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: 7965516
• 负责人: James L. Gulley
• 金额: $ 86.37万
• 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/7965516
• 关键词: Active Immunotherapy; Adult; Amendment; Antigen Targeting; Ascites; Autoantigens; Autologous Dendritic Cells; Biology; Blinded; CD58 Antigens; CD58 gene; CD8B1 gene; Cancer Center; Cancer Institute of New Jersey; Cancer Patient; Cancer Vaccines; Carcinoembryonic Antigen; Carcinoma; Castration; Characteristics; Clear Cell; Clinical; Clinical Trials; Collaborations; Colorectal; Comprehensive Cancer Center; Conduct Clinical Trials; Cystectomy; Data; Death Rate; Denileukin Diftitox; Duke Comprehensive Cancer Center; Eastern Cooperative Oncology Group; Engineering; Epithelial; Evaluable Disease; Extramural Activities; Fowlpox; Fowlpox-CEA(D609)-MUC1(L93)-Tricom Vaccine; Genes; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Heating; Human; Immune; Immune Tolerance; Immune response; Immune system; Immunologics; Immunotherapy; Indolent; Injection Site Reaction; Injection of therapeutic agent; Intercellular adhesion molecule 1; Interferon Alfa-2b; Laboratories; Lesion; Life; Local Therapy; Lung; Malignant Neoplasms; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Medical Oncology; Metastatic Adenocarcinoma; Metastatic Carcinoma; Metastatic Neoplasm to the Liver; Metastatic Prostate Cancer; Mucins; NCI Center for Cancer Research; Non-Small-Cell Lung Carcinoma; Ohio; Patients; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phase III Clinical Trials; Pilot Projects; Poxviridae; Prognostic Factor; Progression-Free Survivals; Prostate; Prostate Cancer Vaccine; Prostate-Specific Antigen; Proteins; Randomized; Recombinant Fowlpox-GM-CSF Vaccine; Recombinant Vaccines; Recombinants; Reporting; Resistance; Saccharomyces cerevisiae; Safety; Saline; Schedule; Secondary Immunization; Series; Serum; Solid Carcinoma; T-Cell Depletion; T-Lymphocyte; Testing; Therapeutic; Therapeutic Agents; Therapy Clinical Trials; Toxic effect; Transgenes; Treatment Protocols; Triad Acrylic Resin; Tumor Antigens; Vaccinated; Vaccination; Vaccine Clinical Trial; Vaccine Therapy; Vaccines; Vaccinia; Vaccinia-TRICOM Vaccine; Viral Vector; Yeasts; anticancer research; base; bladder Carcinoma; booster vaccine; breast cancer vaccine; cancer therapy; chemotherapy; cohort; collaborative trial; hazard; indexing; killings; malignant breast neoplasm; meetings; men; novel; open label; overexpression; rVaccinia-CEA(D609)/MUC1(L93)/TRICOM Vaccine; reconstitution; response; sargramostim; trend; tumor immunology; vaccine efficacy; vaccine safety; 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. A concurrent multicenter, randomized Phase II trial employing a recombinant poxviral vaccine provided evidence of enhanced median overall survival (OS) (p=0.0061) in patients with metastatic castrate-resistant prostate cancer (mCRPC). 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 < 18 months (predicted 12.3 months) had an actual median OS of 14.6 months, while those with a Halabi predicted survival of ≥ 18 months (predicted survival 20.9 months) will meet or exceed 37.3 months, with 12/15 patients living longer than predicted (p=0.035). Treg suppressive function was shown to decrease in patients surviving longer than predicted and increase in patients surviving less than predicted. These studies provide evidence that patients with more indolent mCRPC (Halabi predicted survival ≥ 18 months) may best benefit from vaccine therapy. Pilot study of vaccination with recombinant CEA-MUC-1-TRICOM poxviral-based vaccines 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 (breast cancer associated epithelial mucin) are overexpressed in a substantial proportion of common solid carcinomas. The primary end point of this study was vaccine safety, with immunologic and clinical responses as secondary end points. We report here a pilot study of 25 patients 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 vaccination and into fowlpox (PANVAC-F) as a booster vaccination. The vaccine was well tolerated. Apart from injection-site reaction, no grade ≥2 toxicity was seen in more than 2% of the cycles. Immune responses to MUC-1and/or CEA were seen following vaccination in 9 of 16 patients tested. 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 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 FY08-09 the following collaborative vaccine clinical trials at the NCI Clinical Center. A Phase I-II study of tumor vaccine following chemotherapy in patients with previously untreated metastatic breast cancer: Vaccine-induced bias of T-cell repertoire reconstitution after T-cell Reinfusion. (Collaboration with Dr. Sportes) MOB, CCR, NCI. This trial combines the concepts of T-cell repertoire reconstitution with vaccine therapy. 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. A recent amendment allowed additional patients to further analyze the efficacy of the vaccine. 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. 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. 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) A Phase I study of sequential vaccinations with fowlpox-CEA(6D)-TRICOM and vaccinia-CEA(6D)-TRICOM, in combination with GM-CSF and Interferon-Alfa-2B in patients with CEA expressing carcinomas. (Ohio State Comprehensive Cancer Center) A Phase I study of regulatory T cell depletion with Denileukin Diftitox followed by active immunotherapy with autologous dendritic cells infected with CEA-6D expressing fowlpox-TRICOM in patients with advanced or metastatic malignancies expressing CEA (Duke Comprehensive Cancer Center) Phase I study of intravessical recombinant fowlpox-GM-CSF and or recombinant fowlpox-TRICOM in patients with bladder carcinoma scheduled for cystectomy (Cancer Institute of New Jersey, CINJ)

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）；估计风险比为 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，但需要在更大规模的 III 期研究中得到证实。一项同时进行的多中心、随机 II 期试验采用重组痘病毒疫苗，证明转移性去势抵抗性前列腺癌 (mCRPC) 患者的中位总生存期 (OS) 有所提高 (p=0.0061)。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，该重组牛痘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。 Halabi 预测生存期 < 18 个月（预测 12.3 个月）的患者的实际中位 OS 为 14.6 个月，而 Halabi 预测生存期为 14.6 个月。 18 个月（预测生存期 20.9 个月）将达到或超过 37.3 个月，其中 12/15 患者的生存期比预测长（p=0.035）。 研究表明，存活时间长于预期的患者的 Treg 抑制功能会下降，而存活时间短于预期的患者的 Treg 抑制功能会增加。这些研究提供的证据表明，惰性 mCRPC 患者（Halabi 预测生存期 – 18 个月）可能从疫苗治疗中获益最多。在转移性癌患者中接种重组 CEA-MUC-1-TRICOM 痘病毒疫苗的初步研究。痘病毒载体具有经过验证的安全记录，可用于整合多种转基因。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（乳腺癌相关上皮粘蛋白）在大部分常见实体癌中过度表达。这项研究的主要终点是疫苗安全性，免疫学和临床反应作为次要终点。我们在这里报告了一项试点研究，对 25 名患者进行了痘病毒疫苗方案的治疗，该方案由 CEA 和 MUC-1 基因以及三联体共刺激分子 (TRICOM；由 B7.1、ICAM-1 和 LFA-3 组成) ）被工程化为牛痘（PANVAC-V）作为初级疫苗接种，并被工程化为鸡痘（PANVAC-F）作为加强疫苗接种。该疫苗耐受性良好。除了注射部位反应外，在超过 2% 的周期中未观察到 2 级毒性。在接受测试的 16 名患者中，有 9 名在接种疫苗后出现了对 MUC-1 和/或 CEA 的免疫反应。一名患有透明细胞卵巢癌和症状性腹水的患者在放射学和生化方面显示出持久（18 个月）的临床反应，一名乳腺癌患者的大型肝转移瘤尺寸已确认减少了 20% 以上。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) 肿瘤内科分部 (MOB) 的同事正在进行或最近于 2008-09 财年完成了以下合作疫苗临床在 NCI 临床中心进行的试验。对先前未经治疗的转移性乳腺癌患者进行化疗后肿瘤疫苗的 I-II 期研究：T 细胞回输后疫苗诱导的 T 细胞库重建偏差。 （与 Sportes 博士合作）MOB、CCR、NCI。该试验将 T 细胞库重建的概念与疫苗疗法结合起来。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。最近的一项修正案允许更多患者进一步分析疫苗的功效。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，该疫苗由完整的热灭活重组酿酒酵母（酵母）组成，经过基因改造，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。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。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）一项针对表达 CEA 的癌症患者序贯接种鸡痘-CEA(6D)-TRICOM 和牛痘-CEA(6D)-TRICOM 疫苗，联合 GM-CSF 和干扰素-Alfa-2B 的 I 期研究。 （俄亥俄州综合癌症中心）一项 I 期研究，针对表达 CEA 的晚期或转移性恶性肿瘤患者，使用 Denileukin Diftitox 消除调节性 T 细胞，然后用感染表达鸡痘的 CEA-6D 的自体树突状细胞进行主动免疫治疗（杜克综合癌症中心） ) 对计划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）