31 results on '"Gulley, James L."'
Search Results
2. Adaptive Immunity in Genitourinary Cancers
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Koti, Madhuri, Bivalacqua, Trinity, Black, Peter C., Cathomen, Toni, Galsky, Matthew D., Gulley, James L., Ingersoll, Molly A., Kamat, Ashish M., Kassouf, Wassim, Siemens, D. Robert, and Gao, Jianjun
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- 2023
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3. A Phase 2, Double-blind, Randomized Controlled Trial of PROSTVAC in Prostate Cancer Patients on Active Surveillance
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Parsons, J. Kellogg, Pinto, Peter A., Pavlovich, Christian P., Uchio, Edward, Nguyen, Mike N., Kim, Hyung L., Gulley, James L., Sater, Houssein Abdul, Jamieson, Christina, Hsu, Chiu-Hsieh, Wojtowicz, Malgorzata, House, Margaret, Schlom, Jeffrey, Donahue, Renee N., Dahut, William L., Madan, Ravi A., Bailey, Shania, Centuori, Sara, Bauman, Julie E., Parnes, Howard L., and Chow, H.-H. Sherry
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- 2023
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4. Immune correlates with response in patients with metastatic solid tumors treated with a tumor targeting immunocytokine NHS-IL12
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Toney, Nicole J., Gatti-Mays, Margaret E., Tschernia, Nicholas P., Strauss, Julius, Gulley, James L., Schlom, Jeffrey, and Donahue, Renee N.
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- 2023
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5. Developing immunotherapy strategies in the treatment of prostate cancer
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Gulley, James L. and Madan, Ravi A.
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- 2016
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6. Anaplastic Features in Advanced Prostate Cancer With and Without DNA Damage Repair Mutations.
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Chau, Vincent, Madan, Ravi A., Bilusic, Marijo, Owens, Helen, Cordes, Lisa M., Marte, Jennifer L., Gulley, James L., Jung-Min Lee, Dahut, William L., and Karzai, Fatima
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ANAPLASTIC thyroid cancer ,PROSTATE cancer ,DNA damage ,PROGRESSION-free survival ,DISEASE progression - Abstract
Relationships between DNA-damage repair (DDR) mutations and anaplastic features, which confer poor prognosis, are unknown. Fifty-five patients with mCRPC treated with olaparib and durvalumab were classified into anaplastic and nonanaplastic groups and had similar rates of DDR mutations. Anaplastic patients had a trend toward improved progression-free survival when treated with olaparib and durvalumab compared with nonanaplastic patients. Background: Anaplastic prostate cancer has a poor prognosis with limited treatment options. Seven clinical features of anaplastic prostate cancer have been prospectively identified. In this phase II clinical trial, we identified mutations, including DNA damage repair (DDR) mutations, in patients with metastatic castration-resistant prostate cancer (mCRPC) who were treated with durvalumab and olaparib and determined how many of them can be described as anaplastic, and we examined the overlap between anaplastic features and DDR mutations. Methods: Eligible patients with mCRPC received prior enzalutamide, abiraterone, or both. Patients were treated with durvalumab 1500 mg i.v. every 28 days and olaparib 300 mg p.o. every 12 hours until disease progression or unacceptable toxicity. Patients underwent mandatory baseline biopsies of metastatic lesions. Results: Baseline characteristics were similar between anaplastic and nonanaplastic patients. Eleven patients (20%) displayed clear anaplastic features, and 43 (78.2%) lacked anaplastic features. In the anaplastic group, 2/11 (18.2%) had germline DRR mutations, and 4/11 (36.3%) had somatic DDR mutations. In the nonanaplastic group, 7/43 (16.3%) had germline mutations, and 13/43 (30.2%) had somatic mutations. Median progression-free survival (PFS) times in patients with anaplastic features (6.5 months) and without anaplastic features (5.1 months) were similar (hazard ratio 0.998, P = .996). Conclusions: Patients with and without anaplastic features appear to have similar total rates of DDR mutations and also similar rates of somatic and germline DDR mutations. Patients with anaplastic features have a trend toward improved PFS when treated with olaparib and durvalumab compared with nonanaplastic patients. [ABSTRACT FROM AUTHOR]
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- 2021
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7. A Randomized, Double-blind, Phase II Trial of PSA-TRICOM (PROSTVAC) in Patients with Localized Prostate Cancer: The Immunotherapy to Prevent Progression on Active Surveillance Study
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Parsons, J. Kellogg, Pinto, Peter A., Pavlovich, Christian P., Uchio, Edward, Kim, Hyung L., Nguyen, Mikel N., Gulley, James L., Jamieson, Christina, Hsu, Paul, Wojtowicz, Margarita, Parnes, Howard, Schlom, Jeffrey, Dahut, William L., Madan, Ravi A., Donahue, Renee N., and Chow, H.-H. Sherry
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- 2018
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8. A rare insight into the immunosuppressive landscape of prostate cancer bone metastases.
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Palena, Claudia and Gulley, James L.
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BONE metastasis , *METASTASIS , *BONE cancer , *PROSTATE cancer , *PROSTATE cancer patients , *T cells - Abstract
Therapeutic options for metastatic prostate cancer patients are currently limited. In this issue of Cancer Cell , Kfoury et al. characterized the tumor and immune compartments of prostate cancer bone metastasis, revealing a mechanism of immunosuppression that involves infiltration with M2 macrophages and T cell exhaustion mediated by the CCL20-CCR6 axis. [ABSTRACT FROM AUTHOR]
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- 2021
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9. Bintrafusp Alfa, a Bifunctional Fusion Protein Targeting TGF-β and PD-L1, in Second-Line Treatment of Patients With NSCLC: Results From an Expansion Cohort of a Phase 1 Trial.
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Paz-Ares, Luis, Kim, Tae Min, Vicente, David, Felip, Enriqueta, Lee, Dae Ho, Lee, Ki Hyeong, Lin, Chia-Chi, Flor, Maria Jose, Di Nicola, Massimo, Alvarez, Rosa Maria, Dussault, Isabelle, Helwig, Christoph, Ojalvo, Laureen S., Gulley, James L., and Cho, Byoung Chul
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- 2020
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10. Augmented Radiologist Workflow Improves Report Value and Saves Time: A Potential Model for Implementation of Artificial Intelligence.
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Do, Huy M., Spear, Lillian G., Nikpanah, Moozhan, Mirmomen, S. Mojdeh, Machado, Laura B., Toscano, Alexandra P., Turkbey, Baris, Bagheri, Mohammad Hadi, Gulley, James L., and Folio, Les R.
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Rationale and Objectives: Our primary aim was to improve radiology reports by increasing concordance of target lesion measurements with oncology records using radiology preprocessors (RP). Faster notification of incidental actionable findings to referring clinicians and clinical radiologist exam interpretation time savings with RPs quantifying tumor burden were also assessed.Materials and Methods: In this prospective quality improvement initiative, RPs annotated lesions before radiologist interpretation of CT exams. Clinical radiologists then hyperlinked approved measurements into interactive reports during interpretations. RPs evaluated concordance with our tumor measurement radiologist, the determinant of tumor burden. Actionable finding detection and notification times were also deduced. Clinical radiologist interpretation times were calculated from established average CT chest, abdomen, and pelvis interpretation times.Results: RPs assessed 1287 body CT exams with 812 follow-up CT chest, abdomen, and pelvis studies; 95 (11.7%) of which had 241 verified target lesions. There was improved concordance (67.8% vs. 22.5%) of target lesion measurements. RPs detected 93.1% incidental actionable findings with faster clinician notification by a median time of 1 hour (range: 15 minutes-16 hours). Radiologist exam interpretation times decreased by 37%.Conclusions: This workflow resulted in three-fold improved target lesion measurement concordance with oncology records, earlier detection and faster notification of incidental actionable findings to referring clinicians, and decreased exam interpretation times for clinical radiologists. These findings demonstrate potential roles for automation (such as AI) to improve report value, worklist prioritization, and patient care. [ABSTRACT FROM AUTHOR]- Published
- 2020
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11. Efficacy and safety of PARP inhibitors in metastatic castration-resistant prostate cancer: A systematic review and meta-analysis of clinical trials.
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Iannantuono, Giovanni Maria, Chandran, Elias, Floudas, Charalampos S., Choo-Wosoba, Hyoyoung, Butera, Gisela, Roselli, Mario, Gulley, James L., and Karzai, Fatima
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• PARPi are a standard-of-care treatment option in patients with mCRPC. • The benefit of PARPi is not uniform in mCRPC patients. • The optimal patient selection for PARPi remains a clinical challenge. PARP inhibitors (PARPi) are a standard-of-care (SoC) treatment option for patients with metastatic castration-resistant prostate cancer (mCRPC). Several clinical trials have shown the potential of combining PARPi with other anticancer agents. Therefore, we conducted a systematic review and meta-analysis to comprehensively evaluate the efficacy and safety of PARPi in patients with metastatic prostate cancer. MEDLINE, Cochrane CENTRAL, EMBASE, CINAHL, and Web of Science were searched on March 22nd, 2023, for phase 2 or 3 clinical trials. Efficacy (progression-free survival [PFS], overall survival [OS], PSA decline >50% [PSA50], and objective response rate [ORR]) and safety outcomes were assessed in the included studies. Seventeen clinical trials (PARPi monotherapy [n = 7], PARPi + androgen-receptor signaling inhibitors [ARSI] [n = 6], and PARPi + immune checkpoint inhibitors [ICI] [n = 4]) were included in the quantitative analyses. PARPi monotherapy improved radiographic PFS and OS over SoC in mCRPC patients with alterations in BRCA1 or BRCA2 genes but not in those with alterations in the ATM gene. Higher rates of PSA50 and ORR were reported in participants treated with PARPi + ARSI than in single-agent PARPi or PARPi + ICI. Although the rate of high-grade adverse events was similar across all groups, treatment discontinuation was higher in patients treated with PARPi-based combinations than PARPi monotherapy. The efficacy of PARPi is not uniform across mCRPC patients with alterations in DNA damage repair genes, and optimal patient selection remains a clinical challenge. No unexpected safety signals for this class of agents emerged from this analysis. [ABSTRACT FROM AUTHOR]
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- 2023
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12. Combining immunotherapies for the treatment of prostate cancer.
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Redman, Jason M., Gulley, James L., and Madan, Ravi A.
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PROSTATE cancer treatment , *PROSTATE cancer patients , *CANCER immunotherapy , *CASTRATION-resistant prostate cancer , *PROSTATE cancer , *VACCINATION , *PROSTATE tumors treatment , *COMBINED modality therapy , *IMMUNOTHERAPY , *PROSTATE tumors , *TISSUE extracts , *CANCER vaccines , *TREATMENT effectiveness , *THERAPEUTICS , *VACCINES - Abstract
Sipuleucel-T, a therapeutic dendritic-cell vaccine, was Food and Drug Administration-approved for prostate cancer in 2010. No new immunotherapies for prostate cancer have been approved since. However, novel agents and combination approaches offer great promise for improving outcomes for prostate cancer patients. Here we review the latest developments in immunotherapy for prostate cancer. Sipuleucel-T has demonstrated a survival advantage of 4.1 months in metastatic castration-resistant prostate cancer. PSA-TRICOM (PROSTVAC), a prostate-specific antigen-targeted vaccine platform, showed evidence of clinical and immunologic efficacy in early-phase clinical trials, and results from a phase III trial in advanced disease are pending. While immune checkpoint inhibitors appear to have modest activity as monotherapy, preclinical and clinical data suggest that they may synergize with vaccines, poly [ADP-ribose] polymerase inhibitors, and other agents. Several clinical studies that combine these therapies are underway. Combining prostate cancer vaccines with immune checkpoint inhibitors has great potential for improving clinical outcomes in prostate cancer. Such combination approaches may create and then recruit tumor-specific T cells to tumor while also increasing their effector function. Other emerging agents may also enhance immune-mediated tumor destruction. [ABSTRACT FROM AUTHOR]
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- 2017
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13. Avelumab for patients with previously treated metastatic or recurrent non-small-cell lung cancer (JAVELIN Solid Tumor): dose-expansion cohort of a multicentre, open-label, phase 1b trial.
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Gulley, James L, Rajan, Arun, Spigel, David R, Iannotti, Nicholas, Chandler, Jason, Wong, Deborah J L, Leach, Joseph, Edenfield, W Jeff, Wang, Ding, Grote, Hans Juergen, Heydebreck, Anja von, Chin, Kevin, Cuillerot, Jean-Marie, and Kelly, Karen
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CANCER treatment , *NON-small-cell lung carcinoma , *SMALL cell lung cancer , *MULTI-centre shell model , *COHORT analysis , *MONOCLONAL antibodies , *DRUG dosage , *PLATINUM compounds , *ANTINEOPLASTIC agents , *CANCER relapse , *CLINICAL trials , *COMPARATIVE studies , *DRUG resistance in cancer cells , *DYSPNEA , *FATIGUE (Physiology) , *INTRAVENOUS therapy , *LIPASES , *LUNG cancer , *OBSTRUCTIVE lung diseases , *LUNG tumors , *RESEARCH methodology , *MEDICAL cooperation , *NAUSEA , *PNEUMONIA , *REOPERATION , *RESEARCH , *RESEARCH funding , *EVALUATION research , *TREATMENT effectiveness , *SEVERITY of illness index , *DISEASE progression , *THERAPEUTICS - Abstract
Background: Avelumab, a human Ig-G1 monoclonal antibody targeting PD-L1 and approved in the USA for the treatment of metastatic Merkel cell carcinoma, has shown antitumour activity and an acceptable safety profile in patients with advanced solid tumours in a dose-escalation phase 1a trial. In this dose-expansion cohort of that trial, we assess avelumab treatment in a cohort of patients with advanced, platinum-treated non-small-cell lung cancer (NSCLC).Methods: In this dose-expansion cohort of a multicentre, open-label, phase 1 study, patients with progressive or platinum-resistant metastatic or recurrent NSCLC were enrolled at 58 cancer treatment centres and academic hospitals in the USA. Eligible patients had confirmed stage IIIB or IV NSCLC with squamous or non-squamous histology, measurable disease by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), tumour biopsy or archival sample for biomarker assessment, and Eastern Cooperative Oncology Group performance status 0 or 1, among other criteria. Patient selection was not based on PD-L1 expression or expression of other biomarkers, including EGFR or KRAS mutation or ALK translocation status. Patients received infusional avelumab monotherapy 10 mg/kg every 2 weeks until disease progression or toxicity. The primary objective was to assess safety and tolerability. This trial is registered with ClinicalTrials.gov, number NCT01772004; enrolment in this cohort is closed and the trial is ongoing.Findings: Between Sept 10, 2013, and June 24, 2014, 184 patients were enrolled and initiated treatment with avelumab. Median follow-up duration was 8·8 months (IQR 7·2-11·9). The most common treatment-related adverse events of any grade were fatigue (46 [25%] of 184 patients), infusion-related reaction (38 [21%]), and nausea (23 [13%]). Grade 3 or worse treatment-related adverse events occurred in 23 (13%) of 184 patients; the most common (occurring in more than two patients) were infusion-related reaction (four [2%] patients) and increased lipase level (three [2%]). 16 (9%) of 184 patients had a serious adverse event related to treatment with avelumab, with infusion-related reaction (in four [2%] patients) and dyspnoea (in two [1%]) occurring in more than one patient. Serious adverse events irrespective of cause occurred in 80 (44%) of 184 patients. Those occurring in more than five patients (≥3%) were dyspnoea (ten patients [5%]), pneumonia (nine [5%]), and chronic obstructive pulmonary disease (six [3%]). Immune-related treatment-related events occurred in 22 patients (12%). Of 184 patients, 22 (12% [95% CI 8-18]) achieved a confirmed objective response, including one complete response and 21 partial responses. 70 (38%) had stable disease. Overall, 92 (50%) of 184 patients achieved disease control (they had a confirmed response or stable disease as their best overall response). One patient was initially thought to have died from grade 5 radiation pneumonitis during the study; however, this adverse event was subsequently regraded to grade 3 and the death was attributed to disease progression.Interpretation: Avelumab showed an acceptable safety profile and antitumour activity in patients with progressive or treatment-resistant NSCLC, providing a rationale for further studies of avelumab in this disease setting.Funding: Merck KGaA and Pfizer. [ABSTRACT FROM AUTHOR]- Published
- 2017
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14. Targeting the immune system in non-small-cell lung cancer: bridging the gap between promising concept and therapeutic reality.
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Kelly RJ, Gulley JL, Giaccone G, Kelly, Ronan J, Gulley, James L, and Giaccone, Giuseppe
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- 2010
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15. Combining vaccines with conventional therapies for cancer.
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Arlen, Philip M., Madan, Ravi A., Hodge, James W., Schlom, Jeffrey, and Gulley, James L.
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CANCER treatment ,THERAPEUTICS ,HYPNOTISM ,MEDICAL care - Abstract
Abstract: Preclinical and clinical investigations currently underway are employing novel strategies for combining vaccines with conventional and experimental anticancer therapies. To date, the FDA has not approved a therapeutic cancer vaccine. However, the results of recent investigations suggest an increasing role for vaccines in new models of combination therapy for many types of cancer. This article reviews and discusses therapeutic cancer strategies that employ vaccines in combination with local radiation, chemotherapy, hormone therapy, and anti-CTLA-4 mAb. Preclinical studies have shown that certain anticancer agents have immune modulatory effects that result in up-regulation of surface expression of MHC molecules, tumor-associated antigens, or Fas on malignant cells, rendering them more susceptible to immune destruction. Preliminary results of clinical studies using combination strategies have demonstrated a postvaccination antigen cascade, prolonged time to disease progression, and improved overall survival. Several larger randomized trials are ongoing, and more are required to support these findings. [Copyright &y& Elsevier]
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- 2007
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16. A novel ELISPOT assay to enhance detection of antigen-specific T cells employing antigen-presenting cells expressing vector-driven human B7-1
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Arlen, Philip M., Gulley, James L., Palena, Claudia, Marshall, John, Schlom, Jeffrey, and Tsang, Kwong-Yok
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CLINICAL trials , *CANCER treatment , *PREVENTIVE medicine , *INFLUENZA - Abstract
The ELISPOT assay is used to detect T-cell responses in patients enrolled in vaccine clinical trials; it is a relatively sensitive assay that can be performed without in vitro stimulation (IVS) of PBMC. However, this assay may be limited in some cases because of a weak signal 1 (as is the case for tumor-associated antigens [TAA]), or by a limited number of PBMC available from patients. The objective of this study is to enhance the sensitivity of the ELISPOT by increasing the level of signal 2, in this case, B7-1 expression on antigen-presenting cells (APC), allowing for a more sensitive detection of antigen-specific T-cell precursors. C1RA2 cells were used as APC and were uninfected, or infected with either recombinant avipox (fowlpox)-B7-1 (rF-B7-1) or control fowlpox wild-type (FP-WT) vector. The expressions of B7-1, MHC Class II, as well as HLA-A2 on the infected cells were analyzed by flow cytometry. A nearly threefold increase in B7-1 mean fluorescence intensity (MFI) occurred in the rF-B7-1-infected C1RA2 cells with no changes in MHC Class II or HLA-A2 expression. Various PBMC/APC ratios were used to further analyze the use of rF-B7-1-infected C1RA2 cells as APC in the ELISPOT assay. Fewer APC were required to activate PBMC when C1RA2 infected with rF-B7-1 were used as APC. Furthermore, using a PBMC/APC ratio of 1:1, similar detection was achieved using fewer PBMC. In addition, we demonstrated that the reactivity can be blocked by adding anti-B7-1 antibody. We performed the assay using APC on five normal healthy donors. All five donors showed substantial increases in PF to the Flu matrix peptide (Flu peptide) using the rF-B7-1-infected C1RA2 cells. Finally, we evaluated five cancer patients who received a carcinoembryonic antigen (CEA) vaccine-based therapy. Increases in CEA peptide precursors were noted in all five patients using the B7-1-infected APC. In conclusion, we have demonstrated the ability to enhance the sensitivity of the ELISPOT assay through infection of C1RA2 with rF-B7-1. [Copyright &y& Elsevier]
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- 2003
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17. Moving the goal posts in prostate cancer trials.
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Madan, Ravi A and Gulley, James L
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PROSTATE cancer treatment , *CLINICAL trials , *ONCOLOGY research , *ONCOLOGY periodicals , *PUBLISHING - Published
- 2015
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18. 14937 Keratoacanthomas associated with anti–TGF-β immunotherapy.
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Wang, Catherine J., Lamping, Elizabeth, Strauss, Julius, and Gulley, James L.
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- 2020
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19. New frontiers in therapy for metastatic prostate cancer.
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Gulley, James L.
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- 2010
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20. Radium-223 in prostate cancer: emitting the right signals.
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Madan, Ravi A, Gulley, James L, and Dahut, William L
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RADIUM , *PROSTATE cancer , *PROSTATE-specific antigen , *RADIOISOTOPES , *RADIOPHARMACEUTICALS , *BONE tumors , *PROSTATE tumors - Published
- 2016
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21. Progress in prostate cancer imaging
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Gulley, James L., Emberton, Mark, Kurhanewicz, John, and Choyke, Peter
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PROSTATE cancer , *IMAGING of cancer , *UROLOGY , *ONCOLOGY - Abstract
Abstract: There are multiple new technologies being developed for imaging of advanced prostate cancer. This Seminar article highlights several of these emerging modalities that were discussed at the Society of Urologic Oncology annual meeting in Bethesda, MD. [Copyright &y& Elsevier]
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- 2012
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22. Enhancing efficacy of therapeutic vaccinations by combination with other modalities
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Gulley, James L., Madan, Ravi A., and Arlen, Philip M.
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CANCER treatment , *CANCER endocrinology , *PREVENTIVE medicine , *HORMONE therapy - Abstract
Abstract: Novel strategies are emerging from preclinical and clinical investigations for combining vaccines with conventional and experimental anticancer therapies. Several lines of research show that combining either radiation or certain chemotherapeutic agents with vaccine can alter the phenotype of tumor cells, rendering them more susceptible to T cell-mediated killing. Furthermore, there is emerging data suggesting that an immune response elicited by vaccine may augment the antitumor effectiveness of subsequent therapies. This article reviews and discusses therapeutic cancer strategies that employ vaccines sequentially or in combination with conventional cytotoxic therapies such as local radiation, chemotherapy, and hormone therapy, or immunopotentiating therapies such as anti-CTLA-4 monoclonal antibodies. Preliminary results of clinical studies using these combination strategies have demonstrated a postvaccination antigen cascade, prolonged time to disease progression, and preliminary evidence of improved overall survival. Large randomized studies are currently underway to further investigate these findings. [Copyright &y& Elsevier]
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- 2007
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23. HLA-A*03 and response to immune checkpoint blockade in cancer: an epidemiological biomarker study.
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Naranbhai, Vivek, Viard, Mathias, Dean, Michael, Groha, Stefan, Braun, David A, Labaki, Chris, Shukla, Sachet A, Yuki, Yuko, Shah, Parantu, Chin, Kevin, Wind-Rotolo, Megan, Mu, Xinmeng Jasmine, Robbins, Paul B, Gusev, Alexander, Choueiri, Toni K, Gulley, James L, and Carrington, Mary
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BLADDER cancer , *EVEROLIMUS , *IMMUNE checkpoint proteins , *PROGRESSION-free survival , *CANCER patients , *RENAL cell carcinoma , *IMMUNE checkpoint inhibitors - Abstract
Background: Predictive biomarkers could allow more precise use of immune checkpoint inhibitors (ICIs) in treating advanced cancers. Given the central role of HLA molecules in immunity, variation at the HLA loci could differentially affect the response to ICIs. The aim of this epidemiological study was to determine the effect of HLA-A*03 as a biomarker for predicting response to immunotherapy.Methods: In this epidemiological study, we investigated the clinical outcomes (overall survival, progression free survival, and objective response rate) after treatment for advanced cancer in eight cohorts of patients: three observational cohorts of patients with various types of advanced tumours (the Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets [MSK-IMPACT] cohort, the Dana-Farber Cancer Institute [DFCI] Profile cohort, and The Cancer Genome Atlas) and five clinical trials of patients with advanced bladder cancer (JAVELIN Solid Tumour) or renal cell carcinoma (CheckMate-009, CheckMate-010, CheckMate-025, and JAVELIN Renal 101). In total, these cohorts included 3335 patients treated with various ICI agents (anti-PD-1, anti-PD-L1, and anti-CTLA-4 inhibitors) and 10 917 patients treated with non-ICI cancer-directed therapeutic approaches. We initially modelled the association of HLA amino-acid variation with overall survival in the MSK-IMPACT discovery cohort, followed by a detailed analysis of the association between HLA-A*03 and clinical outcomes in MSK-IMPACT, with replication in the additional cohorts (two further observational cohorts and five clinical trials).Findings: HLA-A*03 was associated in an additive manner with reduced overall survival after ICI treatment in the MSK-IMPACT cohort (HR 1·48 per HLA-A*03 allele [95% CI 1·20-1·82], p=0·00022), the validation DFCI Profile cohort (HR 1·22 per HLA-A*03 allele, 1·05-1·42; p=0·0097), and in the JAVELIN Solid Tumour clinical trial for bladder cancer (HR 1·36 per HLA-A*03 allele, 1·01-1·85; p=0·047). The HLA-A*03 effect was observed across ICI agents and tumour types, but not in patients treated with alternative therapies. Patients with HLA-A*03 had shorter progression-free survival in the pooled patient population from the three CheckMate clinical trials of nivolumab for renal cell carcinoma (HR 1·31, 1·01-1·71; p=0·044), but not in those receiving control (everolimus) therapies. Objective responses were observed in none of eight HLA-A*03 homozygotes in the ICI group (compared with 59 [26·6%] of 222 HLA-A*03 non-carriers and 13 (17·1%) of 76 HLA-A*03 heterozygotes). HLA-A*03 was associated with shorter progression-free survival in patients receiving ICI in the JAVELIN Renal 101 randomised clinical trial for renal cell carcinoma (avelumab plus axitinib; HR 1·59 per HLA-A*03 allele, 1·16-2·16; p=0·0036), but not in those receiving control (sunitinib) therapy. Objective responses were recorded in one (12·5%) of eight HLA-A*03 homozygotes in the ICI group (compared with 162 [63·8%] of 254 HLA-A*03 non-carriers and 40 [55·6%] of 72 HLA-A*03 heterozygotes). HLA-A*03 was associated with impaired outcome in meta-analysis of all 3335 patients treated with ICI at genome-wide significance (p=2·01 × 10-8) with no evidence of heterogeneity in effect (I2 0%, 95% CI 0-0·76) INTERPRETATION: HLA-A*03 is a predictive biomarker of poor response to ICI. Further evaluation of HLA-A*03 is warranted in randomised trials. HLA-A*03 carriage could be considered in decisions to initiate ICI in patients with cancer.Funding: National Institutes of Health, Merck KGaA, and Pfizer. [ABSTRACT FROM AUTHOR]- Published
- 2022
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24. Nascent Prostate Cancer Heterogeneity Drives Evolution and Resistance to Intense Hormonal Therapy.
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Wilkinson, Scott, Ye, Huihui, Karzai, Fatima, Harmon, Stephanie A., Terrigino, Nicholas T., VanderWeele, David J., Bright, John R., Atway, Rayann, Trostel, Shana Y., Carrabba, Nicole V., Whitlock, Nichelle C., Walker, Stephanie M., Lis, Rosina T., Abdul Sater, Houssein, Capaldo, Brian J., Madan, Ravi A., Gulley, James L., Chun, Guinevere, Merino, Maria J., and Pinto, Peter A.
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PROSTATE cancer , *MAGNETIC resonance imaging , *DNA sequencing , *HORMONE therapy , *ANDROGEN deprivation therapy , *RECEIVER operating characteristic curves , *GLEASON grading system , *PROSTATECTOMY - Abstract
Patients diagnosed with high risk localized prostate cancer have variable outcomes following surgery. Trials of intense neoadjuvant androgen deprivation therapy (NADT) have shown lower rates of recurrence among patients with minimal residual disease after treatment. The molecular features that distinguish exceptional responders from poor responders are not known. To identify genomic and histologic features associated with treatment resistance at baseline. Targeted biopsies were obtained from 37 men with intermediate- to high-risk prostate cancer before receiving 6 mo of ADT plus enzalutamide. Biopsy tissues were used for whole-exome sequencing and immunohistochemistry (IHC). We assessed the relationship of molecular features with final pathologic response using a cutpoint of 0.05 cm3 for residual cancer burden to compare exceptional responders to incomplete and nonresponders. We assessed intratumoral heterogeneity at the tissue and genomic level, and compared the volume of residual disease to the Shannon diversity index for each tumor. We generated multivariate models of resistance based on three molecular features and one histologic feature, with and without multiparametric magnetic resonance imaging estimates of baseline tumor volume. Loss of chromosome 10q (containing PTEN) and alterations to TP53 were predictive of poor response, as were the expression of nuclear ERG on IHC and the presence of intraductal carcinoma of the prostate. Patients with incompletely and nonresponding tumors harbored greater tumor diversity as estimated via phylogenetic tree reconstruction from DNA sequencing and analysis of IHC staining. Our four-factor binary model (area under the receiver operating characteristic curve [AUC] 0.89) to predict poor response correlated with greater diversity in our cohort and a validation cohort of 57 Gleason score 8–10 prostate cancers from The Cancer Genome Atlas. When baseline tumor volume was added to the model, it distinguished poor response to NADT with an AUC of 0.98. Prospective use of this model requires further retrospective validation with biopsies from additional trials. A subset of prostate cancers exhibit greater histologic and genomic diversity at the time of diagnosis, and these localized tumors have greater fitness to resist therapy. Some prostate cancer tumors do not respond well to a hormonal treatment called androgen deprivation therapy (ADT). We used tumor volume and four other parameters to develop a model to identify tumors that will not respond well to ADT. Treatments other than ADT should be considered for these patients. A subset of patients present with high-risk localized prostate cancer that exhibits greater histologic and genomic diversity. These patients are less likely to respond to intense neoadjuvant androgen deprivation therapy. [ABSTRACT FROM AUTHOR]
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- 2021
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25. Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial.
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Patel, Manish R, Ellerton, John, Infante, Jeffrey R, Agrawal, Manish, Gordon, Michael, Aljumaily, Raid, Britten, Carolyn D, Dirix, Luc, Lee, Keun-Wook, Taylor, Mathew, Schöffski, Patrick, Wang, Ding, Ravaud, Alain, Gelb, Arnold B, Xiong, Junyuan, Rosen, Galit, Gulley, James L, and Apolo, Andrea B
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TRANSITIONAL cell carcinoma , *CISPLATIN , *ANTINEOPLASTIC agents , *CANCER chemotherapy , *DRUG efficacy , *THERAPEUTICS , *CANCER-related mortality , *THERAPEUTIC use of monoclonal antibodies , *CANCER , *COMPARATIVE studies , *EPITHELIUM , *RESEARCH methodology , *MEDICAL cooperation , *MONOCLONAL antibodies , *ORGANOPLATINUM compounds , *PLATINUM compounds , *PROGNOSIS , *RESEARCH , *TIME , *URINARY organs , *EVALUATION research , *TREATMENT effectiveness , *TUMORS - Abstract
Background: The approval of anti-programmed death ligand 1 (PD-L1) and anti-programmed death 1 agents has expanded treatment options for patients with locally advanced or metastatic urothelial carcinoma. Avelumab, a human monoclonal anti-PD-L1 antibody, has shown promising antitumour activity and safety in this disease. We aimed to assess the safety profile in patients (both post-platinum therapy and cisplatin-naive) treated with avelumab and to assess antitumour activity of this drug in post-platinum patients.Methods: In this pooled analysis of two cohorts from the phase 1 dose-expansion JAVELIN Solid Tumor study, patients aged 18 years and older with histologically or cytologically confirmed locally advanced or metastatic urothelial carcinoma that had progressed after at least one previous platinum-based chemotherapy were enrolled from 80 cancer treatment centres or hospitals in the USA, Europe, and Asia. Eligible patients had adequate end-organ function, an Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 3 months, and at least one measurable lesion. Cisplatin-ineligible patients who might have been previously treated in the perioperative setting, including platinum-naive patients, were also eligible. Patients unselected for PD-L1 expression received avelumab (10 mg/kg, 1 h intravenous infusion) every 2 weeks until confirmed disease progression, unacceptable toxicity, or other criterion for withdrawal. The primary endpoint for this efficacy expansion cohort was confirmed best overall response (according to RECIST version 1.1), adjudicated by independent review. Safety analysis was done in all patients who received at least one dose of avelumab. Antitumour activity was assessed in post-platinum patients who received at least one dose of avelumab. This trial is registered with ClinicalTrials.gov, number NCT01772004; enrolment in this cohort of patients with metastatic urothelial carcinoma is closed and the trial is ongoing.Findings: Between Sept 3, 2014, and March 15, 2016, 329 patients with advanced metastatic urothelial carcinoma were screened for enrolment into this study; 249 patients were eligible and received treatment with avelumab for a median of 12 weeks (IQR 6·0-19·7) and followed up for a median of 9·9 months (4·3-12·1). Safety and antitumour activity were evaluated at data cutoff on June 9, 2016. In 161 post-platinum patients with at least 6 months of follow-up, a best overall response of complete or partial response was recorded in 27 patients (17%; 95% CI 11-24), including nine (6%) complete responses and 18 (11%) partial responses. The most frequent treatment-related adverse events (any grade in ≥10% patients) were infusion-related reaction (73 [29%]; all grade 1-2) and fatigue (40 [16%]). Grade 3 or worse treatment-related adverse events occurred in 21 (8%) of 249 patients, the most common of which were fatigue (four [2%]), and asthenia, elevated lipase, hypophosphataemia, and pneumonitis in two (1%) patients each. 19 (8%) of 249 patients had a serious adverse event related to treatment with avelumab, and one treatment-related death occurred (pneumonitis).Interpretation: Avelumab showed antitumour activity in the treatment of patients with platinum-refractory metastatic urothelial carcinoma; a manageable safety profile was reported in all avelumab-treated patients. These data provide the rationale for therapeutic use of avelumab in metastatic urothelial carcinoma and it has received accelerated US FDA approval in this setting on this basis.Funding: Merck KGaA, and Pfizer Inc. [ABSTRACT FROM AUTHOR]- Published
- 2018
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26. Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial.
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Heery, Christopher R, O'Sullivan-Coyne, Geraldine, Madan, Ravi A, Cordes, Lisa, Rajan, Arun, Rauckhorst, Myrna, Lamping, Elizabeth, Oyelakin, Israel, Marté, Jennifer L, Lepone, Lauren M, Donahue, Renee N, Grenga, Italia, Cuillerot, Jean-Marie, Neuteboom, Berend, Heydebreck, Anja von, Chin, Kevin, Schlom, Jeffrey, Gulley, James L, and O'Sullivan-Coyne, Geraldine
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MONOCLONAL antibodies , *TUMOR treatment , *DRUG dosage , *CANCER treatment , *METASTASIS , *ABDOMINAL pain , *AMYLASES , *ANTINEOPLASTIC agents , *ASPARTATE aminotransferase , *AUTOIMMUNE diseases , *CLINICAL trials , *COMPARATIVE studies , *CREATINE kinase , *FATIGUE (Physiology) , *FEVER , *IMMUNOGLOBULINS , *RESEARCH methodology , *MEDICAL cooperation , *MYOSITIS , *RESEARCH , *TIME , *TUMORS , *VOICE disorders , *EVALUATION research , *TREATMENT effectiveness , *SHIVERING - Abstract
Background: Avelumab (MSB0010718C) is a human IgG1 monoclonal antibody that binds to PD-L1, inhibiting its binding to PD-1, which inactivates T cells. We aimed to establish the safety and pharmacokinetics of avelumab in patients with solid tumours while assessing biological correlatives for future development.Methods: This open-label, single-centre, phase 1a, dose-escalation trial (part of the JAVELIN Solid Tumor trial) assessed four doses of avelumab (1 mg/kg, 3 mg/kg, 10 mg/kg, and 20 mg/kg), with dose-level cohort expansions to provide additional safety, pharmacokinetics, and target occupancy data. This study used a standard 3 + 3 cohort design and assigned patients sequentially at trial entry according to the 3 + 3 dose-escalation algorithm and depending on the number of dose-limiting toxicities during the first 3-week assessment period (the primary endpoint). Patient eligibility criteria included age 18 years or older, Eastern Cooperative Oncology Group performance status 0-1, metastatic or locally advanced previously treated solid tumours, and adequate end-organ function. Avelumab was given as a 1-h intravenous infusion every 2 weeks. Patients in the dose-limiting toxicity analysis set were assessed for the primary endpoint of dose-limiting toxicity, and all patients enrolled in the dose-escalation part were assessed for the secondary endpoints of safety (treatment-emergent and treatment-related adverse events according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0), pharmacokinetic and pharmacodynamic profiles (immunological effects), best overall response by Response Evaluation Criteria, and antidrug antibody formation. The population for the pharmacokinetic analysis included a subset of patients with rich pharmacokinetic samples from two selected disease-specific expansion cohorts at the same study site who had serum samples obtained at multiple early timepoints. This trial is registered with ClinicalTrials.gov, number NCT01772004. Patient recruitment to the dose-escalation part reported here is closed.Findings: Between Jan 31, 2013, and Oct 8, 2014, 53 patients were enrolled (four patients at 1 mg/kg, 13 at 3 mg/kg, 15 at 10 mg/kg, and 21 at 20 mg/kg). 18 patients were analysed in the dose-limiting toxicity analysis set: three at dose level 1 (1 mg/kg), three at dose level 2 (3 mg/kg), six at dose level 3 (10 mg/kg), and six at dose level 4 (20 mg/kg). Only one dose-limiting toxicity occurred, at the 20 mg/kg dose, and thus the maximum tolerated dose was not reached. In all 53 enrolled patients (the safety analysis set), common treatment-related adverse events (occurring in >10% of patients) included fatigue (21 patients [40%]), influenza-like symptoms (11 [21%]), fever (8 [15%]), and chills (6 [11%]). Grade 3-4 treatment-related adverse events occurred in nine (17%) of 53 patients, with autoimmune disorder (n=3), increased blood creatine phosphokinase (n=2), and increased aspartate aminotransferase (n=2) each occurring in more than one patient (autoimmune disorder in two patients at 10 mg/kg and one patient at 20 mg/kg, increased blood creatine phosphokinase in two patients at 20 mg/kg, and increased aspartate aminotransferase in one patient at 1 mg/kg, and one patient at 10 mg/kg). Six (11%) of 53 patients had a serious treatment-related adverse event: autoimmune disorder (two [13%]), lower abdominal pain (one [7%]), fatigue (one [7%]), and influenza-like illness (one [7%]) in three patients treated at 10 mg/kg dose level, and autoimmune disorder (one [5%]), increased amylase (one [5%]), myositis (one [5%]), and dysphonia (one [5%]) in three patients who received the 20 mg/kg dose. We recorded some evidence of clinical activity in various solid tumours, with partial confirmed or unconfirmed responses in four (8%) of 53 patients; 30 (57%) additional patients had stable disease. Pharmacokinetic analysis (n=86) showed a dose-proportional exposure between doses of 3 mg/kg and 20 mg/kg and a half-life of 95-99 h (3·9-4·1 days) at the 10 mg/kg and 20 mg/kg doses. Target occupancy was greater than 90% at doses of 3 mg/kg and 10 mg/kg. Antidrug antibodies were detected in two (4%) of 53 patients. No substantial differences were found in absolute lymphocyte count or multiple immune cell subsets, including those expressing PD-L1, after treatment with avelumab. 31 (58%) of 53 patients in the overall safety population died; no deaths were related to treatment on study.Interpretation: Avelumab has an acceptable toxicity profile up to 20 mg/kg and the maximum tolerated dose was not reached. Based on pharmacokinetics, target occupancy, and immunological analysis, we chose 10 mg/kg every 2 weeks as the dose for further development and phase 3 trials are ongoing.Funding: National Cancer Institute and Merck KGaA. [ABSTRACT FROM AUTHOR]- Published
- 2017
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27. Tumor cell HLA class I expression and pathologic response following neoadjuvant immunotherapy for newly diagnosed head and neck cancer.
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Robbins, Yvette, Friedman, Jay, Redman, Jason, Sievers, Cem, Lassoued, Wiem, Gulley, James L., and Allen, Clint T.
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HEAD & neck cancer , *HISTOCOMPATIBILITY antigens , *T cells , *IMMUNOTHERAPY , *HLA-B27 antigen - Abstract
• Tumor cell HLA class I expression is not associated with tumor cell PD-L1 expression. • Tumor cell HLA class I expression after treatment associates with pathologic response. • Tumor cell PD-L1 expression does not associate with pathologic response. • Study of HLA class I expression as a biomarker of response in neoadjuvant studies is warranted. Biomarkers are needed to identify patients likely to respond to neoadjuvant immunotherapy (NIT) prior to receiving definitive treatment. We hypothesized that expression of tumor cell HLA class I would correlate with pathologic response (PR) following NIT for primary untreated head and neck cancer. Multispectral immunofluorescence of pre- and post-treatment biopsy specimens from a neoadjuvant study of bintrafusp alfa, a dual TGF-β and PD-L1 inhibitor, was performed. Discordant expression of tumor cell HLA class I and PD-L1 measured by multispectral immunofluorescence was observed with most positive tumor cells expressing HLA class I or PD-L1 but not both. Spatial analysis revealed colocalization between tumor parenchyma T cells and HLA class I positive tumors cells, but no clear colocalization between T cells and PD-L1 positive tumor cells. Greater pre-treatment tumor cell HLA class I expression, but not PD-L1 expression or tumor T cell infiltration, correlated with the development of a PR. Additionally, increased tumor cell HLA class I expression after NIT compared to before NIT correlated with development of a PR, whereas inconsistent changes in PD-L1 and T cell infiltration were observed after treatment in all patients. These data provide the rationale for the study of tumor cell HLA class I expression in larger prospective studies powered to determine the performance of biomarkers of PR in newly diagnosed HNSCC patients receiving NIT. [ABSTRACT FROM AUTHOR]
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- 2023
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28. A National Multicenter Phase 2 Study of Prostate-specific Antigen (PSA) Pox Virus Vaccine with Sequential Androgen Ablation Therapy in Patients with PSA Progression: ECOG 9802.
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DiPaola, Robert S., Chen, Yu-Hui, Bubley, Glenn J., Stein, Mark N., Hahn, Noah M., Carducci, Michael A., Lattime, Edmund C., Gulley, James L., Arlen, Philip M., Butterfield, Lisa H., and Wilding, George
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PROSTATE cancer patients , *PROSTATE cancer treatment , *VIRAL vaccines , *CLINICAL trials , *PROSTATE-specific antigen , *POXVIRUSES , *ABLATION techniques , *VACCINES - Abstract
Background E9802 was a phase 2 multi-institution study conducted to evaluate the safety and effectiveness of vaccinia and fowlpox prostate-specific antigen (PSA) vaccine (step 1) followed by combination with androgen ablation therapy (step 2) in patients with PSA progression without visible metastasis. Objective To test the hypothesis that vaccine therapy in this early disease setting will be safe and have a biochemical effect that would support future studies of immunotherapy in patients with minimal disease burden. Design, setting, and participants Patients who had PSA progression following local therapy were treated with PROSTVAC-V (vaccinia)/TRICOM on cycle 1 followed by PROSTVAC-F (fowlpox)/TRICOM for subsequent cycles in combination with granulocyte-macrophage colony-stimulating factor (step 1). Androgen ablation was added on progression (step 2). Outcome measurements and statistical analysis Step 1 primary end points included progression at 6 mo and characterization of change in PSA velocity pretreatment to post-treatment. Step 2 end points included PSA response with combined vaccine and androgen ablation. Results and limitations In step 1, 25 of 40 eligible patients (63%) were progression free at 6 mo after registration (90% confidence interval [CI], 48–75). The median pretreatment PSA velocity was 0.13 log(PSA)/mo, in contrast to median postregistration velocity of 0.09 log(PSA)/mo ( p = 0.02), which is an increase in median PSA doubling time from 5.3 mo to 7.7 mo. No grade ≥4 treatment-related toxicity was observed. In the 27 patients eligible and treated for step 2, 20 patients achieved a complete response (CR) at 7 mo (CR rate: 74%; 90% CI, 57–87). Although supportive of larger studies in the cooperative group setting, this study is limited by the small number of patients and the absence of a control group as in a phase 3 study. Conclusions A viral PSA vaccine can be administered safely in the multi-institutional cooperative group setting to patients with minimal disease volume alone and combined with androgen ablation, supporting the feasibility of future phase 3 studies in this population. Patient summary These data support consideration of vaccine therapy earlier in the course of prostate cancer progression with minimal disease burden in future studies of vaccine approaches in earlier stages of disease. [ABSTRACT FROM AUTHOR]
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- 2015
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29. Ipilimumab and a poxviral vaccine targeting prostate-specific antigen in metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial
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Madan, Ravi A, Mohebtash, Mahsa, Arlen, Philip M, Vergati, Matteo, Rauckhorst, Myrna, Steinberg, Seth M, Tsang, Kwong Y, Poole, Diane J, Parnes, Howard L, Wright, John J, Dahut, William L, Schlom, Jeffrey, and Gulley, James L
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IPILIMUMAB , *PROSTATE cancer treatment , *PROSTATE-specific antigen , *DIARRHEA , *DRUG therapy , *AMINOTRANSFERASES , *DRUG dosage - Abstract
Summary: Background: Therapeutic cancer vaccines have shown activity in metastatic castration-resistant prostate cancer (mCRPC), and methods are being assessed to enhance their efficacy. Ipilimumab is an antagonistic monoclonal antibody that binds cytotoxic T-lymphocyte-associated protein 4, an immunomodulatory molecule expressed by activated T cells, and to CD80 on antigen-presenting cells. We aimed to assess the safety and tolerability of ipilimumab in combination with a poxviral-based vaccine targeting prostate-specific antigen (PSA) and containing transgenes for T-cell co-stimulatory molecule expression, including CD80. Methods: We did a phase 1 dose-escalation trial, with a subsequent expansion phase, to assess the safety and tolerability of escalating doses of ipilimumab in combination with a fixed dose of the PSA-Tricom vaccine. Patients with mCRPC received 2×108 plaque-forming units of recombinant vaccinia PSA-Tricom subcutaneously on day 1 of cycle 1, with subsequent monthly boosts of 1×109 plaque-forming units, starting on day 15. Intravenous ipilimumab was given monthly starting at day 15, in doses of 1, 3, 5, and 10 mg/kg. Our primary goal was to assess the safety of the combination. This study is registered with ClinicalTrials.gov, number NCT00113984. Findings: We completed enrolment with 30 patients (24 of whom had not been previously treated with chemotherapy) and we did not identify any dose-limiting toxic effects. Grade 1 and 2 vaccination-site reactions were the most common toxic effects: three of 30 patients had grade 1 reactions and 26 had grade 2 reactions. 21 patients had grade 2 or greater immune-related adverse events. Grade 3 or 4 immune-related adverse events included diarrhoea or colitis in four patients and grade 3 rash (two patients), grade 3 raised aminotransferases (two patients), grade 3 endocrine immune-related adverse events (two patients), and grade 4 neutropenia (one patient). Only one of the six patients previously treated with chemotherapy had a PSA decline from baseline. Of the 24 patients who were chemotherapy-naive, 14 (58%) had PSA declines from baseline, of which six were greater than 50%. Interpretation: The use of a vaccine targeting PSA that also enhances co-stimulation of the immune system did not seem to exacerbate the immune-related adverse events associated with ipilimumab. Randomised trials are needed to further assess clinical outcomes of the combination of ipilimumab and vaccine in mCRPC. Funding: US National Institutes of Health. [Copyright &y& Elsevier]
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- 2012
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30. Maturation of human dendritic cells with Saccharomyces cerevisiae (yeast) reduces the number and function of regulatory T cells and enhances the ratio of antigen-specific effectors to regulatory T cells
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Cereda, Vittore, Vergati, Matteo, Huen, Ngar-Yee, di Bari, Maria Giovanna, Jochems, Caroline, Intrivici, Chiara, Gulley, James L., Apelian, David, Schlom, Jeffrey, and Tsang, Kwong Y.
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DENDRITIC cells , *SACCHAROMYCES cerevisiae , *CANCER vaccines , *T cells , *CYTOKINES , *YEAST , *GENE expression , *TUMOR necrosis factors , *CELL proliferation - Abstract
Abstract: We compared the effects of yeast-treated human dendritic cells (DCs) with CD40L-matured human DCs for the induction of effector cells and the number and functionality of CD4+CD25+CD127−FoxP3+ regulatory T cells (Tregs). DCs were treated with yeast or CD40L and cocultured with isolated autologous CD4+ T cells. CD4+CD25+CD127− T cells isolated from the coculture of CD4+ T cells plus yeast-treated DCs (yeast coculture) had a lower expression of FoxP3 and decreased suppressive function compared to CD4+CD25+CD127− T cells isolated from the coculture of CD4+ T cells plus CD40L-treated DCs (CD40L coculture). Also, compared to the CD40L coculture, the yeast coculture showed increases in the ratio of CD4+CD25+ activated T cells to Tregs and in the production of Th1-related cytokines (IL-2, TNF-α, IFN-γ) and IL-6. In addition, yeast-treated DCs used as antigen-presenting cells (APCs) incubated with the tumor antigen CEA enhanced the proliferation of CEA-specific CD4+ T cells compared to the use of CD40L-matured DCs used as APCs. This is the first study to report on the role of yeast-treated/matured human DCs in reducing Treg frequency and functionality and in enhancing effector to Treg ratios. These results provide an additional rationale for the use of yeast as a vector in cancer vaccines. [Copyright &y& Elsevier]
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- 2011
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31. mpMRI preoperative staging in men treated with antiandrogen and androgen deprivation therapy before robotic prostatectomy.
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Gold, Samuel A., VanderWeele, David J., Harmon, Stephanie, Bloom, Jonathan B., Karzai, Fatima, Hale, Graham R., Marhamati, Shawn, Rayn, Kareem N., Mehralivand, Sherif, Merino, Maria J., Gulley, James L., Bilusic, Marijo, Madan, Ravi A., Choyke, Peter L., Turkbey, Baris, Dahut, William, and Pinto, Peter A.
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SEMINAL vesicles , *ANDROGENS , *MAGNETIC resonance imaging , *DIFFUSION coefficients - Abstract
Introduction: Using multiparametric magnetic resonance imaging (mpMRI), we sought to preoperatively characterize prostate cancer (PCa) in the setting of antiandrogen plus androgen deprivation therapy (AA-ADT) prior to robotic-assisted radical prostatectomy (RARP). We present our preliminary findings regarding mpMRI depiction of changes of disease staging features and lesion appearance in treated prostate.Methods: Prior to RARP, men received 6 months of enzalutamide and goserelin. mpMRI consisting of T2 weighted, b = 2,000 diffusion weighted imaging, apparent diffusion coefficient mapping, and dynamic contrast enhancement sequences was acquired before and after neoadjuvant therapy. Custom MRI-based prostate molds were printed to directly compare mpMRI findings to H&E whole-mount pathology as part of a phase II clinical trial (NCT02430480).Results: Twenty men underwent imaging and RARP after a regimen of AA-ADT. Positive predictive values for post-AA-ADT mpMRI diagnosis of extraprostatic extension, seminal vesicle invasion, organ-confined disease, and biopsy-confirmed PCa lesions were 71%, 80%, 80%, and 85%, respectively. Post-treatment mpMRI correctly staged disease in 15/20 (75%) cases with 17/20 (85%) correctly identified as organ-confined or not. Of those incorrectly staged, 2 were falsely positive for higher stage features and 1 was falsely negative. Post-AA-ADT T2 weighted sequences best depicted presence of PCa lesions as compared to diffusion weighted imaging and dynamic contrast enhancement sequences.Conclusion: mpMRI proved reliable in detecting lesion changes after antiandrogen therapy corresponding to PCa pathology. Therefore, mpMRI of treated prostates may be helpful for assessing men for surgical planning and staging. [ABSTRACT FROM AUTHOR]- Published
- 2019
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