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.

在最近对癌症免疫疗法的大型，对照研究中，反复的发现已改善了总体生存（OS），而无需改善中值无进展生存期（PFS）。这为及时完成概念验证效力研究提供了一个障碍。在PFS中缺乏改善，最终证明OS的改善可能是由于给予免疫疗法和临床上显着的免疫介导的肿瘤生长速率减慢速度之间的时间差。批准第一种治疗性癌症疫苗已授予更高的优先级，以增强新型实验治疗疫苗对其他疗法的免疫学影响。仔细的临床前研究突出了标准疗法以免疫学相关的方式杀死细胞的能力（免疫原性死亡），以及（b）改变幸存细胞的表型，使其更容易受到免疫介导的识别和杀伤（免疫原性调节）。这导致了合理设计的研究，将治疗性癌症疫苗与标准疗法相结合。这些最近的临床前和临床研究表明，尽管有标准疗法（例如化学疗法），宿主具有对疫苗免疫反应的能力。这些组合研究提供了一个平台，用于测试组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率的假设是正确的，则表明，如果可以将治疗性疫苗（与延迟作用相关）与标准疗法（与早期但短暂的肿瘤体积减少相关），以不会降低免疫反应的方式，则可以使用诸如PFS（例如PFS），例如使用标准的组合和组合方法。来自标准治疗的3个小型随机II期研究的数据，有或没有疫苗支持这种方法。 CCR与我们的Crada合作伙伴BN联合开发了几种疫苗。其中包括Prostvac（PSA-Tricom），其中包含前列腺特异性抗原（PSA）的基因和含有CEA，MUC-1和TROCOM的Cotimulation Molecules（Tricom）和Panvac的三合会。前列腺癌中的两项组合试验表明，PFS的改善：有或没有前列腺疫苗的二聚体（1.7 vs. 3.7个月，P = 0.035，HR 0.48）在44例疾病转移性疾病到骨骼的患者中（试验结果正在编写）。在48例转移性疾病的患者中，一项乳腺癌试验比较了有或没有panvac疫苗的多西他赛的一项趋势，该趋势符合方案指定的标准，有利于PFS组合（3.8 vs. 6.6个月，P = 0.09，HR 0.67，HR 0.67，编写试验结果）。 MS发表的JAMA肿瘤学2015年合理设计的组合研究有可能在概念证明疗效研究（II阶段）中显着加快分析，并且还可以改善仅标准治疗而不是标准治疗的患者结果。最近开放的合作研究（GMB，UOB，LTIB）正在评估有或没有PANVAC的BCG，无论是否在BCG之前都复发，但伴有或不使用PANVAC。单克隆抗体已与疫苗结合使用，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结合进行了测试。 CTLA-4是T细胞表面糖蛋白，在T细胞激活后被上调以抑制免疫反应。它的主要功能是通过调节人体的免疫活性来防止自身免疫性。 T细胞在其细胞表面表达两个应对受体：CD28和CTLA-4。两者都与APC表面（B7.1和B7.2，也称为CD80和CD86）的同一配体或共刺激分子结合。这些共刺激分子与CD28的结合激活T细胞，而与CTLA-4相互作用抑制了T细胞刺激。用中和抗体阻断CTLA-4可以维持和增强免疫反应。我们最近完成了对Prostvac和ipilimumab结合的安全研究，该研究阻碍了负面刺激。使用可增强阳性共刺激的疫苗安全施用高达10 mg/kg的ipilimumab。免疫相关的不良事件的比例和等级与先前仅用ipilimumab报道的不良事件相似。此外，尽管基于经过验证的诺图的中位数预测生存时间约为18个月，但在本I阶段研究中，实际中位OS超过34个月（发表在柳叶刀肿瘤学上）。 OS更新有关PD1或PDL1抑制的临床数据已加速对免疫疗法领域的兴趣。结果表明，深层耐用的临床反应。但是，从这种方法作为单一药物中获得受益的患者的比例仍然有限，许多研究报告了20％-30％的客观反应率。但是，这些反应通常与肿瘤水平上的潜在PDL1表达有关。已经证明，通过肿瘤浸润淋巴细胞分泌的IFN-GAMMA可以上调PDL1的表达。从头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。但是，新兴数据表明，前列腺癌治疗疫苗可以将活化的T淋巴细胞驱动到肿瘤中，并提高调节PDL1的表达。这可能会使无反应性肿瘤更有可能对免疫检查点抑制作用。我目前正在与许多潜在伴侣进行谈判，以使用其代理人阻止PD-1途径，并在NIH临床中心进行临床试验中的各种治疗疫苗结合使用。