Journal Articles

Conventional therapies

Immunological effects of conventional cancer therapies such as chemotherapy, radiotherapy or targeted therapy

A multi-center phase II study of high dose interleukin-2 sequenced with vemurafenib in patients with BRAF-V600 mutation positive metastatic melanoma

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BACKGROUND: Preclinical studies suggest that BRAF inhibitors enhance anti-tumor immunity and antigen presentation. Combination BRAF inhibition with immunotherapy is an appealing therapeutic approach. We sequenced vemurafenib with HD IL-2 in patients with BRAF-mutated metastatic melanoma to improve long term outcomes. METHODS: Eligible patients were HD IL-2 eligible with metastatic BRAF V600 mutated melanoma. Cohort 1 was treatment naive and received vemurafenib 960 mg BID for 6 weeks before HD IL-2. Cohort 2 received vemurafenib for 7-18 weeks before enrollment. Both cohorts received HD IL-2 at 600,000 IU/kg every 8 h days 1-5 and days 15-19. The primary objective was to assess complete responses (CR) at 10 weeks +/-3 (assessment 1) and 26 weeks +/-3 (assessment 2) from the start of HD IL-2. RESULTS: Fifty-three patients were enrolled, (cohort 1, n = 38; cohort 2, n = 15). Of these, 39 underwent assessment 1 and 15 assessment 2. The CR rate at assessment 1 was 10% (95% CI 3-24) for both cohorts combined, and 27% (95% CI 8-55) at assessment 2. Three-year survival was 30 and 27% for cohort 1 and cohort 2, respectively. No unexpected toxicities occurred. A shift in the melanoma treatment landscape during this trial adversely affected accrual, leading to early trial closure. CONCLUSIONS: Vemurafenib in sequence with HD IL-2 did not change the known toxicity profile for either agent. Lower than expected response rates to vemurafenib were observed. Overall response rates and durability of responses appear similar to that observed with HD IL-2 alone. TRIAL REGISTRATION: NCTN, NCT01683188. Registered 11 September 2012, http://www.clinicaltrials.gov/NCT01683188.

Author Info: (1) Cardinal Bernardin Cancer Center, Loyola University Medical Center, 2160 S. First Avenue, Maywood, IL, 60153, USA. jclark@lumc.edu. (2) Primary Biostatistical Solutions, Victoria, BC, Canada

Author Info: (1) Cardinal Bernardin Cancer Center, Loyola University Medical Center, 2160 S. First Avenue, Maywood, IL, 60153, USA. jclark@lumc.edu. (2) Primary Biostatistical Solutions, Victoria, BC, Canada. (3) Roswell Park Cancer Institute, Buffalo, NY, USA. (4) University of Michigan, Ann Arbor, MI, USA. (5) The Karmanos Cancer Institute, Detroit, MI, USA. (6) Indiana University, Indianapolis, IN, USA. (7) Earle A. Chiles Research Institute, Providence Cancer Center, Portland, OR, USA. (8) St. Luke's Hospital and Health Network, Bethlehem, PA, USA. (9) Columbia University/Herbert Irving Comprehensive Cancer Center, New York, NY, USA. (10) Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA. (11) Mt. Sinai Comprehensive Cancer Center, Miami Beach, FL, USA. (12) Prometheus Laboratories Inc, San Diego, CA, USA. (13) Prometheus Laboratories Inc, San Diego, CA, USA. Nektar Inc, San Diego, CA, USA. (14) Emory Winship Cancer Institute at Emory University, Atlanta, GA, USA.

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Strong PD-L1 expression predicts poor response and de novo resistance to EGFR TKIs among non-small cell lung cancer patients with EGFR mutation

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INTRODUCTION: This study evaluated whether tumor expression of programmed death-ligand 1 (PD-L1) could predict the response of EGFR-mutated non-small cell lung cancer (NSCLC) to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy. METHODS: We retrospectively evaluated patients who received EGFR-TKIs for advanced NSCLC at the Guangdong Lung Cancer Institute between April 2016 and September 2017 and were not enrolled in clinical studies. The patients' EGFR and PD-L1 statuses were simultaneously evaluated. RESULTS: Among the 101 eligible patients, strong PD-L1 expression significantly decreased objective response rate (ORR), compared with weak or negative PD-L1 expression (35.7% vs 63.2% vs 67.3%, P=0.002), and shortened progression-free survival (PFS, 3.8 vs 6.0 vs 9.5 months, P<0.001), regardless of EGFR mutation type (19del or L858R). Furthermore, positive PD-L1 expression was predominantly observed among patients with de novo resistance rather than acquired resistance to EGFR-TKIs (66.7% vs 30.2%, P=0.009). Notably, we found a high proportion of PD-L1 and CD8 dual-positive cases among patients with de novo resistance (46.7%, 7/15). Finally, one patient with de novo resistance to EGFR-TKIs and PD-L1 and CD8 dual positivity experienced a favorable response to anti-PD-1 therapy. CONCLUSION: This study revealed the adverse effects of PD-L1 expression on EGFR-TKI efficacy, especially in NSCLC patients with de novo resistance. The findings indicate the reshaping of an inflamed immune phenotype characterized by PD-L1 and CD8 dual positivity and suggest potential therapeutic sensitivity to PD-1 blockade.

Author Info: (1) Southern Medical University, Guangzhou, China; Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China. (2) Department of Radiation

Author Info: (1) Southern Medical University, Guangzhou, China; Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China. (2) Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China. (3) Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China. (4) Department of Pathology and Laboratory Medicine, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China. (5) Department of Pathology and Laboratory Medicine, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China. (6) Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China. (7) Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China. (8) Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China. (9) Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China. (10) Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China. (11) Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China. (12) Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China. (13) Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China. (14) Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China. (15) Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China. (16) Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China. (17) Southern Medical University, Guangzhou, China; Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China. Electronic address: syylwu@live.cn.

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Oncogenic activation of STAT3 pathway drives PD-L1 expression in natural killer/T cell lymphoma

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Mature T-cell lymphomas, including peripheral T-cell lymphoma (PTCL) and extranodal NK/T-cell lymphoma (NKTL), represent a heterogeneous group of non-Hodgkin lymphomas with dismal outcomes and limited treatment options. To determine the extent of involvement of JAK/STAT pathway in this malignancy, we performed targeted capture sequencing of 188 genes in this pathway in 171 PTCL and NKTL cases. A total of 272 non-synonymous somatic mutations in 101 genes were identified in 73% of the samples, including 258 single nucleotide variants and 14 insertions or deletions. Recurrent mutations were most frequently located in STAT3 and TP53 (15%) followed by JAK3 and JAK1 (6%) and SOCS1 (4%). A high prevalence of STAT3 mutation (21%) was observed specifically in NKTL. Novel STAT3 mutations (p.D427H, E616G, p.E616K and p.E696K) were shown to increase STAT3 phosphorylation and transcriptional activity of STAT3 in the absence of cytokine, in which p.E616K induced PD-L1 expression by robust binding of activated STAT3 to the PD-L1 gene promoter. Consistent with these findings, PD-L1 was overexpressed in NKTL cell lines harboring hotspot STAT3 mutations and similar findings were observed by the overexpression of p.E616K and p.E616G in STAT3 wild-type NKTL cell line. Conversely, STAT3 silencing and inhibition decreased PD-L1 expression in STAT3 mutant NKTL cell lines. In NKTL tumors, STAT3 activation correlated significantly with PD-L1 expression. We demonstrated that STAT3 activation confers high PD-L1 expression, which may promote tumor immune evasion. The combination of PD-1/PD-L1 antibodies and STAT3 inhibitors might be a promising therapeutic approach for NKTL and possibly PTCL.

Author Info: (1) Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, National Cancer Centre Singapore, Singapore. (2) Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology

Author Info: (1) Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, National Cancer Centre Singapore, Singapore. (2) Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, National Cancer Centre Singapore, Singapore. (3) Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, National Cancer Centre Singapore, Singapore. (4) Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, National Cancer Centre Singapore, Singapore. (5) Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore. (6) Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore. (7) Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, National Cancer Centre Singapore, Singapore. (8) Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore. (9) Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore. (10) Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, National Cancer Centre Singapore, Singapore. (11) Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore. (12) Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, National Cancer Centre Singapore, Singapore. (13) Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, National Cancer Centre Singapore, Singapore. (14) Department of Pathology, Guangdong General Hospital, Guangdong Academy of Medical Science, Guangzhou, China. (15) Department of Pathology, Guangdong General Hospital, Guangdong Academy of Medical Science, Guangzhou, China. (16) Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China. (17) Division of Medical Oncology, National Cancer Centre Singapore, Singapore. (18) Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, National Cancer Centre Singapore, Singapore. (19) State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China. (20) Department of Anatomical Pathology, Division of Pathology, Singapore General Hospital, Singapore. (21) Department of Haematology, Singapore General Hospital, Singapore. (22) Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. (23) National University Cancer Institute of Singapore, Singapore. (24) Division of Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore. (25) Institute of Cell and Molecular Biology, A*STAR, Singapore. (26) Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore. (27) Bioinformatics Institute, A*STAR, Singapore. (28) Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, National Cancer Centre Singapore, Singapore. (29) Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, National Cancer Centre Singapore, Singapore; cmrock@nccs.com.sg.

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Long-term survival follow-up of atezolizumab in combination with platinum-based doublet chemotherapy in patients with advanced non-small-cell lung cancer

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BACKGROUND: Before the availability of immunotherapy, chemotherapy was standard first-line therapy for non-small-cell lung cancer (NSCLC) lacking actionable gene alterations. Preclinical evidence suggests chemotherapy is immunomodulatory, supporting chemotherapy/immunotherapy combinations. Atezolizumab, anti-programmed death ligand-1 (PD-L1) antibody, blocks programmed cell death protein-1 and B7.1 interaction with PD-L1. GP28328 (NCT01633970) assessed atezolizumab with chemotherapy in multiple tumours; we report results for advanced, treatment-naive NSCLC. METHODS: Patients received atezolizumab plus carboplatin with paclitaxel (Arm C: atezo/cb/pac), pemetrexed (Arm D: atezo/cb/pem, maintenance pemetrexed permitted), or nab-paclitaxel (Arm E: atezo/cb/nab-pac), four-six cycles, then atezolizumab maintenance. Primary end-point was safety; secondary end-points were objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). RESULTS: Seventy-six NSCLC patients were enrolled (n = 25, 25 and 26 for Arms C, D and E, respectively). Common treatment-related grade III/IV adverse events were neutropenia (36% atezo/cb/pac, 36% atezo/cb/pem, 42% atezo/cb/nab-pac) and anaemia (16% atezo/cb/pac, 16% atezo/cb/pem, 31% atezo/cb/nab-pac). Confirmed ORRs were 36% atezo/cb/pac, 68% atezo/cb/pem (one complete response [CR]) and 46% atezo/cb/nab-pac (four CRs). Median PFS was 7.1 months, (95% confidence interval [CI]: 4.2-8.3), 8.4 months (95% CI: 4.7-11) and 5.7 months (95% CI: 4.4-14.8), respectively. Median OS was 12.9 months (95% CI: 8.8-21.3), 18.9 months (95% CI: 9.9-27.4) and 17.0 months (95% CI: 12.7-not evaluable), respectively. CONCLUSION: Atezolizumab with chemotherapy was well tolerated with encouraging efficacy, though the analysis was limited by small numbers. NSCLC chemotherapy combination studies are ongoing. CLINICALTRIALS. GOV IDENTIFIER: NCT01633970.

Author Info: (1) Lombardi Comprehensive Cancer Center, Georgetown University, 3800 Reservoir Rd NW, Washington, DC, USA. Electronic address: Stephen.V.Liu@gunet.georgetown.edu. (2) University of Colorado Denver, 13001 E 17th

Author Info: (1) Lombardi Comprehensive Cancer Center, Georgetown University, 3800 Reservoir Rd NW, Washington, DC, USA. Electronic address: Stephen.V.Liu@gunet.georgetown.edu. (2) University of Colorado Denver, 13001 E 17th Place, Aurora, CO, USA. Electronic address: ross.camidge@ucdenver.edu. (3) Yale Cancer Center, 333 Cedar St, New Haven, CT, USA. Electronic address: scott.gettinger@yale.edu. (4) Lombardi Comprehensive Cancer Center, Georgetown University, 3800 Reservoir Rd NW, Washington, DC, USA. Electronic address: gg496@georgetown.edu. (5) Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114, USA. Electronic address: rheist@partners.org. (6) Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215, USA. Electronic address: Stephen_Hodi@dfci.harvard.edu. (7) Duke University Medical Center, 10 Duke Medicine Circle, Durham, NC 27710, USA. Electronic address: neal.ready@duke.edu. (8) Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: zhang.wei_zhanw107@gene.com. (9) Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: jwallin@seagen.com. (10) Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: funke.roel@gene.com. (11) Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: waterkamp.daniel@gene.com. (12) Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: foster.paul@gene.com. (13) Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: iizuka.koho@gene.com. (14) Carolina BioOncology Institute, 9801 Kincey Ave, Huntersville, NC 28078, USA. Electronic address: jpowderly@carolinabiooncology.org.

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Resistance to radiotherapy and PD-L1 blockade is mediated by TIM-3 upregulation and regulatory T-cell infiltration

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PURPOSE: Radiation therapy (RT) can transform the immune landscape and render poorly immunogenic tumors sensitive to PD-L1 inhibition. Here we established that the response to combined RT and PD-L1 inhibition is transient and investigated mechanisms of resistance. EXPERIMENTAL DESIGN: Mechanisms of resistance to RT and PD-L1 blockade were investigated in orthotopic murine HNSCC tumors using mass cytometry and whole genome sequencing. Mice were treated with anti-PD-L1 or anti-TIM-3 alone and in combination with and without RT. Tumor growth and survival were assessed. Flow cytometry was used to assess phenotypic and functional changes in intratumoral T cell populations. Depletion of regulatory T cells was performed using anti-CD25 antibody. RESULTS: We show that the immune checkpoint receptor, TIM-3, is upregulated on CD8 T cells and Tregs in tumors treated with RT and PD-L1 blockade. Treatment with anti-TIM-3 concurrently with anti-PD-L1 and RT led to significant tumor growth delay, enhanced T cell cytotoxicity, decreased Tregs and improved survival in orthotopic models of head and neck squamous cell carcinoma. Despite this treatment combination, the response was not durable and analysis of relapsed tumors revealed resurgence of Tregs. Targeted Treg depletion, however, restored anti-tumor immunity in mice treated with RT and dual immune checkpoint blockade and resulted in tumor rejection and induction of immunologic memory. CONCLUSIONS: These data reveal multiple layers of immunoregulation that can promote tumorigenesis, and the therapeutic potential of sequential targeting to overcome tumor resistance mechanisms. We propose that targeted Treg inhibitors may be critical for achieving durable tumor response with combined radiotherapy and immunotherapy.

Author Info: (1) Radiation Oncology, University of Colorado Denver. (2) Otolaryngology and Head and Neck Surgery, University of Colorado Denver, Anschutz Medical Campus. (3) Department of Radiation

Author Info: (1) Radiation Oncology, University of Colorado Denver. (2) Otolaryngology and Head and Neck Surgery, University of Colorado Denver, Anschutz Medical Campus. (3) Department of Radiation Oncology, University of Colorado Denver. (4) Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus. (5) Radiation Oncology, University of Colorado Denver. (6) Radiation Oncology, University of Colorado Denver. (7) Radiation Oncology, University of Colorado Denver. (8) Radiation Oncology, University of Colorado Denver. (9) Radiation Oncology, University of Colorado Denver. (10) Radiation Oncology, University of Colorado Denver. (11) Department of Medicine, University of Colorado Anschutz Medical Campuso. (12) Radiation Oncology, University of Colorado Denver. (13) Department of Medicine, University of Colorado Denver. (14) Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus. (15) Anesthesiology, University of Colorado Anschutz Medical Campus. (16) Medicine, University of Colorado Anschutz Medical Campus. (17) Radiation Oncology, University of Colorado Denver sana.karam@ucdenver.edu.

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Immunological Mechanisms Responsible for Radiation-Induced Abscopal Effect

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Radiotherapy has been used for more than a hundred years as a local tumor treatment. The occurrence of systemic antitumor effects manifesting as regression of tumors outside of the irradiated field (abscopal effect) was occasionally observed but deemed too rare and unpredictable to be a therapeutic goal. This has changed with the advent of immunotherapy. Remarkable systemic effects have been observed in patients receiving radiotherapy to control tumors that were progressing during immune checkpoint blockade, stimulating interest in using radiation to overcome primary and acquired cancer resistance to immunotherapy. Here, we review the immunological mechanisms that are responsible for the ability of focal radiation to promote antitumor T cell responses that mediate tumor rejection and, in some cases, result in systemic effects.

Author Info: (1) Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Department of Radiation Oncology, University Hospital of Navarra

Author Info: (1) Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Department of Radiation Oncology, University Hospital of Navarra, Pamplona, Spain; Co-first authors. (2) Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA; Co-first authors. (3) Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain. (4) Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA; Sandra and Edward Meyer Cancer Center, New York, NY, USA. (5) Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA; Sandra and Edward Meyer Cancer Center, New York, NY, USA; Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA. Electronic address: szd3005@med.cornell.edu.

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The influence of radiation in the context of developing combination immunotherapies in cancer

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In addition to tumouricidal activity, radiotherapy is now recognized to display potent immunostimulatory properties that can contribute to the generation of anti-cancer immune responses. Treatment with radiation can induce a variety of pro-immunogenic and phenotypic changes in malignant cells, and recalibrate the immune contexture of the tumour microenvironment, leading to enhanced activation of the innate immune system, and priming of tumour-specific T-cell immunity. The immune-dependent effects of radiotherapy provide a sound rationale for the development of combination strategies, whereby the immunomodulatory properties of radiation can be exploited to augment the activity of immunotherapeutic agents. Encouraged by the recent success of breakthrough therapies such as immune checkpoint blockade, and a wealth of experimental data demonstrating the efficacy of radiotherapy and immunotherapy combinations, the clinical potential of this approach is now being explored in numerous trials. Successful translation will require careful consideration of the most suitable dose and fractionation of radiation, choice of immunotherapy and optimal sequencing and scheduling regimen. Immunological control of cancer is now becoming a clinical reality. There is considerable optimism that the development of effective radiotherapy and immunotherapy combinations with the capacity to induce durable, systemic immunity will further enhance patient outcome and transform the future management of cancer.

Author Info: (1) Targeted Therapy Group, Division of Cancer Sciences, Manchester Cancer Research Centre, Christie Hospital, Manchester Academic Health Sciences Centre, National Institute of Health Research Biomedical

Author Info: (1) Targeted Therapy Group, Division of Cancer Sciences, Manchester Cancer Research Centre, Christie Hospital, Manchester Academic Health Sciences Centre, National Institute of Health Research Biomedical Research Centre, Manchester, M20 4BX, UK. (2) Targeted Therapy Group, Division of Cancer Sciences, Manchester Cancer Research Centre, Christie Hospital, Manchester Academic Health Sciences Centre, National Institute of Health Research Biomedical Research Centre, Manchester, UK.

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Janus Kinase Inhibitor Baricitinib Modulates Human Innate and Adaptive Immune System

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The purpose of this study was to elucidate the mechanism of action of baricitinib on Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling, which involves in human innate and adaptive immune system. The effects of baricitinib were evaluated using human monocyte-derived dendritic cells (MoDCs), plasmacytoid dendritic cells (pDCs), B cells, and T cells. Baricitinib concentration-dependently suppressed the expression of CD80/CD86 on MoDCs and the production of type-I interferon (IFN) by pDCs. Baricitinib also suppressed the differentiation of human B cells into plasmablasts by B cell receptor and type-I IFN stimuli and inhibited the production of interleukin (IL)-6 from B cells. Human CD4(+) T cells proliferated after T cell receptor stimulation with anti-CD3 and anti-CD28 antibody; however, such proliferation was suppressed by baricitinib in a concentration-dependent manner. In addition, baricitinib inhibited Th1 differentiation after IL-12 stimulation and Th17 differentiation by TGF-beta1, IL-6, IL-1beta, and IL-23 stimulation. Tofacitinib showed similar effects in these experiments. In naive CD4(+) T cells, IFN-alpha and IFN-gamma induced phosphorylation of STAT1, which was inhibited by baricitinib and tofacitinib. Furthermore, IL-6-induced phosphorylation of STAT1 and STAT3 was also inhibited by JAK inhibitors. In conclusion, the results indicated that baricitinib suppresses the differentiation of plasmablasts, Th1 and Th17 cells, as well as innate immunity, such as the T cell stimulatory capacity of dendritic cells. Thus, JAK inhibitors can be potentially clinically effective not only in rheumatoid arthritis but other immune-related diseases.

Author Info: (1) The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. (2) The First Department of Internal Medicine, University of Occupational

Author Info: (1) The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. (2) The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. (3) The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. Mitsubishi Tanabe Pharma, Yokohama, Japan. (4) The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. Astellas Pharma Inc., Tokyo, Japan. (5) The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. The Department of Pediatrics, The First Hospital of China Medical University, Shenyang, China. (6) The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. (7) The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. Mitsubishi Tanabe Pharma, Yokohama, Japan. (8) The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. (9) The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. (10) The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.

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Irradiation enhanced the effects of PD-1 blockade in brain metastatic osteosarcoma

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Brain metastasis of osteosarcoma are rare but carry a dismal prognosis. Despite the advances in both systemic immunotherapy and localized radiation, it is still difficult to treat brain metastasis, with less than 12 months of survival from the time of diagnosis for most patients. Currently, there is interest in combining strategies to take advantage of the potential synergy. In this study, the mouse model of metastatic osteosarcoma to brain was used to explore the ability of local radiation and anti-PD-1 blockade to induce beneficial anti-tumor immune responses against distant, unirradiated brain metastatic tumors. Immune markers from the peripheral blood and tumor tissue were analyzed by flow cytometry, real-time PCR and western blot. The combination treatment produced a stronger systemic anti-tumor response than either treatment alone, shown by the reduced tumor burden and larger numbers of cytotoxic CD8(+) T cells in the unirradiated tumors, indicating an abscopal effect. These data suggested that combination treatment of irradiation with anti-PD-1 immunotherapy can induce abscopal anti-tumor responses and improve both local and distant control.

Author Info: (1) Department of Musculoskeletal Cancer Surgery, Zhejiang Cancer Hospital, Hangzhou 310000, People's Republic of China. (2) Department of Musculoskeletal Cancer Surgery, Zhejiang Cancer Hospital, Hangzhou

Author Info: (1) Department of Musculoskeletal Cancer Surgery, Zhejiang Cancer Hospital, Hangzhou 310000, People's Republic of China. (2) Department of Musculoskeletal Cancer Surgery, Zhejiang Cancer Hospital, Hangzhou 310000, People's Republic of China. (3) Department of Musculoskeletal Cancer Surgery, Zhejiang Cancer Hospital, Hangzhou 310000, People's Republic of China.

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Ineffective anti PD-1 therapy after BRAF inhibitor failure in advanced melanoma

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BACKGROUND: Anti-PD-1 and BRAF-inhibitors (BRAFi) have been approved as first-line treatments in advanced melanoma. To date, no prospective data are available to give the best sequence of treatment. The objective of this study was to evaluate in real-life the efficacy of anti-PD-1 after BRAFi, ipilimumab, or chemotherapy failure. METHODS: This was a single institution cohort analysis in patients treated with anti-PD-1 right after BRAFi, ipilimumab, or chemotherapy failure. Melanoma evolution after anti-PD-1 initiation was analyzed in BRAF-mutated and BRAF wild-type patients. The efficacy of treatment was evaluated by Objective Response Rate (ORR), Disease Control Rate (DCR), Progression-Free Survival (PFS), and Overall Survival (OS). RESULTS: Seventy-four patients were included: 33 wild-type and 41 BRAF-mutated melanoma. ORR to anti-PD-1 was significantly lower in BRAF-mutated patients (12.2% vs. 45.5%, p = 0.002). After anti-PD-1 initiation, the median PFS and OS was significantly shorter in the BRAF mutated group (2 vs. 5 months and 7 vs. 20 months, p = 0.001). The hazard ratio for disease progression was of 2.3 (95%CI:1.3-3.9; p = 0.003) and 2.5 (95%CI:1.3-4.5; p = 0.005) for death. Thirty-nine percent of BRAF-mutated-patients died within 3 months after anti-PD-1 initiation. Rapid death (

Author Info: (1) Department of Dermatology, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Lyon 1 University, 165 Chemin du Grand Revoyet, 69495, Pierre Benite Cedex, France

Author Info: (1) Department of Dermatology, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Lyon 1 University, 165 Chemin du Grand Revoyet, 69495, Pierre Benite Cedex, France. mona.amini-adle@chu-lyon.fr. (2) Unit of Epidemiology and Infection Control Unit, Hopital Edouard Herriot, Hospices Civils de Lyon, Laboratory of Emergent Pathogens, CIRI, Claude Bernard Lyon 1 University, Lyon, France. (3) Department of Dermatology, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Lyon 1 University, 165 Chemin du Grand Revoyet, 69495, Pierre Benite Cedex, France. (4) Department of Biostatistics, Claude Bernard Lyon 1 University, 43 Bd 11 novembre 1918 BP 761, 69622, Villeurbanne Cedex, France. (5) Department of Dermatology, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Lyon 1 University, 165 Chemin du Grand Revoyet, 69495, Pierre Benite Cedex, France. (6) Department of Dermatology, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Lyon 1 University, 165 Chemin du Grand Revoyet, 69495, Pierre Benite Cedex, France.

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