Clinical trials employing cancer vaccine combination therapies

在过去的5年里，许多癌症新疗法的重点已经转移到包括免疫疗法。这部分是由于免疫检查点抑制剂的快速、深刻和持久的反应。然而，这些重要的临床结果只出现在一小部分患者身上，即那些对肿瘤有免疫识别的患者。Gulley博士的临床试验数据表明，治疗性疫苗可以有效地对疫苗中存在的靶点和肿瘤细胞中的靶点产生免疫识别和激活（多篇出版物）。此外，接种疫苗后浸润增加（ASCO 2018提出）。然而，如果没有在肿瘤微环境中提供足够的效应功能，这种抗肿瘤免疫反应可能不足以改善患者的临床结果。有多个免疫检查点参与免疫激活。CCR临床前研究提示疫苗与CTLA4阻断剂有协同作用。Gulley博士是首批将CCR开发的疫苗（PSA-TRICOM）与抗ctla4抗体ipilimumab相结合的研究之一的负责人。ipilimumab与PSA-TRICOM一起安全给药高达10mg /kg。免疫相关不良事件的比例和级别与先前单独使用伊匹单抗报道的相似。此外，虽然基于有效的nomogram中位预测生存期约为18个月，但在该I期研究中，实际中位OS超过了34个月。这也优于单独使用易普利姆单抗的OS数据，然而，需要一项随机研究来验证这些假设产生的结果。最近关于PD1或PDL1抑制的临床数据加速了人们对免疫治疗领域的兴趣。Gulley博士是唯一一种抗PDL1抗体的I期剂量递增研究的协调PI，该抗体不仅可以拮抗PDL1，还可以启动抗体介导的细胞毒性（ADCC）。该药物的首次人体国际研究由我们的CRADA合作伙伴EMD-Serono赞助，在NIH临床中心招募了125名患者，并在各种癌症（包括肺癌，胸腺上皮恶性肿瘤，间皮瘤，膀胱癌和卵巢癌）中显示出显着的长期反应。我们的数据还表明，ADCC对也能表达PDL1的免疫细胞没有影响（尽管其表达水平通常低于肿瘤细胞）。基于这些临床数据，FDA最近批准了avelumab用于膀胱癌患者。这一数据也在一定程度上用于批准avelumab治疗默克尔细胞癌。然而，免疫检查点抑制需要一个潜在的抗肿瘤免疫反应，它可以释放。在前列腺癌中，前列腺内激活的免疫细胞水平是有限的。因此，疫苗联合PDL1阻断剂是一种合理的免疫治疗方法。我们现在有多个正在进行的CCR研究着眼于免疫检查点抑制的疫苗。我们最近还开展了一项首次在人体中使用的一流抗pdl1 /TGF β诱捕剂（M7824），其初步数据在ASCO 2017和ASCO 2018上公布，并于2019年发表，证明了安全性和活性的初步证据（包括前19名患者的pr和CR）。与单独抑制PD-1或PDL-1相比，HPV相关癌症（约35% ORR）和非小细胞肺癌（约28% ORR）的活性似乎有所增加（数据提交于ASCO 2018）。这项研究为利用M7824阻断两种重要的抑制有效抗癌免疫反应的负调控机制的多重联合治疗研究打开了大门。这些正在进行的研究还将建立活检和其他相关研究，以分析联合治疗对肿瘤微环境的影响。此外，使用标准护理疗法来促进免疫识别和/或杀死肿瘤，这一过程称为免疫原性调节，已由Gulley博士进行了测试。最近发表的两项小型CCR随机II期研究的数据表明，使用或不使用疫苗的标准治疗可能影响无进展生存期。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)，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，Panvac包含CEA， MUC-1和TRICOM。一项针对前列腺癌的联合试验表明，在44例疾病转移至骨的患者中，使用或不使用Prostvac疫苗的Quadramet（1.7个月vs 3.7个月，P = 0.041, HR 0.51）的PFS得到改善（Oncotarget 2016）。一项在48例转移性疾病患者中比较多西他赛加或不加Panvac疫苗的乳腺癌试验显示，在PFS（7.9个月vs 3.9个月，P = 0.09, HR 0.65）中，符合预先定义的阳性研究标准的趋势，有利于联合用药（JAMA Oncology 2015）。Gulley博士和团队也进行了多项研究，结合启动免疫反应的方式（疫苗或肿瘤靶向细胞因子）以及免疫检查点抑制和/或tgb - β抑制、细胞因子、IDO抑制或小分子抑制剂。疫苗和免疫检查点抑制的初步研究显示，前列腺癌患者产生了深刻而持久的反应，正在积累更多的患者进行进一步研究。

Much of the focus of new therapies for cancer has shifted in the last 5 years to include immunotherapy. This is in part due to the rapid, profound and durable responses seen with immune checkpoint inhibitors. However, these important clinical results are only seen in a subset of patients, ones with and underlying immune recognition of the tumor. Data from Dr. Gulley's clinical trials has suggested that therapeutic vaccines can efficiently generate immune recognition and activation against targets present in the vaccine and found in tumor cells (multiple publications). In addition, there is an increased infiltrate following vaccine (presented ASCO 2018). However, this anti-tumor immune response may not be sufficient to generate an improvement in clinical outcome for the patient without providing for adequate effector functionality within the tumor microenvironment. There are multiple immune checkpoints that are engaged on immune activation. CCR preclinical studies suggested synergy of vaccine with CTLA4 blockade. Dr. Gulley was the PI of one of the first studies combining a CCR developed vaccine (PSA-TRICOM) along with ipilimumab, an anti-CTLA4 antibody. Up to 10 mg/kg of ipilimumab was safely administered with PSA-TRICOM. 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. This also compares favorably to OS data of ipilimumab alone, however a randomized study would be required to validate these hypothesis generating findings. Recent clinical data on PD1 or PDL1 inhibition have accelerated interest in the field of immunotherapy. Dr. Gulley is the coordinating PI of a phase I dose-escalation study of the only anti-PDL1 antibody designed to not only antagonize PDL1, but to initiate antibody mediated cellular cytotoxicity (ADCC). This first-in-human international study of this agent sponsored by our CRADA partner, EMD-Serono, enrolled 125 patients at the NIH Clinical Center and has demonstrated dramatic prolonged responses seen in a variety of cancers including lung cancer, thymic epithelial malignancies, mesothelioma, bladder cancer and ovarian cancer. Our data also demonstrated no impact of ADCC on immune cells which can also express PDL1 (albeit often at lower levels than tumor cells). Based on this clinical data the FDA recently approved avelumab for use in patients with bladder cancer. This data was also used in part to approve avelumab for Merkel Cell Carcinoma. However, immune checkpoint inhibition requires an underlying anti-tumor immune response that it can unleash. In prostate cancer, the level of activated immune cells within the prostate is limited. Thus, combining vaccine with PDL1 blockade is a rational immunotherapeutic approach. We now have multiple ongoing studies in the CCR looking at vaccine with immune checkpoint inhibition. We also have recently opened a first-in-human, first-in-class anti-PDL1/TGF Beta Trap agent (M7824) with initial data presented at ASCO 2017 and ASCO 2018 and published in 2019 demonstrating safety and preliminary evidence of activity (including PRs and a CR in the first 19 patients tested). The activity appears to be increased in HPV associated cancers (about 35% ORR) and in non-small cell lung cancer (about 28% ORR) compared to PD-1 or PDL-1 inhibition alone (data presented at ASCO 2018). This study has opened the door for multiple combination therapy studies utilizing M7824 to block two important negative regulatory mechanisms that dampen an effective anti-cancer immune response. These ongoing studies will also have built in biopsies and other correlative studies to analyze the impact of the combined therapy on the tumor microenvironment. In addition, the use of standard of care therapies to facilitate immune recognition and / or killing of the tumor, a process called immunogenic modulation, has been tested by Dr. Gulley. Data from 2 small, recently published CCR randomized phase II studies of standard therapy with or without vaccine suggest that this approach may impact progression free survival. 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. One combination trial in prostate cancer suggest an improvement in PFS: Quadramet with or without Prostvac vaccine (1.7 vs. 3.7 months, P = 0.041, HR 0.51) in 44 patients with disease metastatic to bone (Oncotarget 2016). 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 (7.9 vs. 3.9 months, P = 0.09, HR 0.65) meeting the pre-defined criteria for a positive study (JAMA Oncology 2015). Dr. Gulley and team also have multiple studies combining modalities to initiate an immune response (vaccine or tumor targeted cytokine) along with immune checkpoint inhibition and / or TGB-beta inhibition, cytokine, IDO inhibition or small molecule inhibitors. Initial studies with vaccine and immune checkpoint inhibition have shown deep and durable responses in patients with prostate cancer and additional patients are being accrued to study this further.