Clinical trials employing cancer vaccine combination therapies

在最近的大型癌症免疫治疗对照研究中，一个反复出现的发现是改善了总生存期(OS)，但没有改善中位无进展生存期(PFS)。这为及时完成概念验证功效研究提供了障碍。PFS没有改善，最终证明OS得到了改善，这可能是由于实施免疫治疗和临床上显著的免疫介导的肿瘤生长速度放缓之间的时间滞后所致。第一种治疗性癌症疫苗的批准使与其他疗法相结合的新型实验性治疗性疫苗的免疫学影响得到了更高的优先考虑。仔细的临床前研究强调了标准疗法的能力：(A)以免疫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，尽管有标准的治疗方法(如化疗)，宿主仍有能力对疫苗产生免疫反应。这些联合研究提供了一个平台，用于测试联合战略对PFS等更传统的第二阶段端点的影响能力。如果上述关于肿瘤生长速度的假设是正确的，它表明，如果一个人能够合理地将治疗性疫苗(与延迟效应相关)与标准疗法(与早期但短暂的肿瘤体积减少相关)结合在一起，而不降低免疫反应，那么人们可能能够使用PFS等事件来区分标准护理方案和联合方案。有或没有疫苗的标准治疗的3个小规模随机II期研究的数据支持这一方法。CCR与我们的CRADA合作伙伴BN合作开发了几种疫苗。其中包括前列腺特异性抗原(PSA-Tricom)，它含有前列腺特异性抗原(PSA)基因和三种共刺激分子(Tricom)，以及PANVAC，它含有CEA，MUC-1和Tricom。前列腺癌的两项联合试验表明，在使用或不使用Prostvac疫苗的情况下，Quadramet在44名骨转移疾病患者中(1.7月vs.3.7月，P=0.035，HR0.48)的治疗效果有所改善(试验结果正在撰写中)。一项乳腺癌试验在48名转移性疾病患者中比较了使用或不使用PANVAC疫苗的多西紫杉醇，结果表明，在PFS中，符合方案规定的标准的趋势有利于这种组合(3.8个月对6.6个月，P=0.09，HR 0.67，试验结果正在撰写中)。MS发表的《美国医学会肿瘤学杂志2015》合理设计的联合研究有可能显著加快概念验证疗效研究(第二阶段)的分析速度，并可能比单独使用标准疗法改善患者结果。最近开展的一项合作研究(GMB、UOB、LTIB)正在评估BCG在使用或不使用PANVAC的浅表性膀胱癌患者中的作用，这些患者尽管有BCG史，但仍有复发。单抗已经与疫苗结合起来，用于治疗各种类型的肿瘤。在前列腺癌中，一种人类细胞毒性T淋巴细胞抗原-4(CTLA-4)的单抗已经与疫苗一起进行了测试。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。它的主要功能是通过调节人体的免疫活动来防止自身免疫。T细胞在其细胞表面表达两种拮抗受体：CD28和CTLA-4。两者都结合到APC表面的相同配体或共刺激分子(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相互作用则抑制T细胞刺激。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联合使用前列环素和单抗的安全性研究，该单抗可以阻断负性共刺激作用。使用增强积极共刺激作用的疫苗可以安全地注射高达10 mg/kg的ipilimumab。与免疫相关的不良事件在比例和分级上与之前报道的单独使用ipilimumab的情况相似。此外，虽然根据有效的诺模图预测的中位生存期约为18个月，但在这项I期研究(发表在《柳叶刀肿瘤学》上)中，实际的中位OS超过34个月。关于PD1或PDL1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，作为单一药物从这种方法中获益的患者比例仍然有限，许多研究报告了20%-30%的客观应答率。然而，这些反应通常与肿瘤水平上潜在的PDL1表达有关。已有研究表明，肿瘤浸润性淋巴细胞分泌的干扰素-γ可上调PDL1的表达。新发前列腺癌只表达很少的PDL1；因此，抗PD1和抗PDL1抗体在这些患者中诱导的反应有限也就不足为奇了。然而，新出现的数据表明，前列腺癌治疗性疫苗可以将激活的T淋巴细胞驱动到肿瘤中，并上调PDL1的表达。这可能会使没有反应的肿瘤更有可能对免疫检查点抑制产生反应。我目前正在与一些潜在的合作伙伴谈判，希望在NIH临床中心进行的临床试验中，将他们阻断PD-1途径的药物与各种治疗性疫苗结合使用。

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.