Clinical trials employing cancer vaccine combination therapies

在过去的5年里，癌症新疗法的大部分重点都转移到了免疫疗法上。这在一定程度上是由于免疫检查点抑制剂具有快速、深刻和持久的反应。然而，这些重要的临床结果只在一小部分患者中看到，这些患者具有和潜在的肿瘤免疫识别。来自Gulley博士临床试验的数据表明，治疗性疫苗可以有效地针对疫苗中存在的和肿瘤细胞中发现的目标产生免疫识别和激活(多篇论文)。此外，疫苗接种后有更多的渗透(JITC 2020)。然而，如果没有在肿瘤微环境中提供足够的效应器功能，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临床前研究表明，疫苗与CTLA4阻断有协同作用。古利博士是第一批将CCR开发的疫苗(PSA-Tricom)和抗CTLA4抗体ipilimumab结合起来的研究之一。PSA-Tricom可安全地给予高达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，虽然根据验证的诺模图预测的中位生存期约为18个月，但在这项I期研究中，实际的中位OS超过34个月。这也比单独使用ipilimumab的OS数据更有利，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免疫治疗领域的兴趣。古利博士是唯一一种抗PDL1抗体的I期剂量递增研究的协调人，该抗体不仅旨在对抗PDL1，而且还旨在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赞助的人类首个关于这种药物的国际研究在NIH临床中心招募了125名患者，并显示出在包括肺癌、胸腺上皮恶性肿瘤、间皮瘤、膀胱癌和卵巢癌在内的各种癌症中都出现了戏剧性的长期反应。我们的数据也表明ADCC对免疫细胞没有影响，免疫细胞也可以表达PDL1(尽管水平通常低于肿瘤细胞)。根据这一临床数据，FDA最近批准了阿维卢单抗用于膀胱癌患者。这一数据也被部分用于批准Avelumab用于治疗默克尔细胞癌。然而，免疫检查点抑制需要潜在的抗肿瘤免疫反应，它可以释放出来。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阻断是一种合理的免疫治疗方法。我们现在CCR上正在进行多项研究，寻找具有免疫检查点抑制的疫苗。我们最近还开放了一种人类第一、一流的抗PDL1/转化生长因子β诱捕剂(M7824)，2019年公布的初步数据证明了安全性和初步活性证据(包括前19名接受测试的患者的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(在ASCO 2018和AACR 2019上公布的数据)。这项研究为利用M7824进行多种联合治疗研究打开了大门，以阻断两种重要的负面调节机制，这两种机制抑制了有效的抗癌免疫反应。这些正在进行的研究还将建立在活检和其他相关研究的基础上，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对肿瘤的免疫识别和/或杀伤，这一过程被称为免疫原性调节，古利博士已经对此进行了测试。最近发表的两项小型CCR随机第二阶段标准治疗研究的数据表明，这种方法可能会影响无进展生存率。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。前列腺癌的一项联合试验表明，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改善了PFS(1.7月vs.3.7个月，P=0.041，HR0.51)(OncoTarget 2016)。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，结果显示，在符合预先定义的阳性研究标准(JAMA Oncology 2015)的乳腺癌试验中，符合方案指定的标准的趋势有利于PFS(7.9个月对3.9个月，P=0.09，HR 0.65)。Gulley博士和他的团队还进行了多项研究，将启动免疫反应(疫苗或肿瘤靶向细胞因子)的方法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相结合(JITC 2018，ESMO 2020)。疫苗和免疫检查点抑制的初步研究表明，前列腺癌患者的反应深刻而持久，正在积累更多的患者来进一步研究这一问题。

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 (JITC 2020). 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 served as 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 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 and AACR 2019). 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 (JITC 2018, ESMO 2020). 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.