Clinical trials employing cancer vaccine combination therapies

最近癌症免疫疗法的大型对照研究中反复出现的发现是总生存期（OS）改善，而中位无进展生存期（PFS）没有改善。这为及时完成概念验证有效性研究提供了障碍。PFS没有改善，最终证实OS改善，这可能是由于免疫治疗给药与临床显著免疫介导的肿瘤生长速率减缓之间存在时滞。第一个治疗性癌症疫苗的批准赋予了更高的优先权，以加强与其他疗法的新型实验性治疗性疫苗的免疫影响。仔细的临床前研究已经强调了标准疗法的能力：（a）以免疫学相关的方式杀死细胞（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已经证明，尽管有标准疗法（例如，化疗）。这些联合研究提供了一个平台，用于检测联合策略影响更传统的II期终点（如PFS）的能力。如果上述关于肿瘤生长速率的假设是正确的，则表明如果可以以不降低免疫应答的方式将联合收割机治疗性疫苗（与延迟效应相关）与标准疗法（与早期但短暂的肿瘤体积减小相关）合理地组合，则可以使用诸如PFS的事件来区分标准治疗方案和组合方案。来自3项小型、随机、II期标准治疗（有或无疫苗）研究的数据支持这种方法。CCR与我们的CRADA合作伙伴BN合作开发了几种疫苗。这些包括Prostvac（PSA-TRICOM），其含有前列腺特异性抗原（PSA）和共刺激分子三联体（TRICOM）的基因，以及Panvac，其含有CEA，MUC-1和TRICOM。两项前列腺癌联合试验表明PFS改善：在44例骨转移性疾病患者中进行的Quadramet联合或不联合Prostvac疫苗（1.7 vs 3.7个月，P = 0.035，HR 0.48）（试验结果正在撰写中）。一项在48例转移性疾病患者中比较多西他赛联合或不联合Panvac疫苗的乳腺癌试验显示，符合方案规定的标准的趋势有利于联合治疗的PFS（3.8 vs 6.6个月，P = 0.09，HR 0.67，试验结果正在撰写中）。合理设计的组合研究有可能显著加快概念验证疗效研究（II期）的分析，并且还可能改善单独标准治疗的患者结局。最近开放的一项合作研究（GMB，UOB，LTIB）正在评估BCG联合或不联合Panvac治疗浅表性膀胱癌患者，这些患者尽管既往接受过BCG治疗，但仍复发。单克隆抗体已与疫苗组合用于治疗各种肿瘤类型。在前列腺癌中，已经测试了人细胞毒性T淋巴细胞抗原-4（CTLA-4）单克隆抗体与疫苗的组合。CTLA-4是T细胞表面糖蛋白，其在T细胞活化后上调以抑制免疫应答。其主要功能是通过调节机体的免疫活性来预防自身免疫。T细胞在其细胞表面上表达两种对抗受体：CD 28和CTLA-4。两者都与APC表面上的相同配体或共刺激分子（B7.1和B7.2，也称为CD 80和CD 86）结合。这些共刺激分子与CD 28的结合激活T细胞，而与CTLA-4的相互作用抑制T细胞刺激。用中和抗体阻断CTLA-4已显示出维持和增强免疫应答。我们最近完成了一项PROSTVAC联合ipilimumab的安全性研究，它阻断了负性共刺激。高达10 mg/kg的易普利姆玛与增强阳性共刺激的疫苗一起安全给药。免疫相关不良事件的比例和级别与先前报告的ipilimumab单药相似。此外，虽然基于经验证的列线图，中位预测生存期约为18个月，但在这项I期研究中，实际中位OS超过34个月（发表在Lancet Oncology上）。OS更新PD 1或PDL 1抑制的最新临床数据加速了免疫治疗领域的兴趣。结果表明，临床反应深刻而持久。然而，从这种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PDL 1表达相关。已经证明，PDL 1表达可以被肿瘤浸润淋巴细胞分泌的IFN-γ上调。原发性前列腺癌表达非常少的PDL 1;因此，抗PD 1和抗PDL 1抗体在这些患者中诱导有限的应答并不奇怪。然而，新的数据表明，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PDL 1表达。这可能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的合作伙伴进行谈判，以便在NIH临床中心进行的临床试验中使用他们阻断PD-1通路的药物与各种治疗性疫苗联合使用。

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.