Cancer Therapy Clinical Trials Using Novel Recombinant Vaccines

Gulley博士对上皮恶性肿瘤的免疫治疗感兴趣，重点是前列腺癌。作为泌尿生殖系统恶性肿瘤科免疫治疗科的负责人，他根据有希望的实验室发现设计并进行临床试验。这些创新的研究者发起的研究包括使用癌症疫苗和其他免疫刺激剂来调节癌症患者的免疫反应，以及增加其他策略来增强疫苗介导的肿瘤杀伤。Gulley博士在前列腺癌疫苗Prostvac的临床开发中发挥了关键作用。他与实验室的科学家合作，开发了将这种在CCR内开发的后勤简单但免疫学复杂的疫苗策略带入前列腺癌临床试验I期（首次人体安全性研究）和II期（首次临床活性测试）所需的数据。与Gulley博士合作设计的一项多中心随机II期试验提供了转移性去势抵抗性前列腺癌患者中位总生存期（OS） （P = 0.0061）提高的证据。CCR的Gulley博士同时进行的一项研究表明，具有更高psa特异性t细胞反应的患者表现出提高生存率的趋势（P = 0.055）。中位OS为26.6个月，在侵袭性较弱或病情较轻的患者中有更明显的治疗获益。Gulley博士和他的同事随后与FDA会面，并设计了一个III期临床试验，随后他通过重组咨询委员会、FDA和欧洲药品管理局的批准过程。他领导的这项随机对照III期研究，招募了1297名患者，令人失望的是，总体生存率没有提高。该疫苗的一项新佐剂研究表明，不仅可以在外周血中产生疫苗特异性免疫细胞，而且与疫苗前相比，接种疫苗后这些患者的肿瘤内部或周围可以看到浸润增加（Sater, JITC 2020）。这导致了在Gulley博士的另一个项目中详细描述的联合免疫疗法的努力。Gulley博士帮助进入临床I期或II期研究的其他疫苗包括针对CEA、MUC-1和Brachyury的痘病毒平台；针对CEA和Brachyury的酵母平台和针对CEA、MUC-1、PSA和Brachyury的腺病毒疫苗。他还参与了几种针对HPV特异性靶点的疫苗的临床翻译，这些疫苗比大多数现成的肿瘤相关抗原靶点更具免疫原性。Gulley博士还参与了不同疫苗给药途径（皮内、皮下、肿瘤内和静脉注射）的临床评估。免疫治疗仍然是癌症研究中最活跃的领域，部分基于针对PD-1或PD-L1蛋白的免疫检查点抑制剂的快速，深刻和持久的反应。(免疫检查点是调节免疫系统信号的分子。许多癌症利用它们来逃避免疫攻击。)Gulley博士曾担任avelumab（一种抗pd - l1抗体）国际试验的协调PI。该试验是与EMD Serono（也与辉瑞合作）的CCR合作。早期数据显示avelumab具有强大的活性，其副作用与其他药物相似。然而，与其他抗pdl1药物不同，avelumab还具有抗体依赖性细胞毒性（ADCC）。因此，该抗体除了直接增强T细胞的活性外，还可以介导ADCC，其中包括自然杀伤细胞介导的对肿瘤和阻断T细胞功能的免疫细胞的杀伤。最近的研究结果表明，可以介导ADCC的抗pd - l1药物比不能介导ADCC的药物具有更高的活性。Gulley博士的研究目前已经招募了1700多名患者（约130名在CCR），提供了初步的安全性和有效性数据，这些数据导致了六项正在进行的avelumab III期临床试验，更多的临床试验正在规划阶段。2017年，FDA批准avelumab用于二线膀胱癌和默克尔细胞癌，2019年批准avelumab用于肾细胞癌，2020年批准avelumab用于膀胱癌的扩展适应症。虽然免疫检查点调节剂的临床反应是深刻的，但它仅限于具有潜在t细胞炎症肿瘤的患者。因此，确定在肿瘤微环境中运作的免疫相关细胞和途径的重要性对于选择可能从免疫检查点调节疗法单独获益的患者至关重要，但更重要的是设计用于产生t细胞炎症肿瘤的疗法的影响，并指导潜在联合研究的基本原理。为了进一步探索这一点，我们与几个团体（包括外科医生、放射肿瘤学家、介入放射学家、病理学家和各种行业合作组织）建立了多个强有力的合作关系，他们可以帮助我们在各种不同疾病的免疫治疗前后获取和分析组织。此外，我们正在研究一系列不同的方式来诱导t细胞炎症，这些方式正在进行临床试验，包括疫苗、免疫细胞因子（例如，nhl - il - 12）和计划的临床试验（NK细胞）。作为在肿瘤微环境中克服负面免疫调节影响的重要性的延伸，我们还将一种一流的药物（M7824或bintrafusp alfa）引入临床，该药物针对细胞内在（PDL-1）和细胞外在（tgf - β）途径，并已看到其耐受性良好，并有初步的活性证据。这项在NCI进行的初步研究现在有多个扩展队列，在许多不同的肿瘤中发现了有希望的活性水平，包括胆道癌（获得FDA孤儿药认定）、肺癌（客观缓解率28%）和HPV相关恶性肿瘤（客观缓解率30%，Strauss等人，JITC 2021）。这导致了许多第二阶段的研究。在国际上，已有700多名患者接受了M7824的治疗。我们有多项正在进行的研究，将疫苗与旨在增强疫苗激活免疫反应临床活性的药物结合起来。Gulley博士还致力于引入其他新型药物，如针对il - 8 (Humax), Lair-1 （NC-410）和肿瘤靶向IL-12 （nhs - IL-12）的药物，目标是将这些药物从首次人体研究带入联合临床试验。

Dr. Gulley is interested in immunotherapy for epithelial malignancies with a focus on prostate cancer. As head of the Immunotherapy Section of the Genitourinary Malignancies Branch, he designs and conducts clinical trials based on promising laboratory findings. These innovative investigator-initiated studies involve the use of cancer vaccines and other immunostimulatory agents to modulate the immune response in cancer patients, and the addition of other strategies to enhance vaccine-mediated tumor killing. Dr. Gulley played a pivotal role in the clinical development of the prostate cancer vaccine Prostvac. Working with scientists in the laboratory, he developed the data needed to bring this logistically simple but immunologically sophisticated vaccine strategy, developed within the CCR, into phase I (first-in-human safety studies) and phase II (first test for clinical activity) clinical trials in prostate cancer. A multicenter, randomized phase II trial designed in collaboration with Dr. Gulley provided evidence of enhanced median overall survival (OS) (P = 0.0061) in patients with metastatic castration-resistant prostate cancer. A concurrent study ran by Dr. Gulley at the CCR demonstrated that patients with greater PSA-specific T-cell responses showed a trend (P = 0.055) toward enhanced survival. Median OS was 26.6 months, with a greater apparent treatment benefit in patients with less aggressive or less advanced disease. Dr. Gulley and colleagues then met with the FDA and designed a phase III clinical trial that he subsequently shepherded through the process of gaining approvals from the Recombinant Advisory Committee, the FDA, and European Medicines Agency. This randomized, controlled phase III study, which he led, enrolled 1,297 patients and disappointingly showed no improvement in overall survival. A neoadjuvant study of this vaccine demonstrated that not only could vaccine specific immune cells be generated in the peripheral blood, but that increase infiltrates following vaccine could be seen in or around the tumors of these patients compared with pre-vaccine (Sater, JITC 2020). This has led to combination immunotherapy efforts described in detail in Dr. Gulley's other project. Other vaccines that Dr. Gulley has helped bring into the clinic in phase I or II studies include pox-viral platforms targeting CEA, MUC-1 and Brachyury; yeast platforms targeting CEA and Brachyury and adenoviral vaccines targeting CEA, MUC-1, PSA, and Brachyury. He has also been involved in the clinical translation of several vaccines targeting HPV specific targets, which are more immunogenic than most off the shelf tumor associated antigen targets. Dr. Gulley has also been involved in the clinical evaluation of different routes of administration of vaccines (intradermal, subcutaneous, intratumoral and intravenous). Immunotherapy remains the most active area of research in cancer, based in part on the rapid, profound, and durable responses seen with immune checkpoint inhibitors targeting PD-1 or PD-L1 proteins. (Immune checkpoints are molecules that modulate immune system signals. Many cancers use them to evade immune attack.) Dr. Gulley served as the coordinating PI of an international trial of avelumab, an anti-PD-L1 antibody. This trial is a CCR collaboration with EMD Serono (who also partnered with Pfizer). Early data suggest robust activity for avelumab, with a side-effect profile similar to other agents. However, unlike other anti-PDL1 agents, avelumab is also capable of antibody-dependent cellular cytotoxicity (ADCC). Thus this antibody, in addition to directly enhancing the activity of T cells, can mediate ADCC which involves Natural Killer Cell-mediated killing of the tumors and immune cells that block T-cell function. Recent findings suggest that anti-PD-L1 agents that can mediate ADCC have improved activity over agents that cannot do so. Dr. Gulley's study has now enrolled over 1,700 patients (about 130 at the CCR), providing the initial safety and efficacy data that have led to six ongoing phase III clinical trials of avelumab, with more in the planning stages. In 2017 the FDA approved avelumab for 2nd line bladder cancer and Merkel Cell cancer and in 2019 for Renal Cell Carcinoma and in 2020 for an expansion indication in bladder cancer. While the clinical response with immune checkpoint modulators has been profound, it is limited to patients who have an underlying T-cell inflamed tumor. The importance of determining the immune relevant cells and pathways operational within the tumor microenvironment is thus crucial to selecting patients who may benefit from immune checkpoint modulating therapies alone but more importantly the impact of therapies designed to generate a T-cell inflamed tumor and to guide rationale for potential combination studies. To further explore this, we have established multiple strong collaborations with several groups (including surgeons, radiation oncologists, interventional radiologists, pathologists and various industry collaborations) who can assist us with obtaining and analyzing tissue before and after immunotherapy in various different disease settings. Furthermore, we are investigating a range of different modalities to induce T-cell inflammation which are in active clinical trials including vaccines, immunocytokines (e.g., NHL-IL12), and planned clinical trials (NK cells). As an extension of the importance of overcoming negative immune regulatory influences within the tumor microenvironment we also have brought into the clinic a first-in-class agent (M7824 or bintrafusp alfa) that targets both cell intrinsic (PDL-1) and cell extrinsic (TGF-beta) pathways and have seen that this is well tolerated and has preliminary evidence of activity. This initial study performed at the NCI now has multiple expansion cohorts with promising levels of activity seen in a number of different tumors including biliary tract cancer (for which it received FDA orphan drug designation), lung cancer (objective response rate 28%) and HPV associated malignancies (objective response rate 30%, Strauss et al., JITC 2021). This has led to a number of phase 2 studies. Internationally, over 700 patients have been treated with M7824. We have multiple ongoing studies combining vaccines with agents designed to augment the clinical activity of the vaccine activated immune response. Dr. Gulley is also leading efforts to bring in other novel agents such a agents targeting IL8 (Humax), Lair-1 (NC-410), and tumor targeted IL-12 (NHS-IL12) with the goal to bring these from first-in-human studies into combination clinical trials.