Vaccine Clinical Trials

主要的科学成就包括：(A)使用含有共刺激分子和TAA转基因的载体混合物完成了第一批临床试验。对不同阶段前列腺癌患者的三项临床研究表明，疫苗(RV-PSA+RV-B7.1，然后是RF-PSA)可以安全地与肿瘤外照射、二线激素治疗和泰索帝一起使用，并提供了疫苗接种后延长疾病进展时间和抗原级联的初步证据。(B)在转移性前列腺癌患者中使用RV-、RF-PSA-Tricom疫苗完成了第一批临床试验。这些研究提供了与产生PSA特异性T细胞反应相关的临床益处的证据。这些试验导致了计划中的NCI赞助的D0和D0.5患者的随机多中心II期和III期试验。(C)使用含有三个共刺激分子(RV-、RF-CEA-Tricom)转基因疫苗的第一阶段I/II合作临床试验完成。这项试验证明了包括GM-CSF在内的多样化的基础和加强疫苗接种方案的优势。初步证据显示CEA特异性T细胞反应与存活率相关；这项试验也提供了需要继续加强疫苗以维持疾病稳定的证据。(D)使用轮状病毒、RF-PANVAC(CEA-MUC-1-Tricom)疫苗和GM-CSF完成了第一个NCI临床试验。这项试验提供了临床活动的证据，导致了NCI和其他癌症中心随后的临床试验。基于A1-A3项目中描述的有希望的假设驱动的临床前结果，已经启动了涉及(E)S.C./肿瘤内疫苗接种的基于科学的试验，使用I.T.治疗局部晚期前列腺癌。Rf-PSA-Tricom联合RF-GM-CSF疫苗接种，(F)CEA-Tricom疫苗联合外照射治疗结肠癌转移灶，(G)转移性前列腺癌患者应用疫苗+抗CTLA-4单抗，(H)前列腺癌患者使用姑息性153Sm-螯合物(改变骨转移表型)加PSA-Tricom疫苗接种(综述)。(I)建立协作临床试验网络，为癌症疫苗临床试验开发提供基于科学的方案方法。

Major scientific achievements include: (a) The completion of the first clinical trials employing an admixture of vectors containing transgenes for a costimulatory molecule and a TAA. Three clinical studies in patients with different stages of prostate cancer demonstrated that vaccine (rV-PSA + rV-B7.1 followed by rF-PSA) could be safely employed with external beam irradiation of tumor, second line hormone therapy, and Taxotere, and provided preliminary evidence of prolongation of time to disease progression, and antigen cascade post-vaccination. (b) The completion of the first clinical trials with rV-, rF-PSA-TRICOM vaccines in patients with metastatic prostate cancer. These studies provided evidence of clinical benefit that correlated with the generation of PSA-specific T-cell responses. These trials have led to planned NCI-sponsored randomized multicenter Phase II and III trials in D0 and D0.5 patients. (c) Completion of the first Phase I/II collaborative clinical trial employing vaccines containing transgenes for three costimulatory molecules (rV-, rF-CEA-TRICOM). This trial demonstrated the advantage of a diversified prime and boost vaccination schema with the inclusion of GM-CSF. Preliminary evidence was seen correlating CEA-specific T-cell responses and survival; this trial also provided evidence for the need for continued boosting with vaccine to maintain disease stabilization. (d) Completion of the first NCI clinical trial employing rV-, rF-PANVAC (CEA-MUC-1-TRICOM) vaccines plus GM-CSF. This trial provided evidence of clinical activity that has led to subsequent clinical trials at NCI and other Cancer Centers. Based on promising hypothesis-driven preclinical results, described in Projects A1-A3, science-based trials have been initiated involving (e) s.c./intratumoral vaccination, in locally advanced prostate cancer, employing i.t. vaccination of rF-PSA-TRICOM plus rF-GM-CSF, (f) CEA-TRICOM vaccination plus external beam irradiation of colon cancer metastatic lesions, (g) vaccine plus anti-CTLA-4 MAb in patients with metastatic prostate cancer, (h) the use of palliative 153Sm-chelate (to alter the phenotype of bone metastases) plus PSA-TRICOM vaccination in prostate cancer patients with bone metastases (in review). (i) The establishment of a network of collaborative clinical trials to provide a scientific-based programmatic approach to cancer vaccine clinical trial development.