Cancer Therapy Trials using novel vaccine platforms

使用新型疫苗平台进行癌症治疗试验

• 批准号: 8553077
• 负责人: Ravi Madan
• 金额: $ 16.17万
• 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/8553077
• 关键词: Adult; Androgens; Antibodies; Antigen Targeting; Antigens; Biological Markers; Blinded; Brachyury protein; CA-15-3 Antigen; CD58 Antigens; CD58 gene; CD8B1 gene; Cancer Patient; Carcinoembryonic Antigen; Carcinoma; Characteristics; Clinical; Cold Therapy; Colorectal Cancer; Country; DNA; Data; Death Rate; Dose; Double-Blind Method; Drug resistance; Epithelial; Epitopes; Evaluable Disease; Failure; Fowlpox; Fowlpox-CEA(D609)-MUC1(L93)-Tricom Vaccine; Granulocyte-Macrophage Colony-Stimulating Factor; Growth; Heating; Human; Immune; Immune response; Immune system; Immunoglobulin G; Immunologics; Immunotherapy; Injection of therapeutic agent; Intercellular adhesion molecule 1; Interleukin-12; Investigation; Lesion; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Manuscripts; Medical Oncology; Metastatic Adenocarcinoma; Metastatic Neoplasm to the Liver; Metastatic Prostate Cancer; Mucins; NCI Center for Cancer Research; Necrosis; Patients; Phase; Pilot Projects; Poxviridae; Prognostic Factor; Progression-Free Survivals; Prostate; Prostate Cancer Vaccine; Prostate-Specific Antigen; Proteins; Publications; Publishing; Radiation therapy; Randomized; Recombinant Vaccines; Recombinants; Recruitment Activity; Resistance; Safety; Saline; Series; T cell response; T-Lymphocyte; Testing; Therapeutic; Therapeutic Agents; Tissues; Transgenes; Treatment Efficacy; Tumor Antigens; Tumor Biology; Vaccinated; Vaccination; Vaccine Clinical Trial; Vaccines; Vaccinia; Vaccinium; Yeasts; anticancer research; base; booster vaccine; cancer therapy; cohort; efficacy trial; indexing; killings; malignant breast neoplasm; medullary thyroid carcinoma; men; metastatic process; novel; novel vaccines; open label; phase 1 study; phase 2 study; phase 3 study; rVaccinia-CEA(D609)/MUC1(L93)/TRICOM Vaccine; response; transcription factor; 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 wererandomized in a multi-center trial of vaccination series. Eligible patients had minimally symptomaticcastration resistant metastatic prostate cancer (mCRPC). PROSTVAC-VF comprises 2 recombinantviral vectors, each encoding transgenes for prostate specific antigen (PSA) and 3 immune costimulatorymolecules (B7.1, ICAM-1, and LFA3: TRICOM). Vaccinia-based vector was used for priming followedby 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 40received Control vectors. Patient characteristics were similar. The primary endpoint was PFS, whichwas similar in the two groups (P=0.6). However, at 3 years post study, PROSTVAC-VF patients had abetter overall survival with 25/82 (30%) alive, versus 7/40 (17%) controls. There was a longer mediansurvival by 8.5 months (24.5 months for vaccine versus 16 months controls); and estimated hazardratio 0.56 (95% CI 0.37-0.85); stratified log rank P=0.0061. PROSTVAC-VF immunotherapy was welltolerated and associated with a 44% reduction in the death rate and an 8.5 month improvement inmedian 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 randomizedPhase II trial employing a recombinant poxviral vaccine provided evidence of immune responses withimproved overall survival in patients with the best immune response. This study employed the identicalvaccine in mCRPC to investigate the influence of GM-CSF with vaccine, and the influence ofimmunologic and prognostic factors on median OS. 32 patients were vaccinated once with recombinantvaccinia containing the transgenes for prostate-specific antigen (PSA) and three human costimulatorymolecules (B7.1, ICAM-1 and LFA-3, designated as TRICOM). Patients received booster vaccines withrecombinant fowlpox containing the same four transgenes. 12/32 patients showed declines in serumPSA and 2/12 showed evaluable decrease in index lesions. Median OS was 26.6 months. Patients withgreater PSA-specific T-cell responses showed a trend (p=0.055) toward enhanced survival. There wasno 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 vaccinestrategy seems to be safe, is associated with both CD8 and CD4 immune responses, and has shownevidence of clinical activity. Further trials with this agent, either alone or in combination withimmunopotentiating and other therapeutic agents, are warranted. Dr. Gulley and his colleagues in theLaboratory of Tumor Immunology and Biology (LTIB) and the Medical Oncology Branch (MOB),Center for Cancer Research (CCR), NCI, have ongoing or recently completed in FY11-12 the followingcollaborative vaccine clinical trials at the NCI Clinical Center. An open label pilot study to evaluate thesafety and tolerability of PANVAC-V (Vaccinia) and PANVAC-F (Fowlpox) in combination withSargramostim (GM-CSF) in patients with metastatic adenocarcinoma, MOB, CCR, NCI. This trialemployed vectors with transgenes of both multiple tumor antigens and multiple costimulatorymolecules. This includes a breast cancer patient who initially had a PR followed by a durable CR forover 3 years. This was recently published in Clinical Cancer Research. An open label phase I study toevaluate the safety and tolerability of a vaccine (GI-6207) consisting of whole, heat-killed recombinantSaccharomyces cerevisiae (yeast) genetically modified to express CEA protein in adults with metastaticCEA-expressing carcinoma. This is a first in humans trial for this vaccine and demonstrated safety ofthis approach. This trial recently completed accrual and a manuscript will soon be submitted. An openlabel pilot study to evaluate the effect on the immune system of talactoferrin in adults with non-smallcell lung cancer (NSCLC). Immunologic response to this agent is the primary endpoint. This trial hascompleted accrual. A manuscript on this study has been submitted for publication. A phase I study todetermine the safety and feasibility of an intraprostatic PSA-based vaccine in men with prostate cancerand local failure following radiotherapy or cryotherapy or clinical progression on androgen deprivationtherapy in the absence of local definitive therapy. This study showed significant intratumoral infiltratesfollowing vaccination. A manuscript on this study has been submitted for publication. A randomized,double-blind, phase 3 efficacy trial of PROSTVAC-V/F GM-CSF in men with asymptomatic orminimally symptomatic metastatic, castrate-resistant prostate cancer has recently opened based on thepreviously mentioned phase II. This study will recruit about 1,200 men with prostate cancer inapproximately 22 countries. Dr. Gulley is the global PI for this study. Tumor regression and growth ratesdetermined in five intramural NCI prostate cancer trials: the growth rate constant as an indicator oftherapeutic efficacy. (published) IgG responses to tissue-associated antigens as biomarkers ofimmunological treatment efficacy. (published) A phase I dose escalation study of an antibody targetingdouble stranded DNA (NHS) conjugated to IL-12 is underway. A phase I dose escalation study ofyeast-brachyury is underway. Brachyury expression is involved in drug resistance, EMT and has been implicated in the metastatic process.

用于前列腺癌的治疗性 PSA 靶向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 名患者被随机分组​​参加疫苗接种系列的多中心试验。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）；估计危险比 0.56 (95% CI 0.37-0.85)；分层对数秩 P=0.0061。 PROSTVAC-VF 免疫疗法具有良好的耐受性，可使 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，可以改善具有最佳免疫反应的患者的总体生存率。本研究采用相同的mCRPC疫苗来研究GM-CSF对疫苗的影响，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，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 例患者血清 PSA 下降，2/12 例患者指数病变明显下降。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。接受 Halabi 治疗的患者预计，大面积肝转移患者的生存率为 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 博士和他在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在 2011-12 财年完成了以下合作疫苗临床试验： NCI 临床中心。一项开放标签试点研究，旨在评估 PANVAC-V（牛痘）和 PANVAC-F（鸡痘）与沙格莫司亭（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 3 年。该研究最近发表在《临床癌症研究》杂志上。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，并证明了该方法的安全性。该试验最近已完成应计，并将很快提交稿件。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。这项研究的手稿已提交出版。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。这项研究的手稿已提交出版。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 期疗效试验最近在前面提到的 II 期试验的基础上启动。这项研究将招募约 22 个国家的约 1,200 名患有前列腺癌的男性。 Gulley 博士是这项研究的全球 PI。五项壁内 NCI 前列腺癌试验确定的肿瘤消退和生长速率：生长速率常数作为治疗效果的指标。 （已发表）对组织相关抗原的 IgG 反应作为免疫治疗功效的生物标志物。 （已发表） 针对与 IL-12 缀合的双链 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 表达参与耐药性、EMT 并与转移过程有关。