Cancer Therapy Clinical Trials Using Novel Recombinant Vaccines

使用新型重组疫苗的癌症治疗临床试验

• 批准号: 8763169
• 负责人: James L. Gulley
• 金额: $ 76.72万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8763169
• 关键词: Active Immunotherapy; Adult; Androgens; Antibodies; Antigen Targeting; Autologous; Blinded; Brachyury protein; CA-15-3 Antigen; CD58 Antigens; CD58 gene; CD8B1 gene; Cancer Center; Cancer Institute of New Jersey; Cancer Patient; Carcinoembryonic Antigen; Carcinoma; Castration; Characteristics; Clinical; Clinical Trials; Cold Therapy; Colorectal Cancer; Conduct Clinical Trials; Cooperative Research and Development Agreement; Country; Cystectomy; DNA; Data; Death Rate; Dendritic Cells; Dose; Double-Blind Method; Drug resistance; Duke Comprehensive Cancer Center; Eastern Cooperative Oncology Group; Enrollment; Epithelial; Epitopes; Evaluable Disease; Excision; Extramural Activities; Failure; Fowlpox; Fowlpox-CEA(D609)-MUC1(L93)-Tricom Vaccine; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Heating; Human; Immune; Immune response; Immune system; Immunologic Factors; Immunologics; Immunotherapy; Injection of therapeutic agent; Intercellular adhesion molecule 1; Interleukin-12; Laboratories; Large Intestine Carcinoma; Lesion; Local Therapy; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Manuscripts; Medical Oncology; Metastatic Adenocarcinoma; Metastatic Neoplasm to the Liver; Metastatic Prostate Cancer; Mucins; NCI Center for Cancer Research; Necrosis; Non-Small-Cell Lung Carcinoma; Patients; Phase; Phase II Clinical Trials; Pilot Projects; Poxviridae; Prognostic Factor; Progression-Free Survivals; Property; Prostate; Prostate Cancer Vaccine; Prostate-Specific Antigen; Proteins; Publishing; Radiation therapy; Randomized; Recombinant Granulocyte-Macrophage Colony-Stimulating Factors; Recombinant Vaccines; Recombinants; Recruitment Activity; Resistance; Saccharomyces cerevisiae; Safety; Saline; Schedule; Series; Serum; Solid Neoplasm; Stem cells; T cell response; T-Lymphocyte; Testing; Therapeutic; Therapeutic Agents; Therapy Clinical Trials; Transgenes; Tumor Antigens; Tumor Biology; Vaccinated; Vaccination; Vaccine Clinical Trial; Vaccines; Vaccinia; Vaccinia-TRICOM Vaccine; Vaccinium; Yeasts; anticancer research; base; bladder Carcinoma; booster vaccine; cancer therapy; cohort; collaborative trial; deprivation; ds-DNA; efficacy trial; hazard; human study; improved; indexing; intravesical; killings; malignant breast neoplasm; men; novel; open label; phase 1 study; phase 2 study; phase 3 study; rVaccinia-CEA(D609)/MUC1(L93)/TRICOM Vaccine; recombinant viral vector; response; sargramostim; subcutaneous; trend; tumor; tumor immunology; vector; vector control

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.

针对前列腺癌的治疗性 PSA 痘病毒疫苗具有良好的耐受性。在一项随机、对照、盲法 II 期研究中，对 PROSTVAC-VF 治疗的安全性、无进展生存期 (PFS) 延长和总生存期进行了评估。 125 名患者被随机参加一项疫苗接种系列多中心试验。符合条件的患者患有症状轻微的去势抵抗性转移性前列腺癌（mCRPC）。 PROSTVAC-VF 包含 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）。使用基于牛痘的载体进行启动，然后进行 6 次计划的基于禽痘的载体加强。患者被分配 (2:1) 至 PROSTVAC-VF + GM-CSF，而对照空载体 + 盐水注射。 2 名患者接受 PROSTVAC-VF，40 名患者接受对照载体。患者特征相似。主要终点是 PFS，两组相似 (P=0.6)。然而，在研究 3 年后，PROSTVAC-VF 患者的总体生存率更高，存活率为 25/82 (30%)，而对照组为 7/40 (17%)。中位生存期延长了 8.5 个月（疫苗组为 24.5 个月，对照组为 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 免疫疗法耐受性良好，mCRPC 男性死亡率降低 44%，中位 OS 改善 8.5 个月。这些令人兴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。同时进行的一项采用重组痘病毒疫苗的随机 II 期试验提供了免疫反应的证据，可以改善具有最佳免疫反应的患者的总体生存率。本研究在 mCRPC 中使用相同的疫苗来研究 GM-CSF 与疫苗的影响，以及免疫学和预后因素对中位 OS 的影响。 32名患者接受了一次重组牛痘疫苗接种，该疫苗含有前列腺特异性抗原（PSA）转基因和三种人类共刺激分子（B7.1、ICAM-1和LFA-3，命名为TRICOM）。患者接受了含有相同四种转基因的重组鸡痘加强疫苗。 12/32 名患者的血清 PSA 下降，2/12 名患者的指数病变明显减少。中位 OS 为 26.6 个月。 PSA 特异性 T 细胞反应较高的患者显示出生存率提高的趋势 (p=0.055)。接受 GM-CSF 治疗的患者与未接受 GM-CSF 治疗的患者相比，T 细胞反应或生存率没有差异。患有 Halabi 的患者预测，如果发生大面积肝转移，其存活率为 20%。这种疫苗策略似乎是安全的，与 CD8 和 CD4 免疫反应相关，并且已显示出临床活性的证据。有必要对该药物进行进一步的试验，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。 Gulley 博士及其肿瘤免疫学和生物学实验室 (LTIB) 以及 NCI 癌症研究中心 (CCR) 肿瘤内科肿瘤学分部 (MOB) 的同事正在进行或最近于 2012-13 财年完成了以下合作疫苗临床在 NCI 临床中心进行的试验。一项开放标签试点研究，旨在评估 PANVAC-V（牛痘）和 PANVAC-F（鸡痘）与沙格司亭（GM-CSF）联合治疗转移性腺癌、MOB、CCR、NCI 患者的安全性和耐受性。该试验采用了带有多种肿瘤抗原和多种共刺激分子转基因的载体。这包括一名乳腺癌患者，最初获得 PR，随后获得持续 CR，持续时间超过 5 年。该试验最近发表在《临床癌症研究》上。一项开放标签 I 期研究，旨在评估疫苗 (GI-6207) 的安全性和耐受性，该疫苗由经过基因改造的完整热灭活重组酿酒酵母（酵母）组成，可在患有转移性 CEA 表达癌的成人中表达 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。该试验最近完成了应计并已提交稿件。一项开放标签试点研究，旨在评估总乳铁蛋白对成人非小细胞肺癌 (NSCLC) 免疫系统的影响。对该药物的免疫反应是主要终点。本次试用已完成计提工作。关于这项研究的手稿最近出版了。一项 I 期研究，旨在确定前列腺癌患者使用基于 PSA 的前列腺内疫苗的安全性和可行性，这些患者在放疗或冷冻疗法后局部失败，或者在缺乏局部确定性治疗的情况下雄激素剥夺疗法的临床进展。该研究显示疫苗接种后出现显着的瘤内浸润。这项研究的手稿最近发表。一项针对无症状或症状轻微的转移性去势抵抗性前列腺癌男性的 PROSTVAC-V/F GM-CSF 随机、双盲、3 期疗效试验最近在之前提到的 II 期试验的基础上启动。这项研究将在大约 22 个国家招募大约 1,200 名患有前列腺癌的男性。 Gulley 博士是这项研究的全球 PI。针对与 IL-12 结合的双链 DNA (NHS) 的抗体的 I 期剂量递增研究正在进行中。酵母-brachyury 的 I 期剂量递增研究正在进行中。 Brachyury 表达与耐药性、EMT 和其他干细胞样特性有关。抗 PDL1 抗体在实体瘤患者中的 I 期剂量递增研究。 Gulley 博士是这项针对该药物的首次人体研究的协调 PI，该研究由我们的 CRADA 合作伙伴 EMD-Serono 赞助。所有剂量递增部分的患者都将在 NCI 入组，其他患者将在其他中心的扩展队列中入组。与校外癌症中心的合作试验 PROSTVAC-V（牛痘）/TRICOM 和 PROSTVAC-F（鸡痘）/TRICOM 与 GM-CSF 联合治疗前列腺癌局部治疗后 PSA 进展的患者的 II 期研究。 （东部肿瘤合作组）研究完成，手稿最近提交。对计划进行膀胱切除术的膀胱癌患者进行膀胱内重组鸡痘-GM-CSF 和/或重组鸡痘-TRICOM 的 I 期研究（新泽西州癌症研究所，CINJ）研究已完成。胰腺癌患者瘤内重组鸡痘 PANVAC (PANVAC-F) 加皮下重组痘苗 PANVAC (PANVAC-V)、PANVAC-F 和重组粒细胞巨噬细胞集落刺激因子 (rH-GMCSF) 的 I 期研究。 （新泽西州癌症研究所，CINJ）试验正在进行中。结直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的 II 期研究。 （杜克综合癌症中心）。这项研究最近发表。