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。在一项随机、对照、盲法II期研究中，评估了PROSTVAC-VF治疗的安全性、延长无进展生存期（PFS）和总生存期。125名患者被随机分配到疫苗系列的多中心试验中。符合条件的患者有最小症状去势抵抗性转移性前列腺癌（mCRPC）。PROSTVAC-VF包括2个重组病毒载体，每个载体编码前列腺特异性抗原（PSA）的转基因和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。患者按2:1分配到PROSTVAC-VF + GM-CSF组，对照空载体+生理盐水注射组。2例接受PROSTVAC-VF治疗，40例接受对照载体治疗。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-VF患者的总生存率为25/82(30%)，而对照组为7/40（17%）。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-VF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提供了具有临床意义的益处的初步证据，但需要在目前正在进行的更大规模的III期研究中得到证实。一项采用重组痘病毒疫苗的同时进行的随机II期试验提供了免疫应答改善最佳免疫应答患者总生存率的证据。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。32例患者接种含有前列腺特异性抗原（PSA）转基因和3种人共刺激分子（B7.1、ICAM-1和LFA-3，简称TRICOM）的重组痘苗1次。患者接受了含有相同四种转基因的重组鸡痘强化疫苗。12/32的患者显示血清PSA下降，2/12的患者显示可评估的指数病变下降。中位OS为26.6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）。在接受GM-CSF与未接受GM-CSF的患者队列中，t细胞反应或生存率没有差异。有Halabi的患者预测，大肝转移灶的存活率为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。该药物的进一步试验，无论是单独使用还是与免疫增强剂和其他治疗药物联合使用，都是有必要的。Gulley博士及其在NCI肿瘤免疫学和生物学实验室（LTIB）和癌症研究中心（CCR）医学肿瘤学分部（MOB）的同事在NCI临床中心正在进行或最近于12-13财年完成了以下合作疫苗临床试验。一项开放标签试点研究，评估PANVAC-V（痘苗）和PANVAC-F（鸡痘）联合Sargramostim （GM-CSF）治疗转移性腺癌、MOB、CCR、NCI患者的安全性和耐受性。本试验采用了多种肿瘤抗原和多种共刺激分子的转基因载体。这包括一名乳腺癌患者，她最初有PR，随后持续了5年多的CR。这项试验最近发表在《临床癌症研究》杂志上。一项开放标签I期研究，评估一种疫苗（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，经基因修饰后可在表达CEA的转移性癌成人中表达CEA蛋白。这是该疫苗的首次人体试验，并证明了这种方法的安全性。这项试验最近已完成，并已提交了一份手稿。一项开放标签试点研究，评估talactoferrin对成人非小细胞肺癌（NSCLC）免疫系统的影响。对该药物的免疫应答是主要终点。本次试验已完成预提。这项研究的手稿最近发表了。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取得临床进展。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。PROSTVAC-V/F GM-CSF在无症状或轻度症状转移性去势抵抗性前列腺癌患者中的随机、双盲、3期疗效试验最近在之前提到的II期试验的基础上展开。这项研究将在大约22个国家招募约1200名前列腺癌患者。Gulley博士是这项研究的全球PI。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。目前正在进行酵母-brachyury的I期剂量递增研究。Brachyury的表达与耐药性、EMT和其他类似干细胞的特性有关。抗pdl1抗体在实体瘤患者中的I期剂量递增研究。Gulley博士是由我们的CRADA合作伙伴EMD-Serono赞助的该药物的首次人体研究的协调PI。剂量递增部分的所有患者将在NCI入组，其他患者将在其他中心纳入扩展队列。前列腺癌局部治疗后PSA进展的患者中PROSTVAC-V（痘苗）/TRICOM和PROSTVAC-F（禽痘）/TRICOM联合GM-CSF的II期研究（东部肿瘤合作小组）研究已完成，近期提交稿件。一项膀胱内重组fowlpox-GM-CSF和/或重组fowlpox-TRICOM在计划膀胱切除术的膀胱癌患者中的I期研究（新泽西癌症研究所，CINJ）完成。肿瘤内重组鸡痘PANVAC （PANVAC- f）联合皮下重组牛痘PANVAC （PANVAC- v）、PANVAC- f和重组粒细胞-巨噬细胞集落刺激因子（rH-GMCSF）在胰腺癌患者中的I期研究（新泽西癌症研究所，CINJ）试验正在进行中。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）。这项研究最近发表。

Therapeutic PSA-targeted poxviral vaccines for prostate cancer have been well tolerated. PROSTVAC-VF treatment was evaluated for safety, prolongation of progression free of survival (PFS), and overall survival, in a randomized, controlled, and blinded phase II study. 125 patients were randomized in a multi-center trial of vaccination series. Eligible patients had minimally symptomatic castration resistant metastatic prostate cancer (mCRPC). PROSTVAC-VF comprises 2 recombinant viral vectors, each encoding transgenes for prostate specific antigen (PSA) and 3 immune costimulatory molecules (B7.1, ICAM-1, and LFA3: TRICOM). Vaccinia-based vector was used for priming followed by 6 planned Fowlpox-based vector boosts. Patients were allocated (2:1) to PROSTVAC-VF + GM-CSF, versus Control empty vectors + saline injections. 2 patients received PROSTVAC-VF and 40 received Control vectors. 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-VF patients had a better overall survival with 25/82 (30%) alive, versus 7/40 (17%) Controls. There was a longer median survival by 8.5 months (24.5 months for vaccine versus 16 months Controls); and estimated hazard ratio 0.56 (95% CI 0.37-0.85); stratified log rank P=0.0061. PROSTVAC-VF 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 clinically meaningful benefit, but need to be confirmed in a larger Phase III study, which is currently ongoing. A concurrent randomized Phase II trial employing a recombinant poxviral vaccine provided evidence of immune responses with improved overall survival in patients with the best immune response. 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. 32 patients were vaccinated once with recombinant vaccinia containing the transgenes for prostate-specific antigen (PSA) and three human costimulatory molecules (B7.1, ICAM-1 and LFA-3, designated as TRICOM). Patients received booster vaccines with recombinant fowlpox containing the same four transgenes. 12/32 patients showed declines in serum PSA and 2/12 showed evaluable decrease in index lesions. Median OS was 26.6 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 Halabi predicted survival of 20% in the size of large liver metastasis. This vaccine strategy seems to be safe, is associated with both CD8 and CD4 immune responses, and has shown evidence of clinical activity. Further trials with this agent, either alone or in combination with immunopotentiating and other therapeutic agents, are warranted. Dr. Gulley and his colleagues in the Laboratory of Tumor Immunology and Biology (LTIB) and the Medical Oncology Branch (MOB), Center for Cancer Research (CCR), NCI, have ongoing or recently completed in FY12-13 the following collaborative vaccine clinical trials at the NCI Clinical Center. An open label pilot study to evaluate the safety and tolerability of PANVAC-V (Vaccinia) and PANVAC-F (Fowlpox) in combination with Sargramostim (GM-CSF) in patients with metastatic adenocarcinoma, MOB, CCR, NCI. This trial employed vectors with transgenes of both multiple tumor antigens and multiple costimulatory molecules. This includes a breast cancer patient who initially had a PR followed by a durable CR for over 5 years. This trial was recently published in Clinical Cancer Research. An open label phase I study to evaluate the safety and tolerability of a vaccine (GI-6207) consisting of whole, heat-killed recombinant Saccharomyces cerevisiae (yeast) genetically modified to express CEA protein in adults with metastatic CEA-expressing carcinoma. This is a first in humans trial for this vaccine and demonstrated safety of this approach. This trial recently completed accrual and a manuscript has been submitted. An open label pilot study to evaluate the effect on the immune system of talactoferrin in adults with non-small cell lung cancer (NSCLC). Immunologic response to this agent is the primary endpoint. This trial has completed accrual. A manuscript on this study was recently publsihed. A phase I study 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 randomized, double-blind, phase 3 efficacy trial of PROSTVAC-V/F GM-CSF in men with asymptomatic or minimally symptomatic metastatic, castrate-resistant prostate cancer has recently opened based on the previously mentioned phase II. This study will recruit about 1,200 men with prostate cancer in approximately 22 countries. Dr. Gulley is the global PI for this study. A phase I dose escalation study of an antibody targeting double stranded DNA (NHS) conjugated to IL-12 is underway. A phase I dose escalation study of yeast-brachyury is underway. Brachyury expression is involved in drug resistance, EMT and other stem cell like properties. A phase I dose escalation study of an anti-PDL1 antibody in patients with solid tumors. Dr. Gulley is the coordinating PI of this first-in-human study of this agent sponsored by our CRADA partner, EMD-Serono. All the patients on the dose escalation portion will be enrolled at the NCI and others will be enrolled at other centers in expansion cohorts. Collaborative Trials with Extramural Cancer Centers A phase II study of PROSTVAC-V(Vaccinia)/TRICOM and PROSTVAC-F(fowlpox)/TRICOM with GM-CSF in patients with PSA progression after local therapy for prostate cancer. (Eastern Cooperative Oncology Group) Study completed, manuscript recently 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) Study completed. A phase I study of intratumoral recombinant fowlpox PANVAC (PANVAC-F) plus subcutaneous recombinant vaccinia PANVAC (PANVAC-V), PANVAC-F and recombinant granulocyte-macrophage colony stimulating factor (rH-GMCSF) in pancreatic cancer patients. (Cancer Institute of New Jersey, CINJ) Trial 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). This study was recently published.