Strategies for Therapeutic Cancer Vaccine Clinical Trials

治疗性癌症疫苗临床试验策略

• 批准号: 8763100
• 负责人: JEFFREY SCHLOM
• 金额: $ 56.63万
• 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/8763100
• 关键词: Acute Myelocytic Leukemia; Antibodies; Biological Markers; Biopsy; Blinded; Breast; Breast Carcinoma; CD58 gene; CD8B1 gene; Cancer Patient; Cancer Vaccines; Carcinoembryonic Antigen; Carcinoma; Castration; Characteristics; Clinical; Colorectal Cancer; Combined Modality Therapy; Cytotoxic T-Lymphocyte-Associated Protein 4; Data; Death Rate; Development; Dose; Dose-Limiting; Enrollment; Epithelial; Evolution; External Beam Radiation Therapy; Fowlpox; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Growth; Human; Immune; Immune response; Immunity; Immunologics; Immunotherapy; Inflammatory Infiltrate; Injection of therapeutic agent; Intercellular adhesion molecule 1; Kinetics; Lesion; Local Therapy; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Metastatic Carcinoma; Metastatic Prostate Cancer; Methods; Monoclonal Antibodies; Mucin 1 protein; Mucin-1 Staining Method; Mucins; Multicenter Studies; Multicenter Trials; Multiple Myeloma; Nilutamide; Nomograms; Nonmetastatic; Oncogenes; Outcome; Ovarian; Pancreas; Patients; Peripheral; Phase II Clinical Trials; Phase III Clinical Trials; Polysaccharides; Population; Poxviridae; Progression-Free Survivals; Prostate; Prostate carcinoma; Prostate specific antigen measurement; Prostate-Specific Antigen; Randomized; Recombinant Fowlpox-Prostate Specific Antigen; Recombinant Vaccines; Recombinant Vaccinia-Prostate Specific Antigen; Recombinants; Recurrence; Resistance; Retrospective Studies; Safety; Saline; Secondary Immunization; Series; Serum; Solid Neoplasm; T cell response; Therapeutic; Therapeutic Clinical Trial; Thyroid Gland; Time; Toxic effect; Transgenes; Treatment Efficacy; Triad Acrylic Resin; Tumor Antigens; Vaccinated; Vaccination; Vaccine Clinical Trial; Vaccine Therapy; Vaccines; Vaccinia; Vaccinium; arm; base; blood group A trisaccharide; castration resistant prostate cancer; cohort; docetaxel; gastrointestinal; hazard; improved; in vivo; indexing; inhibitor/antagonist; insight; malignant breast neoplasm; men; novel; novel strategies; overexpression; phase 1 study; phase 2 study; phase 3 study; recombinant viral vector; response; subcutaneous; trend; tumor; tumor growth; vector; vector control; vector-based vaccine

PROSTVAC-VF comprises two recombinant viral vectors, each encoding transgenes for prostate-specific antigen (PSA), and three immune costimulatory molecules (B7.1, ICAM-1, and LFA-3, designated TRICOM). Vaccinia-based vector was used for priming followed by six planned fowlpox-based vector boosts. PROSTVAC-VF treatment was evaluated for safety and for prolongation of progression-free survival (PFS) and overall survival (OS) in a randomized, controlled, and blinded phase II study. In total, 125 patients were randomly assigned in a multicenter trial of vaccination series. Eligible patients had minimally symptomatic castration-resistant metastatic prostate cancer (mCRPC). Patients were allocated (2:1) to PROSTVAC-VF plus granulocyte-macrophage colony-stimulating factor or to control empty vectors plus saline injections. Eighty-two patients received PROSTVAC-VF and 40 received control vectors. Patient characteristics were similar in both groups. The primary end point was PFS, which was similar in the two groups (P = .6). However, at 3 years post study, PROSTVAC-VF patients had a better OS with 25 (30%) of 82 alive versus 7 (17%) of 40 controls, longer median survival by 8.5 months (25.1 v 16.6 months for controls), an estimated hazard ratio of 0.56, and stratified log-rank P = .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 PROSTVAC-VF provided further evidence of enhanced median OS (p = 0.0061) in patients with mCRPC. Thirty-two patients were vaccinated once with recombinant vaccinia containing the transgenes for PSA and three costimulatory molecules. Patients received boosters with recombinant fowlpox containing the same four transgenes. Twelve of 32 patients showed declines in serum PSA post-vaccination and 2/12 showed decreases in index lesions. Median OS was 26.6 months (predicted median OS by the Halabi nomogram was 17.4 months). Patients with greater PSA-specific T-cell responses showed a trend (p = 0.055) toward enhanced survival. In solid tumors such as prostate cancer, novel paradigms are needed to assess therapeutic efficacy. We utilized a method estimating tumor growth and regression rate constants from serial PSA measurements, and assessed its potential in patients with metastatic castration resistant prostate carcinoma (mCRPC). Patients were enrolled in five phase II studies, including an experimental vaccine trial, representing the evolution of therapy in mCRPC. Growth rate constants correlated with survival, except in patients receiving vaccine-based therapy where the evidence demonstrates prolonged survival presumably due to immunity developing subsequent to vaccine administration. The PSA-TRICOM vaccine appears to have provided marked benefit not apparent during vaccination, but consistent with subsequent development of a beneficial immune response. A recently completed study in mCRPC demonstrated that when ipilimumab (anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA4) monoclonal antibody) was combined with PSA-TRICOM (PROSTVAC) at escalating doses, the median survival was 34 months, which compares favorably to previous vaccine trials in mCRPC that resulted in median survivals of approximately 26 months. These and other data support the rationale for randomized studies employing immune checkpoint inhibitors in combination with TRICOM-based vaccines. Two of the most widely studied human tumor-associated antigens (TAAs) are CEA and mucin-1 (MUC-1). CEA is overexpressed in a wide range of human carcinomas, including gastrointestinal, breast, lung, pancreatic, medullary thyroid, ovarian, and prostate. MUC-1 is a tumor-associated mucin, which is overexpressed and hypoglycosylated in all human carcinomas as well as in acute myeloid leukemia (AML) and multiple myeloma. Studies have demonstrated that the C-terminus of MUC-1 functions as an oncogene. A study was conducted to obtain preliminary evidence of clinical response in metastatic breast and ovarian cancer patients with PANVAC (rV,rF-CEA-MUC1-TRICOM). A randomized multicenter study has been initiated evaluating docetaxel vs docetaxel plus PANVAC vaccine (rV-, rF-CEA-MUC1-TRICOM) in patients (n=48) with metastatic breast carcinoma. Preliminary findings to date indicate a substantial increase in time to progression in the combination arm vs the docetaxel alone arm. A Phase I study of intraprostatic vaccine administration in men with locally recurrent or progressive prostate cancer has been completed. The primary end point of this study was to determine the safety and feasibility of intraprostatic administration of PSA-TRICOM vaccine in patients with locally recurrent or progressive prostate cancer. This trial was a standard 3+ 3 dose escalation with 6 patients each in cohorts 4 and 5 to gather more immunologic data. Nineteen of 21 patients enrolled had locally recurrent prostate cancer after definitive radiation therapy, and 2 had no local therapy. All cohorts received initial subcutaneous vaccination with recombinant vaccinia (rV)-PSA-TRICOM and intraprostatic booster vaccinations with recombinant fowlpox (rF)-PSA-TRICOM. There were no dose-limiting toxicities. Overall, 19 of 21 patients on trial had stable (10) or improved (9) PSA values. There was a marked increase in CD4+ (p = 0.0002) and CD8+ (p = 0.0002) tumor infiltrates in post- versus pre-treatment tumor biopsies. Four of 9 patients evaluated had peripheral immune responses to PSA or NGEP. Intraprostatic administration of PSA-TRICOM is safe and feasible and can generate a significant immunologic response. Improved serum PSA kinetics and intense post-vaccination inflammatory infiltrates were seen in the majority of patients. Methods to predict clinical outcomes of therapeutic cancer vaccines will advance the field and provide new insights into critical determinants of in vivo efficacy. A retrospective study included 141 subjects from phase II trials of PROSTVAC-VF, a poxvirus-based cancer vaccine currently in phase III clinical trials for advanced prostate cancer. A glycan microarray was used to profile prevaccination antiglycan antibody populations in sera as potential biomarkers for PROSTVAC-VF. The screen for predictive biomarkers identified antiglycan antibodies that consistently stratified subjects into groups with different Kaplan-Meier survival estimates. Prevaccination antibody levels to blood group A trisaccharide (BG-Atri) were found to have a statistically significant correlation with survival. Long-term survival was approximately doubled in subjects with abundant anti-BG-Atri immunoglobulinM(IgM). This survival correlation was specific to vaccine treatment, as no correlation was observed in control patients immunized with wild-type poxviruses lacking the key tumor antigen, PSA.

PROSTVAC-VF 包含两个重组病毒载体，每个载体编码前列腺特异性抗原 (PSA) 的转基因，以及三个免疫共刺激分子（B7.1、ICAM-1 和 LFA-3，指定为 TRICOM）。使用基于牛痘的载体进行启动，然后进行六次计划的基于鸡痘的载体加强。在一项随机、对照、盲法 II 期研究中，评估了 PROSTVAC-VF 治疗的安全性以及无进展生存期 (PFS) 和总生存期 (OS) 的延长。总共 125 名患者被随机分配参加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）。患者被分配 (2:1) 至 PROSTVAC-VF 加粒细胞巨噬细胞集落刺激因子组或对照空载体加盐水注射组。 82 名患者接受了 PROSTVAC-VF，40 名患者接受了对照载体。两组患者的特征相似。主要终点是 PFS，两组相似 (P = .6)。然而，在研究后 3 年，PROSTVAC-VF 患者的 OS 更好，82 名患者中有 25 名（30%）存活，而 40 名对照患者中有 7 名（17%）存活，中位生存期延长了 8.5 个月（对照为 25.1 个月 vs 16.6 个月）。估计风险比为 0.56，分层对数秩 P = .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。采用 PROSTVAC-VF 的并行多中心、随机 II 期试验提供了 mCRPC 患者中位 OS 提高的进一步证据 (p = 0.0061)。 32 名患者接受了一次含有 PSA 转基因和三种共刺激分子的重组牛痘疫苗接种。患者接受了含有相同四种转基因的重组鸡痘加强疫苗。 32 名患者中有 12 名在接种疫苗后表现出血清 PSA 下降，其中 2/12 表现出指数病变减少。中位 OS 为 26.6 个月（Halabi 列线图预测的中位 OS 为 17.4 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)。在前列腺癌等实体瘤中，需要新的范例来评估治疗效果。我们采用了一种通过连续 PSA 测量来估计肿瘤生长和消退速率常数的方法，并评估了其在转移性去势抵抗性前列腺癌 (mCRPC) 患者中的潜力。患者参加了五项 II 期研究，其中包括一项实验性疫苗试验，代表了 mCRPC 治疗的演变。生长速率常数与生存相关，但接受疫苗治疗的患者除外，有证据表明生存期延长可能是由于疫苗接种后产生的免疫力所致。 PSA-TRICOM 疫苗似乎提供了在疫苗接种期间不明显的显着益处，但与随后产生的有益免疫反应一致。最近完成的一项针对 mCRPC 的研究表明，当 ipilimumab（抗细胞毒性 T 淋巴细胞相关抗原 4 (CTLA4) 单克隆抗体）与 PSA-TRICOM (PROSTVAC) 以递增剂量联合使用时，中位生存期为 34 个月，优于此前 mCRPC 疫苗试验的中位生存期约为 26 个月。这些数据和其他数据支持了采用免疫检查点抑制剂与基于 TRICOM 的疫苗相结合的随机研究的基本原理。研究最广泛的两种人类肿瘤相关抗原 (TAA) 是 CEA 和粘蛋白-1 (MUC-1)。 CEA 在多种人类癌症中过度表达，包括胃肠癌、乳腺癌、肺癌、胰腺癌、甲状腺髓样癌、卵巢癌和前列腺癌。 MUC-1 是一种肿瘤相关粘蛋白，在所有人类癌症以及急性髓性白血病 (AML) 和多发性骨髓瘤中过度表达且糖基化程度低。研究表明，MUC-1 的 C 末端具有癌基因的功能。进行了一项研究，以获得转移性乳腺癌和卵巢癌患者使用 PANVAC (rV,rF-CEA-MUC1-TRICOM) 的临床反应的初步证据。一项随机多中心研究已开始评估多西他赛与多西他赛加 PANVAC 疫苗（rV-、rF-CEA-MUC1-TRICOM）在转移性乳腺癌患者 (n=48) 中的作用。迄今为止的初步研究结果表明，与单用多西他赛组相比，联合治疗组的进展时间显着增加。对患有局部复发或进行性前列腺癌的男性进行前列腺内疫苗接种的 I 期研究已经完成。本研究的主要终点是确定局部复发或进展性前列腺癌患者前列腺内注射 PSA-TRICOM 疫苗的安全性和可行性。该试验是标准的 3+3 剂量递增，第 4 组和第 5 组各有 6 名患者，以收集更多免疫学数据。入组的 21 名患者中有 19 名在明确的放射治疗后患有局部复发性前列腺癌，2 名患者未接受局部治疗。所有队列均接受了重组牛痘 (rV)-PSA-TRICOM 的初始皮下疫苗接种和重组鸡痘 (rF)-PSA-TRICOM 的前列腺内加强疫苗接种。没有剂量限制性毒性。总体而言，参与试验的 21 名患者中有 19 名 PSA 值稳定 (10) 或改善 (9)。与治疗前的肿瘤活检相比，治疗后的 CD4+ (p = 0.0002) 和 CD8+ (p = 0.0002) 肿瘤浸润显着增加。接受评估的 9 名患者中有 4 名对 PSA 或 NGEP 有外周免疫反应。前列腺内注射 PSA-TRICOM 是安全可行的，并且可以产生显着的免疫反应。大多数患者的血清 PSA 动力学得到改善，疫苗接种后炎症浸润明显。预测治疗性癌症疫苗临床结果的方法将推动该领域的发展，并为体内功效的关键决定因素提供新的见解。一项回顾性研究纳入了 PROSTVAC-VF II 期试验的 141 名受试者，PROSTVAC-VF 是一种基于痘病毒的癌症疫苗，目前正在进行晚期前列腺癌的 III 期临床试验。使用聚糖微阵列来分析血清中的疫苗接种前抗聚糖抗体群体，作为 PROSTVAC-VF 的潜在生物标志物。预测性生物标志物的筛选鉴定出抗聚糖抗体，该抗体始终将受试者分为具有不同 Kaplan-Meier 生存估计的组。研究发现，A 型血三糖 (BG-Atri) 的疫苗接种前抗体水平与生存率具有统计学显着相关性。具有丰富抗 BG-Atri 免疫球蛋白 M (IgM) 的受试者的长期生存率大约增加了一倍。这种生存相关性是疫苗治疗所特有的，因为在用缺乏关键肿瘤抗原 PSA 的野生型痘病毒免疫的对照患者中没有观察到相关性。