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: 8349441
• 负责人: Ravi Madan
• 金额: $ 1.58万
• 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/8349441
• 关键词: Active Immunotherapy; Adult; Adverse event; Aftercare; Amendment; Anterior; Antibodies; Autoimmune Process; Autologous Dendritic Cells; Bilateral; Blinded; CA-15-3 Antigen; CD58 Antigens; CD8B1 gene; Cancer Center; Cancer Institute of New Jersey; Carcinoembryonic Antigen; Carcinoma; Castration; Chest wall structure; Clinical; Collaborations; Colorectal Adenocarcinoma; Colorectal Cancer; Comprehensive Cancer Center; Control Groups; Cystectomy; Cytotoxic Chemotherapy; Data; Death Rate; Denileukin Diftitox; Dose; Dose-Limiting; Duke Comprehensive Cancer Center; Eastern Cooperative Oncology Group; Enrollment; Epithelial; Equilibrium; Evaluable Disease; Extramural Activities; FDA approved; Fowlpox; Fowlpox-CEA(D609)-MUC1(L93)-Tricom Vaccine; Frequencies; Future; Granulocyte-Macrophage Colony-Stimulating Factor; Growth; Heating; Human; Immune; Immune response; Immune system; Immunologic Factors; Immunologics; Immunotherapy; Injection Site Reaction; Intercellular adhesion molecule 1; Interferon Alfa-2b; Investigation; Kinetics; Laboratories; Local Therapy; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Medical Oncology; Metastatic Adenocarcinoma; Metastatic Prostate Cancer; Modeling; Mucins; NCI Center for Cancer Research; Non-Small-Cell Lung Carcinoma; Ohio; Outcome; Patients; Pharmaceutical Preparations; Phase III Clinical Trials; Pilot Projects; Poxviridae; Prognostic Factor; Progression-Free Survivals; Prostate-Specific Antigen; Proteins; Publishing; Randomized; Recombinant Vaccines; Recombinants; Recording of previous events; Regulatory T-Lymphocyte; Resistance; Saccharomyces cerevisiae; Safety; Scanning; Schedule; Serum; Site; Stable Disease; Staging; T cell response; T-Cell Depletion; T-Lymphocyte; Therapeutic; Therapeutic Agents; Time; Toxic effect; Transgenes; Tumor Antigens; Tumor Biology; Tumor Volume; Vaccinated; Vaccination; Vaccine Clinical Trial; Vaccines; Vaccinia; Vaccinia-TRICOM Vaccine; Vaccinium; Yeasts; anticancer research; arm; base; bladder Carcinoma; booster vaccine; cancer therapy; cohort; collaborative trial; enzyme linked immunospot assay; hazard; improved; intravesical; killings; malignant breast neoplasm; medullary thyroid carcinoma; men; novel; novel vaccines; open label; particle; patient population; phase 1 study; phase 2 study; phase 3 study; rVaccinia-CEA(D609)/MUC1(L93)/TRICOM Vaccine; recombinant viral vector; response; sargramostim; treatment effect; trend; tumor; tumor growth; tumor immunology; vaccine efficacy; vector; vector control

PROSTVAC-VF is a therapeutic poxviral vaccine-based treatment and has been previously evaluated for safety, prolongation of progression free survival (PFS), and overall survival (OS), in a randomized, controlled, and blinded phase II study published in 2010. In that study, 125 patients with minimally symptomatic metastatic castration resistant prostate cancer (mCRPC) were randomized in a multi-center trial Patients were randomized 2:1 in favor of PROSTVAC-VF which comprises of 2 recombinant viral vectors, each encoding transgenes for prostate specific antigen (PSA) and 3 immune costimulatory molecules (B7.1, ICAM-1, and LFA3: TRICOM). 82 patients received PROSTVAC-VF and 40 received control vectors. The 2 arms of the study were well balanced. 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 OS with 25/82 (30%) alive, versus 7/40 (17%) control group. There was a longer median survival by 8.5 months (24.5 months for vaccine versus 16 months controls); estimated hazard ratio 0.56 (95% CI 0.37-0.85); stratified log rank P=0.0061. This study demonstrated that 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 data provide preliminary evidence of clinically meaningful benefit, but need to be confirmed in a larger Phase III study. A concurrent single center 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 PSA and TRICOM. Patients received monthly booster vaccines with recombinant fowlpox containing the same four transgenes. The median OS was 26.6 months andpatients 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. A recent analysis with Dr. Tsang and colleagues (LTIB) has demonstrated an association of changes in circulating regulatory T-cells and outcomes. Further trials with this agent, either alone or in combination with immunopotentiating and other therapeutic agents, are warranted. A phase III trial of Prostvac-VF in metastatic prostate cancer, largely based on the findings in the above trials will begin later in 2011. 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 has been completed this year. This is a first in human trial for this vaccine. Patients were enrolled at 3 dose levels: 4, 16, and 40 yeast units (each unit =107 yeast particles). The vaccine was administered in equal doses at 4 sites subcutaneously in bilateral inguinal and anterior chest wall regions. Vaccine was administered at 2 week intervals for 3 months, then monthly. Eligible patients were required to have a serum CEA > 5 ng/ml or >20% CEA+ positive tumor block and no autoimmune history. An expansion cohort of 10 ECOG PS 0-1 pts was enrolled to focus primarily on immune response. Patients had re-staging scans at 3 months, then bimonthly. A total of 25 patients with progressive metastatic CEA-expressing carcinoma were enrolled from April 2009 to January 2011, 22 had colorectal adenocarcinoma. Vaccine was well tolerated with no dose limiting toxicities. The most common adverse event was grade 1/2 injection site reaction. Overall, 7 patients had stabilization or declines in serum CEA after treatment. Of these patients, 5 patients had stable disease beyond 3 months and 1 is still on-going (14 +, 8, 8, 4.5 and 4 months). No anti-CEA antibodies were detected. Five out of 9 evaluable patients showed evidence by ELISPOT of CEA-specific CD8+ T-cell immune responses. 8 patients had increased CD4 effector/Treg ratio and 6 had increased NK frequency. In this trial, Saccharomyces cerevisiae-CEA demonstrated an acceptable safety profile. Although this is an advanced population of patients which may not be ideal candidates for immune-based therapy, CEA stabilizations and immune responses were seen in some patients. Further randomized studies are required to determine the clinical benefit of this vaccine. A phase II study of this drug in medullary thyroid cancer is currently being planned. A recent collaboration with Drs. James Gulley (LTIB), William Dahut (MOB), Jeffry Schlom (LTIB), Tito Fojo (MOB), and Wilfred Stein (MOB) has suggested that vaccines may alter the tumor growth kinetics in prostate cancer. This study reviewed 5 NCI prostate cancer trials including one with a vaccine (PROSTVAC-VF). Based on mathematical tumor growth models, this analysis suggests that vaccines (as compared to cytotoxic therapy) may not cause an immediate decrease in tumor volume, but over time the growth rate may slow down leading to improved long-term outcomes. This is of great importance as Protavac and other FDA-approved immunotherapy agents (Sipuleucel-T and Ipilimumab) have demonstrated overall survival improvements without changes in short-term progression. This analysis may provide the first mechanistic evidence of the underlying effects of the treatment and the apparent delayed benefits. Plans to use this change in tumor growth kinetics as a (primary) endpoint in future trials are currently in progress. Additional colloaborations with Dr. James Gulley, the Laboratory of Tumor Immunology and Biology and the Medical Oncology Branch (MOB), Center for Cancer Research (CCR), NCI, have ongoing or recently completed in FY10-11 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. A recent amendment allowed additional patients to further analyze the efficacy of the 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 intravesical recombinant fowlpox-GM-CSF and or recombinant fowlpox-TRICOM in patients with bladder carcinoma scheduled for cystectomy (Cancer Institute of New Jersey, CINJ).

PROSTVAC-VF is a therapeutic poxviral vaccine-based treatment and has been previously evaluated for safety, prolongation of progression free survival (PFS), and overall survival (OS), in a randomized, controlled, and blinded phase II study published in 2010. In that study, 125 patients with minimally symptomatic metastatic castration resistant prostate cancer (mCRPC) were randomized in a multi-center trial Patients were随机2：1支持ProstVAC-VF，由2个重组病毒载体组成，每个编码前列腺特异性抗原（PSA）和3个免疫刺激分子（B7.1，ICAM-1，ICAM-1和LFA3：Tricom）的转基因。 82例患者接受了前列腺vaC-VF，40例接受了对照载体。研究的两个臂是平衡的。主要终点是PFS，在两组中相似（P = 0.6），但是，在研究后3年，ProstVAC-VF患者的OS较好，活着25/82（30％），对7/40（17％）对照组。中位生存期较长8.5个月（疫苗与16个月的对照为24.5个月）；估计危险比0.56（95％CI 0.37-0.85）;分层log等级p = 0.0061。这项研究表明，ProSTVAC-VF免疫疗法的耐受性良好，与MCRPC男性中位OS的死亡率降低44％相关。这些数据提供了临床上有意义的好处的初步证据，但需要在大型III期研究中得到证实。一项并发的单中心研究采用了MCRPC中相同的疫苗来研究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例患者一次接种含有PSA和Tricom的转基因的重组疫苗接种。患者每月接受含有相同四个转基因的重组禽的增强疫苗。中位OS为26.6个月，患者患者具有较大的PSA特异性T细胞反应，显示出一种趋势（P = 0.055），以增强生存率。在接受GM-CSF的患者与无GM-CSF的患者中，T细胞反应或存活没有差异。与Tsang博士及其同事（LTIB）的最新分析表明，循环调节T细胞和结果的变化相关。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。 A phase III trial of Prostvac-VF in metastatic prostate cancer, largely based on the findings in the above trials will begin later in 2011. 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表达CEA的癌已于今年完成。这是该疫苗的人类试验中的第一个。患者以3剂水平招募：4、16和40个酵母单元（每个单位= 107个酵母颗粒）。该疫苗在双侧腹股沟和前胸壁区域的4个位置以相等剂量的剂量给药。疫苗以2周的间隔进行3个月，然后每月一次。符合条件的患者必须具有血清CEA> 5 ng/ml或> 20％CEA+阳性肿瘤阻滞，并且没有自身免疫性病史。招募了10个ECOG PS 0-1 PTS的膨胀队列主要集中于免疫反应。患者在三个月后进行了重新登台扫描，然后进行了两次扫描。从2009年4月至2011年1月，共有25例进行性转移性CEA表达癌的患者招募了22例结肠直肠腺癌。疫苗的耐受性很好，无剂量限制毒性。最常见的不良事件是1/2级注射部位反应。总体而言，治疗后血清CEA的7例患者稳定或下降。在这些患者中，有5例患者患有稳定的疾病，超过3个月，而1例仍在进行中（14 +，8、8、4.5和4个月）。未检测到抗CEA抗体。在9名可评估患者中，有5名通过ELISPOT表明了CEA特异性CD8+ T细胞免疫反应的证据。 8例患者的CD4效应子/Treg比率增加，而NK频率增加了。在这项试验中，酿酒酵母-CEA表现出可接受的安全性。尽管这是患者的晚期人群，这可能不是免疫治疗的理想候选者，但在某些患者中可以看到CEA稳定和免疫反应。需要进一步的随机研究来确定该疫苗的临床益处。目前正在计划对这种药物进行该药物的II期研究。最近与Drs的合作。詹姆斯·古利（James Gulley）（LTIB），威廉·达胡特（William Dahut）（暴民），杰弗里·施洛姆（Jeffry Schlom）（LTIB），铁托·福霍（Tito Fojo）（暴民）和威尔弗雷德·斯坦（Wilfred Stein）（暴民）建议疫苗可能会改变前列腺癌中肿瘤生长动力学。这项研究回顾了5项NCI前列腺癌试验，其中包括一项疫苗（ProstVAC-VF）。基于数学肿瘤生长模型，该分析表明，疫苗（与细胞毒性疗法相比）可能不会立即导致肿瘤体积的立即减少，但是随着时间的流逝，生长速度可能会减慢导致长期结局的改善。这非常重要，因为Patravac和其他FDA批准的免疫疗法（Sipuleucel-T和ipilimumab）已证明了总体生存的改善，而没有短期进展的变化。该分析可以提供第一个机械证据，证明治疗的潜在影响以及明显的延迟益处。目前正在进行中，将这种肿瘤生长动力学变化用作（主要）终点的计划正在进行中。与NCI的癌症免疫学和生物学实验室（CCR）中心（CCR）医学肿瘤学分支机构（MOB）与NCI的医学肿瘤科实验室（MOB）与最近在NCI临床中心的以下协作疫苗临床试验中持续或完成。一项开放式标签试验研究，用于评估Panvac-V（Vaccinia）和Panvac-F（Fowlpox）与Sargramostim（GM-CSF）在转移性腺癌，MOB，MOB，CCR，CCR，NCI中的安全性和耐受性。该试验使用多种肿瘤抗原和多种共刺激分子的转基因载体。最近的一项修正案允许其他患者进一步分析疫苗的功效。一项开放式标签初步研究，以评估非小细胞肺癌（NSCLC）成年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。与室外癌症中心的合作试验：ProstVAC-V（Vaccinia）/Tricom和Prostvac-F（FowlPox）/Tricom的II期研究与GM-CSF的PSA局部治疗患者的PROSTATE癌症患者（东部合作术小组）。与Fowlpox-CEA（6D）-Tricom和Vaccinia-CEA（6D） - 三角体结合GM-CSF和Interferon-Alfa-2b的fowlpox-CEA（6D）-CEA（6D）-CEA（6D）-CEA和Interferon-Alfa-2b的I阶段研究。对denileukin diftitox的调节T细胞耗竭的I期研究，然后是用表达高晚期或转移性恶性肿瘤的患者表达CEA-6D表达Fowlpox-tricom的自体树突状细胞的主动免疫疗法，表达CEA（DUKE综合癌症中心）。 I阶段的研究研究了膀胱癌的患者计划进行膀胱切除术（新泽西州癌症研究所，CINJ）。