antiangiogenic and apoptotic agent, in patients with solid tumors. Cancer Biol. Ther. 5: 22-7, 2006. [Journal] Hodge JW, Greiner JW, Tsang KY, Sabzevari H, Kudo-Saito C, Grosenbach DW, Gulley JL, Arlen PM, Marshall JL, Panicali D, Schlom J. Costimulatory molecules as adjuvants for immunotherapy. Front. Biosci. 11: 788-803, 2006. [Journal