Browsing by Subject "PD-L1"

Now showing 1 - 7 of 7
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    Clinical and Biological Activity of Chemoimmunotherapy in Advanced Endometrial Adenocarcinoma: A Phase II Trial of the Big Ten Cancer Research Consortium
    (American Association for Cancer Research, 2022) Barber, Emma L.; Chen, Siqi; Pineda, Mario Javier; Robertson, Sharon E.; Hill, Emily K.; Teoh, Deanna; Schilder, Jeanne; O’Shea, Kaitlyn L.; Kocherginsky, Masha; Zhang, Bin; Matei, Daniela; Obstetrics and Gynecology, School of Medicine
    Purpose: The objective of this study was to assess the efficacy and safety of pembrolizumab in combination with standard carboplatin/paclitaxel in patients with advanced endometrial cancer (EC). Patients and methods: This single-arm, open-label, multi-center phase II study enrolled patients with RECIST measurable advanced EC. Patients could have received < 1 prior platinum-based regimen and < one non-platinum chemotherapy. The primary endpoint was objective response rate (ORR). Planned sample size of 46 subjects provided 80% power to detect 15% ORR improvement compared to historical control rate of 50%. Results: 46 patients were enrolled, and 43 were evaluable for ORR. Median age was 66 (range: 43-86). Thirty-four (73.9%) patients had recurrent and 12 (26.1%) primary metastatic EC. Patients received carboplatin AUC 6, paclitaxel 175mg/m2 and pembrolizumab 200mg IV every 3 weeks for up to 6 cycles. ORR was 74.4% (32/43), higher than historic controls (p = 0.001). Median PFS was 10.6 months (95% CI 8.3-13.9 months). The most common grade 1-2 treatment related adverse event (TRAEs) included anemia (56.5%), alopecia (47.8%), fatigue (47.8%) and neuropathy (13%), while the most common grade 3-4 TRAEs were lymphopenia, leukopenia, and anemia (19.6% each). High-dimensional spectral flow cytometry (CyTEK) identified enrichment in peripheral CD8+ and CD4+ T cell populations at baseline in responders. The CD8+ T cell compartment in responders exhibited greater expression levels of PD-1 and PD-L1 and higher abundance of effector memory CD8+ cells compared to non-responders. Conclusions: Addition of pembrolizumab to carboplatin and paclitaxel for advanced EC was tolerated and improved ORR compared to historical outcomes.
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    Current Strategies and Novel Therapeutic Approaches for Metastatic Urothelial Carcinoma
    (MDPI, 2020-06-02) Mollica, Veronica; Rizzo, Alessandro; Montironi, Rodolfo; Cheng, Liang; Giunchi, Francesca; Schiavina, Riccardo; Santoni, Matteo; Fiorentino, Michelangelo; Lopez-Beltran, Antonio; Brunocilla, Eugenio; Brandi, Giovanni; Massari, Francesco; Pathology and Laboratory Medicine, School of Medicine
    Urothelial carcinoma (UC) is a frequent cause of cancer-related deaths worldwide. Metastatic UC has been historically associated with poor prognosis, with a median overall survival of approximately 15 months and a 5-year survival rate of 18%. Although platinum-based chemotherapy remains the mainstay of medical treatment for patients with metastatic UC, chemotherapy clinical trials produced modest benefit with short-lived, disappointing responses. In recent years, the better understanding of the role of immune system in cancer control has led to the development and approval of several immunotherapeutic approaches in UC therapy, where immune checkpoint inhibitors have been revolutionizing the treatment of metastatic UC. Because of a better tumor molecular profiling, FGFR inhibitors, PARP inhibitors, anti-HER2 agents, and antibody drug conjugates targeting Nectin-4 are also emerging as new therapeutic options. Moreover, a wide number of trials is ongoing with the aim to evaluate several other alterations and pathways as new potential targets in metastatic UC. In this review, we will discuss the recent advances and highlight future directions of the medical treatment of UC, with a particular focus on recently published data and ongoing active and recruiting trials.
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    The Identification of Immunological Biomarkers in Kidney Cancers
    (Frontiers Media, 2018-11-02) Lopez-Beltran, Antonio; Henriques, Vanessa; Cimadamore, Alessia; Santoni, Matteo; Cheng, Liang; Gevaert, Thomas; Blanca, Ana; Massari, Francesco; Scarpelli, Marina; Montironi, Rodolfo; Pathology and Laboratory Medicine, School of Medicine
    The recent approval of several agents have revolutionized the scenario of therapeutic management of metastatic renal cell carcinoma (RCC) allowing us to reach important clinical end points with extended patients' survival. Actually, every new drug approved has represented an important step forward to the improvement of patient's survival. On the other hand, we now understand that RCC includes a large group of tumor entities, each of them with different genetic and mutational alterations, but also showing different clinical behavior; a reason behind the needs of subtype specific personalized approach to therapy of RCC. Immunotherapy is gradually becoming a key factor in the therapeutic algorithm for patients with locally advanced or metastatic RCC. Due to the combination of potent treatment success and potentially deadly adverse effects from immune checkpoint inhibitors (ICI), gathering prognostic and predictive information about FDA-indicated tumors seems to be prudent. Robust and reliable biomarkers are crucial for patient's selection of treatments with immunomodulatory drugs. PD-L1 expression is a poor prognostic factor and predictive of better responses from both PD-1 and PD-L1 inhibitors in a variety of tumor types including RCC. Each FDA approved PD-1/PD-L1 drug is paired with a PD-L1 Immunohistochemistry (IHC) assay. Thus, there is need for improved knowledge and application of PD-1/PD-L1 IHC biomarkers in daily practice. IHC staining appears in membranous fashion. The atezolizumab approved IHC assay is unique in that only immune cell staining is quantified for the use of this assay in RCC. A single biomarker for patient selection may not be feasible, given that immune responses are dynamic and evolve over time. Biomarker development for ICI drugs will likely require integration of multiple biologic components like PD-L1 expression, TILs and mutational load. New methodological approaches based on digital pathology may be relevant since they will allow recognition of the biomarker and to objectively quantitate its expression, and therefore might produce objective and reproducible cut-off assessment. Multidisciplinary approach is very much needed to fully develop the current and future value of ICI in clinical practice.
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    Low Expression of Programmed Death 1 (PD-1), PD-1 Ligand 1 (PD-L1), and Low CD8+ T Lymphocyte Infiltration Identify a Subgroup of Patients With Gastric and Esophageal Adenocarcinoma With Severe Prognosis
    (Frontiers Media, 2020-04-28) Däste, Silvio; Eppenberger-Castori, Serenella; Mele, Valentina; Schäfer, Hannah M.; Schmid, Lukas; Weixler, Benjamin; Soysal, Savas D.; Droeser, Raoul A.; Spagnoli, Giulio C.; Kettelhack, Christoph; Oertli, Daniel; Terracciano, Luigi; Tornillo, Luigi; von Holzen, Urs; Medicine, School of Medicine
    Prognosis of gastric and esophageal cancer is poor and treatment improvements are needed. Programmed cell death 1 receptor (PD-1) interaction with its ligand PD-L1 in tumor micro-environment promotes immune tolerance and blocking monoclonal antibodies have entered clinical practice. However, clinical significance of PD-1 and PD-L1 expression in gastric and esophageal adenocarcinomas, particularly in non-Asian patients, is still unclear. Three tissue microarrays including 190 clinically annotated esophageal (n = 31) and gastric (n = 159) adenocarcinomas and 58 paired mucosa specimens, were stained with PD-1, PD-L1, and CD8-specific reagents in indirect immunohistochemistry assays. PD-L1 expression was detectable in 23.2% of cancer specimens. High PD-1 expression was detectable in 37.3% of cases and high CD8+ infiltration in 76%. PD-L1 and high PD1 expression significantly correlated with each other (rs = 0.404, P < 0.0001) and both significantly correlated with CD8+ infiltration (rs = 0.435, P = 0.0003, and rs = 0.444; P = 0.0004, respectively). CD8+ lymphocyte infiltration correlated with improved survival in univariate (P = 0.009), but not multivariate analysis. Most interestingly, multivariate analysis and Kaplan-Meier curves indicate that combined low PD-1/PD-L1 expression and low CD8+ lymphocyte infiltration significantly correlate with poor prognosis. Our data document the clinical significance of a microenvironmental signature including PD-1/PD-L1 expression and CD8+ lymphocyte infiltration in gastric and esophageal adenocarcinomas and contribute to identify a patients' subset requiring more aggressive peri-operative treatments.
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    PD-L1 signaling in reactive astrocytes counteracts neuroinflammation and ameliorates neuronal damage after traumatic brain injury
    (BMC, 2022-01-08) Gao, Xiang; Li, Wei; Syed, Fahim; Yuan, Fang; Li, Ping; Yu, Qigui; Neurological Surgery, School of Medicine
    Background: Tissue damage and cellular destruction are the major events in traumatic brain injury (TBI), which trigger sterile neuroimmune and neuroinflammatory responses in the brain. While appropriate acute and transient neuroimmune and neuroinflammatory responses facilitate the repair and adaptation of injured brain tissues, prolonged and excessive neuroimmune and neuroinflammatory responses exacerbate brain damage. The mechanisms that control the intensity and duration of neuroimmune and neuroinflammatory responses in TBI largely remain elusive. Methods: We used the controlled cortical impact (CCI) model of TBI to study the role of immune checkpoints (ICPs), key regulators of immune homeostasis, in the regulation of neuroimmune and neuroinflammatory responses in the brain in vivo. Results: We found that de novo expression of PD-L1, a potent inhibitory ICP, was robustly and transiently induced in reactive astrocytes, but not in microglia, neurons, or oligodendrocyte progenitor cells (OPCs). These PD-L1+ reactive astrocytes were highly enriched to form a dense zone around the TBI lesion. Blockade of PD-L1 signaling enlarged brain tissue cavity size, increased infiltration of inflammatory Ly-6CHigh monocytes/macrophages (M/Mɸ) but not tissue-repairing Ly-6CLowF4/80+ M/Mɸ, and worsened TBI outcomes in mice. PD-L1 gene knockout enhanced production of CCL2 that is best known for its ability to interact with its cognate receptor CCR2 on Ly-6CHigh M/Mϕ to chemotactically recruit these cells into inflammatory sites. Mechanically, PD-L1 signaling in astrocytes likely exhibits dual inhibitory activities for the prevention of excessive neuroimmune and neuroinflammatory responses to TBI through (1) the PD-1/PD-L1 axis to suppress the activity of brain-infiltrating PD-1+ immune cells, such as PD-1+ T cells, and (2) PD-L1 intrinsic signaling to regulate the timing and intensity of astrocyte reactions to TBI. Conclusions: PD-L1+ astrocytes act as a gatekeeper to the brain to control TBI-related neuroimmune and neuroinflammatory responses, thereby opening a novel avenue to study the role of ICP-neuroimmune axes in the pathophysiology of TBI and other neurological disorders.
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    A Systematic Review and Meta-Analysis Assessing the Relative Efficacy of Immune Checkpoint Inhibitors Based on PD-L1 Expression Levels
    (2020-10) Kwiatkowski, Kathy; Han, Jiali; Song, Yiqing; Li, Xin; Tu, Wanzu
    Purpose: The purpose was to comprehensively assess the impact of PD-L1 expression on the efficacy of immune checkpoint inhibitors on Overall Survival (OS) and Progression-Free Survival (PFS). Methods: A systematic literature search and review was conducted through June 2019. I searched all eligible randomized controlled trials comparing PD-1/PD-L1 monotherapy to an active comparator in adult patients with advanced cancer across multiple tumor types. The Cochrane risk-of-bias tool was used to assess trial quality. A random-effects model was used for the meta-analysis. Heterogeneity was assessed using Cochran Q statistic and I2 test. Publication bias was assessed by visual inspection of a funnel plot and Begg’s test. Results: I identified and included 23 trials involving 14,434 participants. When stratifying PD-L1 positive (+) and negative (-) patients using varying thresholds of expression, a significant group difference was observed at PD-L1 >1% ( p=0.04; PD-L1(+): HR, 0.72; 95% CI, 0.65-0.79; PD-L1(-): HR,0.83; 95% CI, 0.75-0.91), at PD-L1 >10% (p=0.02; PD-L1(+): HR,0.50; 95% CI, 0.38-0.62; PD-L1 (-): HR, 0.74; 95% CI, 0.57-0.90) and at PD-L1>50% (p=0.01; PD-L1(+): HR,0.59; 95% CI, 0.51-0.68; PD-L1(-): HR, 0.93; 95% CI, 0.71-1.15). Across tumor types, both PD-L1(+) and PD-L1(-) patients treated with an immunotherapy had improved OS compared with patients receiving standard care therapies. A PFS benefit was observed and favored patients treated with a PD-1/PD-L1 inhibitor versus standard of care. However, there was significant heterogeneity and the benefit on PFS was not statistically significant between PD-L1(+) and PD-L1(-) groups using varying cut-off levels of PD-L1 expression. No differences between sub-groups of interest including median follow-up time, type of inhibitor, and line of therapy for either PD-L1(+) or PD-L1(-) patients at 1% cut-off were identified. Conclusion: This study supports the use of PD-L1 as a predictive biomarker of improved response to immunotherapies. As thresholds increase and specifically above the 10% PD-L1 expression threshold, patients who were positive for PD-L1 appeared to have better OS compared to those who were negative for PD-L1. Further investigation is needed to assess the clinical usefulness of PD-L1 at various expression levels with improved technologies that have the potential to enhance assay accuracy and precision.
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    The Transcription Factor Bhlhe40 Programs Mitochondrial Regulation of Resident CD8+ T Cell Fitness and Functionality
    (Elsevier, 2019-09-17) Li, Chaofan; Zhu, Bibo; Son, Young Min; Wang, Zheng; Jiang, Li; Xiang, Min; Ye, Zhenqing; Beckermann, Kathryn E.; Wu, Yue; Jenkins, James W.; Siska, Peter J.; Vincent, Benjamin G.; Prakash, Y. S.; Peikert, Tobias; Edelson, Brian T.; Taneja, Reshma; Kaplan, Mark H.; Rathmell, Jeffrey C.; Dong, Haidong; Hitosugi, Taro; Sun, Jie; Microbiology and Immunology, School of Medicine