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.

针对前列腺癌的治疗性PSA靶向痘病毒疫苗已得到很好的耐受性。在一项随机，控制和盲目的II期研究中，评估了ProstVAC-VF治疗，以确保安全性，无生存率（PFS）的延长（PFS）以及总体存活率。在疫苗接种系列的多中心试验中，有125名患者伴随着序列。符合条件的患者具有最低症状肿瘤的抗性转移性前列腺癌（MCRPC）。 ProstVAC-VF包含2个重组病毒载体，每个反向载体编码前列腺特异性抗原（PSA）和3个免疫摄取的转基因（B7.1，ICAM-1，ICAM-1和LFA3：tricom）。基于疫苗的载体用于启动启动，然后遵循6个计划的基于FowlPox的载体增强。将患者分配给ProstVAC-VF + GM-CSF（2：1），而对控制空载体 +盐水注射。 2例患者接受了前列腺vaC-VF和40个对照载体。患者特征相似。主要终点是PFS，在两组中相似（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7/40（17％）对照。中位数较长8.5个月（疫苗与16个月的对照相机24.5个月）；并估计有危险性0.56（95％CI 0.37-0.85）;分层log等级p = 0.0061。 ProSTVAC-VF免疫疗法的耐受性良好，并降低了44％的死亡率和MCRPC男性的8.5个月改善INMEDIAN OS。这些挑衅性数据提供了临床上有意义的好处的初步证据，但需要在较大的III期研究中得到证实。采用重组痘病毒疫苗的同时进行的随机相关试验提供了免疫反应的免疫反应的证据，并在具有最佳免疫反应的患者中得到了改善的总体生存。这项研究利用MCRPC中的同一疫苗来研究GM-CSF用疫苗的影响，以及免疫学和预后因素对中值OS的影响。 32例患者接种了一次含有前列腺特异性抗原（PSA）的转基因的重组抗疫霉素和三种人类共刺激物分子（B7.1，ICAM-1，LFA-3），被指定为triCOM）。患者接受了含有相同四个转基因的禽禽接受促进疫苗。 12/32名患者在Serumpsa中显示下降，2/12的患者显示指数病变可评估的降低。中位OS为26.6个月。患者患有PSA特异性T细胞反应的患者显示出一种趋势（P = 0.055），以增强生存率。在接受GM-CSF与无GM-CSF的患者中，T细胞反应或存活率没有差异。患者患有HALABI的患者预计生存期在大肝转移的大小中为20％。这种疫苗仪似乎是安全的，与CD8和CD4免疫反应都相关，并显示了临床活性的证据。有必要与该代理人进行进一步的试验，无论是单独还是与免疫术和其他治疗剂结合使用。 Gulley博士及其在肿瘤免疫学和生物学（LTIB）和NCI癌症研究中心（CCR）的医学肿瘤学分支（MOB）的同事在NCI Clinical Centrical Center的下面促销疫苗临床试验中持续或最近完成。一项开放式标签初步研究，用于评估Panvac-V（Vaccinia）和Panvac-F（Fowlpox）与SargramCramostim（GM-CSF）的耐受性和耐受性。该试验的载体具有多种肿瘤抗原和多种共刺激分子的转基因。这包括一名乳腺癌患者，最初患有PR，然后使用3年的耐用CR。这最近发表在临床癌症研究中。一项开放标签I期研究，以评估由整个热杀死的重组重组抗溶酶（酵母）（酵母）在转移性表达癌的成年人中表达CEA蛋白的疫苗（GI-6207）的安全性和耐受性。这是该疫苗的人类试验中的第一次，并证明了这种方法的安全性。该审判最近完成了应计，并将很快提交手稿。一项开放标签试验研究，以评估非小型肺癌（NSCLC）成人对塔拉托铁蛋白免疫系统的影响。对该试剂的免疫反应是主要终点。该试验的应计。这项研究的手稿已提交出版。第一阶段研究确定性的，在没有局部确定治疗的情况下，放疗，冷冻疗法或冷冻疗法或临床进展后，基于肉体式PSA的疫苗对前列腺癌和局部衰竭的男性的安全性和可行性。这项研究显示，肿瘤内浸润量明显。这项研究的手稿已提交出版。 ProstVAC-V/F GM-CSF的随机，双盲，3阶段的3阶段疗效试验对无症状的或症状的症状转移性转移性，castrate耐药性前列腺癌最近基于预先提到的II期开放。这项研究将招募约有1,200名前列腺癌的男性，约有22个国家。 Gulley博士是这项研究的全球PI。在五个壁内NCI前列腺癌试验中，肿瘤的消退和生长速率确定：生长速率常数是治疗疗效的指标。 （已发表）IgG对组织相关抗原作为免疫治疗功效的生物标志物的反应。 （发表）正在进行一项针对IL-12的抗体靶向双链DNA（NHS）的I剂量升级研究。 Yeast-Brachyury的I期剂量升级研究正在进行中。 Brachyury表达参与耐药性，EMT，并与转移过程有关。