Clinical trials employing cancer vaccine combination therapies

在过去的5年里，癌症新疗法的重点已经转移到包括免疫疗法。这在一定程度上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仅在一部分患者中观察到，这些患者具有肿瘤的潜在免疫识别。Gulley博士的临床试验数据表明，治疗性疫苗可以有效地产生针对疫苗中存在的靶点和肿瘤细胞中发现的靶点的免疫识别和激活（多篇出版物）。此外，接种疫苗后浸润增加（ASCO 2018）。然而，这种抗肿瘤免疫应答可能不足以在肿瘤微环境内不提供足够的效应子功能的情况下为患者产生临床结果的改善。有多个免疫检查点参与免疫激活。CCR临床前研究表明疫苗与CTLA 4阻断剂具有协同作用。Gulley博士是将CCR开发的疫苗（PSA-TRICOM）沿着伊匹单抗（一种抗CTLA 4抗体）组合的首批研究之一的PI。高达10 mg/kg的易普利姆玛与PSA-TRICOM一起安全施用。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，但在本I期研究中，实际中位OS超过34个月。这也优于伊匹单抗单独给药的OS数据，但需要进行随机研究来验证这些假设产生的结果。最近关于PD 1或PDL 1抑制的临床数据加速了对免疫治疗领域的兴趣。Gulley博士是唯一一种抗PDL 1抗体的I期剂量递增研究的协调PI，该抗体不仅可拮抗PDL 1，还可启动抗体介导的细胞毒性（ADCC）。这项由我们的CRADA合作伙伴EMD-Serono赞助的该药物的首次人体国际研究在NIH临床中心招募了125名患者，并在各种癌症中表现出显着的长期反应，包括肺癌，胸腺上皮恶性肿瘤，间皮瘤，膀胱癌和卵巢癌。我们的数据还表明，ADCC对也可以表达PDL 1的免疫细胞没有影响（尽管通常比肿瘤细胞的水平低）。基于这些临床数据，FDA最近批准了avelumab用于膀胱癌患者。该数据也部分用于批准avelumab治疗默克尔细胞癌。然而，免疫检查点抑制需要它可以释放的潜在抗肿瘤免疫应答。在前列腺癌中，前列腺内激活的免疫细胞的水平是有限的。因此，将疫苗与PDL 1阻断剂结合是一种合理的免疫方法。我们现在在CCR中有多项正在进行的研究，研究具有免疫检查点抑制作用的疫苗。我们最近还开发了一种首次用于人体的抗PDL 1/TGF β Trap药物（M7824），其初始数据在ASCO 2017和ASCO 2018上展示，并于2019年发表，证明了安全性和活性的初步证据（包括前19名受试患者的PR和CR）。与PD-1或PDL-1单独抑制相比，HPV相关癌症（约35% ORR）和非小细胞肺癌（约28% ORR）的活性似乎增加（ASCO 2018提供的数据）。这项研究为利用M7824阻断抑制有效抗癌免疫反应的两种重要负调控机制的多种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，Gulley博士已经测试了使用标准治疗来促进免疫识别和/或杀死肿瘤，这是一种称为免疫原性调节的过程。最近发表的2项小型CCR随机II期标准治疗（有或无疫苗）研究的数据表明，这种方法可能影响无进展生存期。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。一项前列腺癌联合治疗试验表明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 = 0.041，HR 0.51）（Oncotarget 2016）。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，符合方案规定标准的趋势有利于联合治疗的PFS（7.9 vs 3.9个月，P = 0.09，HR 0.65）符合阳性研究的预定标准（JAMA Oncology 2015）。Gulley博士和团队还进行了多项研究，将启动免疫应答（疫苗或肿瘤靶向细胞因子）的方式与免疫检查点抑制和/或TGB-β抑制、细胞因子、IDO抑制或小分子抑制剂沿着。疫苗和免疫检查点抑制的初步研究显示，前列腺癌患者的反应是深刻而持久的，正在增加更多的患者来进一步研究这一点。

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.