Clinical trials employing cancer vaccine combination therapies

采用癌症疫苗联合疗法的临床试验

• 批准号: 9153720
• 负责人: James L. Gulley
• 金额: $ 32.42万
• 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/9153720
• 关键词: ARI brand of 153Sm-EDTMP; Adverse event; Antibodies; Autoimmunity; Binding; Bladder; Breast; CA-15-3 Antigen; CCR; CD28 gene; CD80 gene; Cancer Vaccines; Caring; Cell Death; Cell surface; Cells; Clinical; Clinical Data; Clinical Research; Clinical Trials; Colorectal; Combined Modality Therapy; Controlled Study; Cooperative Research and Development Agreement; Cytotoxic T-Lymphocyte-Associated Protein 4; Data; Disease; Event; Genes; Goals; Human; Immune; Immune response; Immunologics; Immunotherapy; Interferon Type II; Investigational Therapies; Ligands; Lung; Malignant Neoplasms; Malignant neoplasm of prostate; Malignant neoplasm of urinary bladder; Mediating; Mediation; Membrane Glycoproteins; Metastatic to; Monoclonal Antibodies; Nomograms; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phenotype; Progression-Free Survivals; Prostate; Prostate-Specific Antigen; Protocols documentation; Publishing; Radiation; Randomized; Recombinant Vaccines; Recombinants; Recurrence; Regimen; Reporting; Research Design; Running; Specific qualifier value; Surface; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Time; Triad Acrylic Resin; Tumor Volume; Tumor-Infiltrating Lymphocytes; United States National Institutes of Health; Update; Vaccines; Writing; base; bone; cancer immunotherapy; cell killing; chemotherapy; clinically significant; cytokine; design; docetaxel; immunogenic; improved; interest; killings; malignant breast neoplasm; meetings; neutralizing antibody; novel; oncology; phase 1 study; phase 2 study; preclinical study; prevent; receptor; response; safety study; therapeutic vaccine; trend; trial comparing; tumor; tumor growth; vaccine efficacy

A recurrent finding in recent large, controlled studies of immunotherapies for cancer has been improved overall survival (OS) without an improvement in median progression-free survival (PFS). This provides a hurdle for timely completion of proof-of-concept efficacy studies. This lack of improvement in PFS with eventual demonstration of improved OS may be due to the time lag between administering the immunotherapy and a clinically significant immune-mediated slowing of the tumor growth rate. Approval of the first therapeutic cancer vaccine has conferred higher priority on the effort to augment the immunologic impact of novel experimental therapeutic vaccines with other therapies. Careful preclinical studies have highlighted the ability of standard therapies to (a) kill cells in an immunologically relevant manner (immunogenic cell death) and (b) change the phenotype of surviving cells to make them more susceptible to immune-mediated recognition and killing (immunogenic modulation). This has led to rationally designed studies combining therapeutic cancer vaccines with standard therapies. These recent preclinical and clinical studies have demonstrated the host's ability to mount immune responses to vaccine despite standard therapies (e.g., chemotherapy). These combination studies provide a platform for testing the ability of combination strategies to impact more traditional phase II endpoints such as PFS. If the above hypothesis on tumor growth rate is correct, it suggests that if one could rationally combine therapeutic vaccines (associated with delayed effects) with standard therapies (associated with an early but transient decrease in tumor volume) in a manner that doesn't decrease immune responses, then one might be able to use events such as PFS to discriminate between standard-of-care and combination regimens. Data from 3 small, randomized phase II studies of standard therapy with or without vaccine support this approach. Several vaccines have been developed within the CCR in association with BN, our CRADA partner. These include Prostvac (PSA-TRICOM), which contains genes for prostate-specific antigen (PSA) and a triad of costimulatory molecules (TRICOM), and Panvac, which contains CEA, MUC-1 and TRICOM. Two combination trials in prostate cancer suggest an improvement in PFS: Quadramet with or without Prostvac vaccine (1.7 vs. 3.7 months, P = 0.035, HR 0.48) in 44 patients with disease metastatic to bone (trial results being written). A breast cancer trial comparing docetaxel with or without Panvac vaccine in 48 patients with metastatic disease shows a trend that met protocol specified criteria favoring the combination in PFS (3.8 vs. 6.6 months, P = 0.09, HR 0.67, trial results being written). MS Published JAMA Oncology 2015 Rationally designed combination studies have the potential to significantly expedite analysis in proof-of-concept efficacy studies (phase II) and may also improve patient outcomes over standard therapy alone. A recently opened collaborative study (GMB, UOB, LTIB) is evaluating BCG with or without Panvac in patients with superficial bladder cancer who have recurrence despite prior BCG. Monoclonal antibodies have been combined with vaccines for the treatment of various tumor types. In prostate cancer, a human cytotoxic T-lymphocyte antigen-4 (CTLA-4) monoclonal antibody has been tested in combination with vaccines. CTLA-4 is a T-cell surface glycoprotein that is upregulated following T-cell activation to inhibit the immune response. Its main function is to prevent autoimmunity by regulating the body's immune activity. T cells express two counteracting receptors on their cell surface: CD28 and CTLA-4. Both bind to the same ligands or costimulatory molecules on the surface of APCs (B7.1 and B7.2, also known as CD80 and CD86). Binding of these costimulatory molecules to CD28 activates T cells, while interacting with CTLA-4 inhibits T-cell stimulation. Blocking CTLA-4 with a neutralizing antibody has been shown to sustain and potentiate immune responses. We have recently completed a safety study of PROSTVAC combined with ipilimumab, which blocks negative costimulation. Up to 10 mg/kg of ipilimumab was safely administered with a vaccine that enhances positive costimulation. Immune-related adverse events were similar in proportion and grade to those previously reported with ipilimumab alone. Furthermore, while the median predicted survival was about 18 months based on a validated nomogram, actual median OS exceeded 34 months in this phase I study (published in Lancet Oncology). OS update recent clinical data on PD1 or PDL1 inhibition have accelerated interest in the field of immunotherapy. Results have suggested deep and durable clinical response. However, the proportion of patients who derive benefit from this approach as a single agent remains limited, with many studies reporting a 20%-30% objective response rate. Often, however, these responses are associated with underlying PDL1 expression at the level of the tumor. It has been demonstrated that PDL1 expression can be upregulated by IFN-gamma secreted by tumor-infiltrating lymphocytes. De novo prostate cancer expresses very little PDL1; thus, it is not surprising that anti-PD1 and anti-PDL1 antibodies have induced limited responses in these patients. However, emerging data suggest that prostate cancer therapeutic vaccines can drive activated T lymphocytes into the tumor and up regulate PDL1 expression. This could make an unresponsive tumor much more likely to respond to immune checkpoint inhibition. I am currently in negotiations with a number of potential partners to use their agents blocking the PD-1 pathway in combination with various therapeutic vaccines in clinical trials to be run at the NIH Clinical Center.

最近针对癌症免疫疗法的大型对照研究反复发现，总生存期 (OS) 得到改善，但中位无进展生存期 (PFS) 却没有改善。这为及时完成概念验证功效研究提供了障碍。 PFS 缺乏改善，但最终证明 OS 有所改善，可能是由于免疫治疗与临床上显着的免疫介导的肿瘤生长速度减慢之间存在时间滞后。第一个治疗性癌症疫苗的批准赋予了我们更加优先的努力，以增强新型实验性治疗性疫苗与其他疗法的免疫学影响。仔细的临床前研究强调了标准疗法能够（a）以免疫相关方式杀死细胞（免疫原性细胞死亡）和（b）改变存活细胞的表型，使它们更容易受到免疫介导的识别和杀死（免疫原性细胞死亡）的影响。调制）。这导致了将治疗性癌症疫苗与标准疗法相结合的合理设计的研究。这些最近的临床前和临床研究表明，尽管采用标准疗法（例如化疗），宿主仍能够对疫苗产生免疫反应。这些联合研究提供了一个平台，用于测试联合策略影响更传统的 II 期终点（例如 PFS）的能力。如果上述关于肿瘤生长速度的假设是正确的，则表明如果人们能够以一种不减少肿瘤体积的方式合理地将治疗性疫苗（与延迟效应相关）与标准疗法（与肿瘤体积的早期但短暂的减少相关）结合起来免疫反应，那么人们也许能够利用 PFS 等事件来区分标准护理方案和联合方案。来自 3 项小型随机 II 期研究的数据支持这种方法，这些研究涉及有或没有疫苗的标准疗法。 CCR 与我们的 CRADA 合作伙伴 BN 合作开发了多种疫苗。其中包括 Prostvac (PSA-TRICOM)，它含有前列腺特异性抗原 (PSA) 和三联体共刺激分子 (TRICOM) 的基因，以及 Panvac，它含有 CEA、MUC-1 和 TRICOM。两项针对前列腺癌的联合试验表明，在 44 名骨转移性疾病患者中，使用或不使用 Prostvac 疫苗的 Quadramet 可以改善 PFS（1.7 个月与 3.7 个月，P = 0.035，HR 0.48）（试验结果正在撰写中）。一项在 48 名转移性疾病患者中比较多西紫杉醇联合或不联合 Panvac 疫苗的乳腺癌试验显示出符合方案规定的有利于 PFS 联合治疗标准的趋势（3.8 个月与 6.6 个月，P = 0.09，HR 0.67，试验结果正在撰写中）。 MS 发表的 JAMA Oncology 2015 合理设计的联合研究有可能显着加快概念验证疗效研究（II 期）的分析，并且还可能比单独的标准治疗改善患者的治疗结果。最近开展的一项合作研究（GMB、UOB、LTIB）正在评估使用或不使用 Panvac 的卡介苗治疗浅表性膀胱癌患者，这些患者既往接受过卡介苗治疗但仍复发。单克隆抗体已与疫苗联合用于治疗各种肿瘤类型。在前列腺癌中，人类细胞毒性 T 淋巴细胞抗原 4 (CTLA-4) 单克隆抗体已与疫苗联合进行了测试。 CTLA-4 是一种 T 细胞表面糖蛋白，在 T 细胞激活后上调以抑制免疫反应。其主要功能是通过调节机体的免疫活性来预防自身免疫性疾病。 T 细胞在其细胞表面表达两种拮抗受体：CD28 和 CTLA-4。两者都与 APC 表面上的相同配体或共刺激分子结合（B7.1 和 B7.2，也称为 CD80 和 CD86）。这些共刺激分子与 CD28 结合可激活 T 细胞，而与 CTLA-4 相互作用则可抑制 T 细胞刺激。使用中和抗体阻断 CTLA-4 已被证明可以维持和增强免疫反应。我们最近完成了一项 PROSTVAC 联合 ipilimumab 的安全性研究，该研究可阻断负性共刺激。高达 10 mg/kg 的易普利姆玛 (ipilimumab) 与可增强正向共刺激的疫苗一起安全施用。免疫相关不良事件的比例和等级与之前单独使用伊匹单抗报告的不良事件相似。此外，虽然根据经过验证的列线图，预测生存期中位数约为 18 个月，但在这项 I 期研究（发表在《柳叶刀肿瘤学》上）中，实际中位 OS 超过 34 个月。 OS 更新有关 PD1 或 PDL1 抑制的最新临床数据加速了人们对免疫治疗领域的兴趣。结果表明有深入而持久的临床反应。然而，从这种单一药物治疗方法中获益的患者比例仍然有限，许多研究报告的客观缓解率为 20%-30%。然而，这些反应通常与肿瘤水平的潜在 PDL1 表达相关。已证明肿瘤浸润淋巴细胞分泌的IFN-γ可以上调PDL1的表达。新发前列腺癌表达很少的 PDL1；因此，抗 PD1 和抗 PDL1 抗体在这些患者中诱导有限的反应也就不足为奇了。然而，新出现的数据表明，前列腺癌治疗疫苗可以驱动活化的 T 淋巴细胞进入肿瘤并上调 PDL1 表达。这可能会使无反应的肿瘤更有可能对免疫检查点抑制做出反应。我目前正在与一些潜在合作伙伴进行谈判，以在 NIH 临床中心进行的临床试验中使用他们的阻断 PD-1 途径的药物与各种治疗性疫苗相结合。