Cancer Therapy Clinical Trials Using Novel Recombinant Vaccines

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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.