Cancer Therapy Clinical Trials Using Novel Recombinant Vaccines

治疗前列腺癌的psa靶向痘病毒疫苗耐受良好。Prostvac （PSA-TRICOM）是CCR内开发的一种疫苗，在一项随机、对照、双盲、多中心II期研究中对125例患者进行了安全性、PFS延长和OS评估。符合条件的患者有最低症状的转移性去势抵抗性前列腺癌（mCRPC）。Prostvac由2个重组病毒载体组成，每个载体编码PSA转基因和3个免疫共刺激分子（B7.1、ICAM-1和LFA3: TRICOM）。以牛痘为基础的载体用于启动，随后计划进行6次以禽流感为基础的载体增强。患者被2:1分配到Prostvac + GM-CSF vs.对照组（空载体+生理盐水）。PROSTVAC组2例，对照组40例。患者特征相似。主要终点为PFS，两组相似（P = 0.6）。然而，在研究后3年，Prostvac患者有更好的OS，在分析时，25/82（30%）存活，对照组患者7/40（17%）存活。中位生存期延长8.5个月（疫苗组24.5个月，对照组16个月；估计风险比0.56 [95% CI 0.37-0.85]，分层对数秩P = 0.0061）。Prostvac免疫治疗耐受性良好，与mCRPC患者死亡率降低44%和中位生存期改善8.5个月相关。这些令人振奋的数据为临床有意义的益处提供了初步证据，但需要在更大的、正在进行的III期研究中得到证实。采用重组痘病毒疫苗的同时随机II期试验提供了免疫反应的证据。本研究采用相同疫苗接种mCRPC，探讨GM-CSF与疫苗的影响，以及免疫和预后因素对中位生存期的影响。接种疫苗的32例患者中，12例血清PSA下降；12例中有2例可评估的指数病变减少。中位OS为26.6个月，而nomogram预测OS为17.5个月。具有更高psa特异性t细胞反应的患者表现出提高生存率的趋势（P = 0.055）。接受GM-CSF治疗的患者与未接受GM-CSF治疗的患者在t细胞反应或生存率方面没有差异。nomogram预测生存率大于中位数的患者似乎从治疗中获益最多，这表明在疾病早期使用疫苗可能会显著改善预后。一项I期研究旨在确定前列腺内psa疫苗用于前列腺癌患者的安全性和可行性，这些患者在放疗或冷冻治疗后局部失败，或在缺乏局部决定性治疗的情况下接受雄激素剥夺治疗的临床进展。本研究显示接种疫苗后显著的肿瘤内浸润。这项研究的手稿最近发表了。最近，一项合作（GMB， UOB， LTIB）的新辅助研究开始了s.c.p sa - tricom在根治性前列腺切除术前的局限性前列腺癌患者中的应用。PSA-TRICOM在主动监测环境中的试验也正在与NCI癌症预防司合作进行审查。基于之前提到的随机II期研究，Prostvac在无症状或轻度症状mCRPC男性患者中的随机、双盲、III期疗效试验最近开始。这项研究将在大约22个国家招募约1200名前列腺癌患者。Gulley博士是这项国际研究的首席PI，预计将于2014年12月完成登记。美国国立卫生研究院临床中心的以下合作疫苗临床试验正在进行或最近完成。我们最近发表了一项开放标签研究，以评估Panvac联合GM-CSF在转移性腺癌（GMB和LTIB）患者中的安全性和耐受性。这包括一名乳腺癌患者，她最初有PR，然后是持久的CR，研究持续了6年多。我们最近还发表了一项首次人类开放标签I期研究，以评估在CCR中开发的一种疫苗（GI-6207）的安全性和耐受性，该疫苗由完整的、热灭活的重组酵母（酵母）组成，经过基因修饰以表达CEA蛋白，用于转移性表达CEA的成人癌。基于这项试验，最近开始了一项针对甲状腺髓样癌的II期试验。最近完成了一项针对酵母短囊菌（一种ccr开发的疫苗）的I期剂量递增研究。Brachyury的表达参与了耐药性和EMT，并具有其他类似干细胞的特性。该试验的最终结果最近在ASCO上公布，其中包括脊索瘤患者的PR。基于此，脊索瘤的II期试验正在计划中。我们最近发表了一项开放标签的先导研究，评估talactoferrin对成人非小细胞肺癌患者免疫系统的影响，以该药物的免疫应答为主要终点。一项针对结合IL-12的双链DNA （NHS）抗体的I期剂量递增研究正在进行中。该CCR联合开发的药物的IND由CCR持有。Gulley博士是实体瘤患者抗pdl1抗体的I期剂量递增研究的协调PI。该药物的首次人体国际研究由我们的CRADA合作伙伴EMD-Serono赞助，已经招募并治疗了450多名患者，其中80名自2013年1月以来在CCR接受治疗。已注意到戏剧性的长期反应，包括高比例的胸腺上皮恶性肿瘤患者（与TGIB合作）。所有剂量递增部分的患者都被纳入CCR；其他人则在CCR和其他中心加入扩展队列。与校外癌症中心的合作试验：一项PSA- tricom联合GM-CSF治疗前列腺癌局部治疗后PSA进展患者的II期研究（东部肿瘤合作组）：最近完成并提交了手稿。膀胱内重组fowlpox-GM-CSF和/或重组fowlpox-TRICOM用于计划膀胱切除术的膀胱癌患者的I期研究（新泽西癌症研究所，CINJ）：完成。肿瘤内Panvac联合GM-CSF治疗胰腺癌（CINJ）的I期研究：正在进行中。近期发表的一项II期研究：在大肠癌肝转移完全切除后，使用Panvac或感染Panvac的自体培养树突状细胞进行主动免疫治疗（杜克综合癌症中心）。

Therapeutic PSA-targeted poxviral vaccines for prostate cancer have been well tolerated. Prostvac (PSA-TRICOM), a vaccine developed within the CCR, was evaluated for safety, prolongation of PFS, and OS in a randomized, controlled, double-blinded, multicenter phase II study with 125 patients. Eligible patients had minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). Prostvac is composed of 2 recombinant viral vectors, each encoding transgenes for PSA and 3 immune costimulatory molecules (B7.1, ICAM-1, and LFA3: TRICOM). A vaccinia-based vector was used for priming, followed by 6 planned fowlpox-based vector boosts. Patients were allocated 2:1 to Prostvac + GM-CSF vs. control (empty vectors + saline). Two patients received PROSTVAC and 40 received the control. Patient characteristics were similar. The primary endpoint was PFS, which was similar in the two groups (P = 0.6). However, at 3 years post-study, Prostvac patients had a better OS, with 25/82 (30%) alive vs. 7/40 (17%) for control patients at time of analysis. Median survival was extended by 8.5 months (24.5 months for vaccine vs. 16 months controls; estimated hazard ratio 0.56 [95% CI 0.37-0.85], stratified log rank P = 0.0061). Prostvac immunotherapy was well tolerated and associated with a 44% reduction in the death rate and an 8.5-month improvement in median OS in men with mCRPC. These provocative data provide preliminary evidence of a clinically meaningful benefit, but need to be confirmed in a larger, ongoing phase III study. A concurrent randomized phase II trial employing a recombinant poxviral vaccine provided evidence of immune responses. This study employed the identical vaccine in mCRPC to investigate the influence of GM-CSF with vaccine, and the influence of immunologic and prognostic factors on median OS. Of 32 patients vaccinated, 12 showed declines in serum PSA; 2 of those 12 had evaluable decreases in index lesions. Median OS was 26.6 months compared with a nomogram-predicted OS of 17.5 months. Patients with greater PSA-specific T-cell responses showed a trend (P = 0.055) toward enhanced survival. There was no difference in T-cell responses or survival in cohorts of patients receiving GM-CSF vs. no GM-CSF. Patients with a nomogram-predicted survival greater than the median appeared benefit most from treatment, suggesting that using the vaccine earlier in the disease process may lead to substantially improved outcomes. A phase I study was conducted to determine the safety and feasibility of an intraprostatic PSA-based vaccine in men with prostate cancer and local failure following radiotherapy or cryotherapy or clinical progression on androgen-deprivation therapy in the absence of local definitive therapy. This study showed significant intratumoral infiltrates following vaccination. A manuscript on this study was recently published. A collaborative (GMB, UOB, LTIB) neoadjuvant study of s.c. PSA-TRICOM in men with localized prostate cancer prior to radical prostatectomy was recently initiated. A trial of PSA-TRICOM in the active surveillance setting is also undergoing review in collaboration with the Division of Cancer Prevention, NCI. A randomized, double-blind, phase III efficacy trial of Prostvac in men with asymptomatic or minimally symptomatic mCRPC has recently opened, based on the previously mentioned randomized phase II study. This study will recruit about 1,200 men with prostate cancer in approximately 22 countries. Dr. Gulley is the lead PI for this international study, which is expected to complete enrollment by December 2014. The following collaborative vaccine clinical trials at the NIH Clinical Center are ongoing or recently completed. We recently published an open-label study to evaluate the safety and tolerability of Panvac with GM-CSF in patients with metastatic adenocarcinoma (GMB and LTIB). This includes a breast cancer patient who initially had a PR followed by a durable CR, on study for over 6 years.We also recently published a first-in-human open-label phase I study to evaluate the safety and tolerability of a vaccine (GI-6207) developed in the CCR consisting of whole, heat-killed recombinant Saccharomyces cerevisiae (yeast), genetically modified to express CEA protein, in adults with metastatic CEA-expressing carcinoma. Based on this trial, a phase II trial in medullary thyroid cancer has recently been initiated. A phase I dose-escalation study of yeast-brachyury (a CCR-developed vaccine) was recently completed. Brachyury expression is involved in drug resistance and EMT, and has other stem cell-like properties. Final results of this trial were recently presented at ASCO and include a PR in a patient with chordoma. Based on this, a phase II trial in chordoma is being planned. We recently published an open-label pilot study to evaluate the effect on the immune system of talactoferrin in adults with non-small cell lung cancer, with immunologic response to this agent as the primary endpoint. A phase I dose-escalation study of an antibody targeting double-stranded DNA (NHS) conjugated to IL-12 is underway. The IND for this CCR co-developed agent is held by the CCR. Dr. Gulley is the coordinating PI of a phase I dose-escalation study of an anti-PDL1 antibody in patients with solid tumors. This first-in-human international study of this agent sponsored by our CRADA partner, EMD-Serono, has already enrolled and treated over 450 patients, with 80 being treated at the CCR since January 2013. Dramatic prolonged responses have been noted, including a high proportion of patients with thymic epithelial malignancies (collaboration with TGIB). All patients on the dose-escalation portion were enrolled at the CCR; others are being enrolled at the CCR and other centers in expansion cohorts. Collaborative Trials with Extramural Cancer Centers: A phase II study of PSA-TRICOM with GM-CSF in patients with PSA progression after local therapy for prostate cancer (Eastern Cooperative Oncology Group): recently completed and manuscript submitted. A phase I study of intravesical recombinant fowlpox-GM-CSF and/or recombinant fowlpox-TRICOM in patients with bladder carcinoma scheduled for cystectomy (Cancer Institute of New Jersey, CINJ): completed. A phase I study of intratumoral Panvac with GM-CSF in pancreatic cancer patients (CINJ): ongoing. A phase II study of active immunotherapy with Panvac or autologous cultured dendritic cells infected with Panvac after complete resection of hepatic metastases of colorectal carcinoma (Duke Comprehensive Cancer Center): recently published.