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News Article | February 27, 2017
Site: www.eurekalert.org

(PRINCETON, N.J., Feb. 27, 2017) - Bristol-Myers Squibb Company (NYSE:BMY) today announced that Columbia University Medical Center and Peter MacCallum Cancer Centre (Peter Mac) have joined the International Immuno-Oncology Network (II-ON), a global peer-to-peer collaboration between Bristol-Myers Squibb and academia that aims to advance Immuno-Oncology (I-O) science and translational medicine to improve patient outcomes. Launched in 2012 by Bristol-Myers Squibb, the II-ON was one of the first networks to bring academia and industry together to further the scientific understanding of I-O, and has expanded from 10 to 15 sites including more than 250 investigators working on over 150 projects across 20 tumor types. The II-ON has generated cutting-edge I-O data that have informed the development of new I-O agents, yielded publications and produced some of the earliest findings on a variety of biomarkers and target identification and validation. "Bristol-Myers Squibb has long believed the future of cancer research is dependent on investments in science and partnerships. We formed the II-ON to facilitate innovation in I-O science and drug discovery by providing a streamlined framework for peer-to-peer collaboration among global cancer research leaders," said Nils Lonberg, Head of Oncology Biology Discovery at Bristol-Myers Squibb. "The significant discoveries generated by the II-ON over the past five years have not only informed our robust early I-O pipeline, but also serve to advance the entire field. We are proud to collaborate with Columbia University Medical Center and Peter Mac, and together with the entire II-ON will continue to lead pioneering research and heighten our collective understanding of the science behind I-O." Through the II-ON, Bristol-Myers Squibb is collaborating with leading cancer research institutions around the world to generate innovative I-O science, launch biology-driven trials and seek out cutting-edge technologies with the goal of translating research findings into clinical trials and, ultimately, clinical practice. "I-O research may be transforming the way we treat cancer," said Charles G. Drake, MD, PhD, Professor of Medicine at Columbia University Medical Center and Director of Genitourinary Oncology and Associate Director for Clinical Research at the Herbert Irving Comprehensive Cancer Center at New York-Presbyterian/Columbia. "The II-ON offers a tremendous opportunity to work smarter and faster along with our colleagues to address fundamental scientific questions in I-O." "We believe the collective knowledge and research power of the II-ON will generate groundbreaking findings in I-O with the potential to improve outcomes for people affected by cancer," said Professor Joe Trapani, Executive Director Cancer Research and Head of the Cancer Immunology Program at Peter MacCallum Cancer Centre, Melbourne, Australia. Building on the success of the II-ON, Bristol-Myers Squibb has invested in several other models of scientific collaboration with academic partners across the globe, including the Global Expert Centers Initiative (GECI) and the Immuno-Oncology Integrated Community Oncology Network (IO-ICON). "We believe a one-size-fits-all research approach does not facilitate innovation," said Lonberg. "Our tailored collaborations with academic centers expand our research capabilities and accelerate our collective ability to deliver potentially life-changing results for patients." The II-ON, formed in 2012, is a global peer-to-peer collaboration between Bristol-Myers Squibb and academia advancing the science of Immuno-Oncology (I-O) through a series of preclinical, translational and biology-focused research objectives. The research in the collaboration is focused on three fundamental scientific pillars: understanding the mechanisms of resistance to immunotherapy; identifying patient populations likely to benefit from immunotherapy; and exploring novel combination therapies that may enhance anti-tumor response through complementary mechanisms of action. The II-ON facilitates the translation of scientific research findings into drug discovery and development, with the goal of introducing new treatment options into clinical practice. In addition to Bristol-Myers Squibb, the II-ON currently comprises 15 leading cancer research institutions, including: Clinica Universidad Navarra, Dana-Farber Cancer Institute, The Earle A. Chiles Research Institute (Providence Health & Services), Institut Gustave Roussy, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G. Pascale", Bloomberg-Kimmel Institute for Cancer Immunotherapy at the Johns Hopkins Kimmel Cancer Center, Memorial Sloan Kettering Cancer Center, National Cancer Center Japan, The Netherlands Cancer Institute, The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, University College London, The University of Chicago, West German Cancer Center/University Hospital Essen, and now Columbia University Medical Center and Peter MacCallum Cancer Centre. Bristol-Myers Squibb: At the Forefront of Immuno-Oncology Science & Innovation At Bristol-Myers Squibb, patients are at the center of everything we do. Our vision for the future of cancer care is focused on researching and developing transformational Immuno-Oncology (I-O) medicines that will raise survival expectations in hard-to-treat cancers and will change the way patients live with cancer. We are leading the scientific understanding of I-O through our extensive portfolio of investigational and approved agents - including the first combination of two I-O agents in metastatic melanoma - and our differentiated clinical development program, which is studying broad patient populations across more than 20 types of cancers with 12 clinical-stage molecules designed to target different immune system pathways. Our deep expertise and innovative clinical trial designs uniquely position us to advance the science of combinations across multiple tumors and potentially deliver the next wave of I-O combination regimens with a sense of urgency. We also continue to pioneer research that will help facilitate a deeper understanding of the role of immune biomarkers and inform which patients will benefit most from I-O therapies. We understand making the promise of I-O a reality for the many patients who may benefit from these therapies requires not only innovation on our part, but also close collaboration with leading experts in the field. Our partnerships with academia, government, advocacy and biotech companies support our collective goal of providing new treatment options to advance the standards of clinical practice. Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol-Myers Squibb, visit us at BMS.com or follow us on LinkedIn, Twitter, YouTube and Facebook. This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding the research, development and commercialization of pharmaceutical products. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb's business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb's Annual Report on Form 10-K for the year ended December 31, 2016 in our Quarterly Reports on Form 10-Q and our Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.


News Article | May 9, 2017
Site: www.biosciencetechnology.com

In experiments with human colon cancer cells and mice, a team led by scientists at the Johns Hopkins Kimmel Cancer Center say they have evidence that cancer arises when a normal part of cells’ machinery generally used to repair DNA damage is diverted from its usual task. The findings, if further studies confirm them, could lead to the identification of novel molecular targets for anticancer drugs or tests for cancer recurrence, the investigators say. Scientists have long known that chronic inflammation, a risk factor for cancer, can damage DNA. They’ve also known that cancer cells’ ability to spread is in part due to so-called “epigenetic” factors that sabotage the ability of genes to turn on or off when they should. In their new study, described in the May 8 issue of Cancer Cell, the scientists uncovered a link between those two phenomena by turning their attention to a protein known as CHD4, short for chromodomain helicase DNA-binding protein. The protein is associated with DNA damage repair. The researchers, principally Limin Xia, a postdoctoral fellow in the laboratory of Stephen B. Baylin, M.D., the Virginia and D.K. Ludwig Professor of Oncology and Medicine and associate director for research programs at the Kimmel Cancer Center, designed a series of experiments to determine how the CHD4 protein repairs DNA damage. First, the researchers exposed human colon cancer cells in the laboratory to hydrogen peroxide, which damages DNA through an inflammatory-like process, namely the generation of negatively charged, highly reactive molecules called reactive oxygen species (ROS). The experiments showed that CHD4 was present at the DNA damage sites within minutes of exposure to hydrogen peroxide, and was soon accompanied by a ”repair crew” of other proteins, composed in part of DNA methyltransferases, proteins that place methyl groups on genes to “silence,” or turn them off. Then, the research team used a laser beam to cause DNA damage in the colon cancer cell lines. Again, CHD4 and its crew of repair proteins swooped into the damage site. “This result suggests that the presence of CHD4 and its accompanying proteins may be part of a universal system for repairing DNA damage,” says Baylin.  Adding support to that idea, he says, when the team stopped cells from making CHD4 by genetically disrupting the gene, the accompanying proteins were no-shows after exposure to hydrogen peroxide or the laser. Presumably, Baylin says, the mechanism exists to shut down genes in damaged regions while cells repair DNA. However, he says, the repair team may stick around in some genes, keeping them turned off even after DNA repair is finished or ongoing. The type of gene that is kept turned off could be linked to cancer, notes the team. The researchers found that eight genes most likely to be already methylated and thus turned off in colon cancer cells are thought to be potential tumor suppressors. Further investigation showed that these genes were also already enriched with CHD4. When researchers prevented cells from making CHD4, these genes lost their methylation and became reactivated, able to produce proteins that prevented the spread of cancer cells. Checking the Cancer Genome Atlas, a database funded by the National Institutes of Health that catalogs genetic mutations thought to be responsible for cancer, the investigators found that a significant subset of colon, lung and other cancers — between 30 and 40 percent — had much higher levels of CHD4 than healthy tissues. Curious as to how CHD4 is drawn to damaged DNA, Xia, Baylin and their colleagues looked for other factors that might attract CHD4 to the DNA damage site. They found that CHD4 interacts directly with an enzyme called 8-oxoguanine glycosylase (OGG1), which removes guanine — one of the units that makes up DNA — when it becomes damaged. When the researchers removed this enzyme from cells, CHD4 failed to arrive at sections of damaged DNA. When the researchers color-stained the DNA of colon cancer cells to find the most likely locations of OGG1, they found it at the locations of the eight tumor suppressor genes that are often turned off when cancer occurs. Finally, the researchers performed a series of experiments to examine the behavior of two sets of colon cancer cells: one set with a characteristically high amount of CHD4, and one in which the researchers had used genetic techniques to reduce levels of this protein. The researchers found that the unmodified colon cancer cells readily moved around in petri dishes, penetrated other cell membranes there, and migrated from one area to another in live mice to create new tumors — the hallmarks of metastases. However, when the researchers tried the same experiments with the cells in which CHD4 had been knocked down, they’d lost all these characteristic cancer cell abilities. “Taken together,” Baylin said, “our experiments suggest that CHD4 and the resulting methylation is a really important phenomenon associated with the cause of colon and probably many other cancer types.” Consequently, he says, finding ways to reduce the amount of CHD4 in tumors could be one way to treat cancer. Additionally, he says, tracking high levels of OGG1, which attracts CHD4, might be useful for doctors to gauge risk of cancer recurrence.


News Article | May 8, 2017
Site: www.eurekalert.org

In experiments with human colon cancer cells and mice, a team led by scientists at the Johns Hopkins Kimmel Cancer Center say they have evidence that cancer arises when a normal part of cells' machinery generally used to repair DNA damage is diverted from its usual task. The findings, if further studies confirm them, could lead to the identification of novel molecular targets for anticancer drugs or tests for cancer recurrence, the investigators say. Scientists have long known that chronic inflammation, a risk factor for cancer, can damage DNA. They've also known that cancer cells' ability to spread is in part due to so-called "epigenetic" factors that sabotage the ability of genes to turn on or off when they should. In their new study, described in the May 8 issue of Cancer Cell, the scientists uncovered a link between those two phenomena by turning their attention to a protein known as CHD4, short for chromodomain helicase DNA-binding protein. The protein is associated with DNA damage repair. The researchers, principally Limin Xia, a postdoctoral fellow in the laboratory of Stephen B. Baylin, M.D., the Virginia and D.K. Ludwig Professor of Oncology and Medicine and associate director for research programs at the Kimmel Cancer Center, designed a series of experiments to determine how the CHD4 protein repairs DNA damage. First, the researchers exposed human colon cancer cells in the laboratory to hydrogen peroxide, which damages DNA through an inflammatory-like process, namely the generation of negatively charged, highly reactive molecules called reactive oxygen species (ROS). The experiments showed that CHD4 was present at the DNA damage sites within minutes of exposure to hydrogen peroxide, and was soon accompanied by a "repair crew" of other proteins, composed in part of DNA methyltransferases, proteins that place methyl groups on genes to "silence," or turn them off. Then, the research team used a laser beam to cause DNA damage in the colon cancer cell lines. Again, CHD4 and its crew of repair proteins swooped into the damage site. "This result suggests that the presence of CHD4 and its accompanying proteins may be part of a universal system for repairing DNA damage," says Baylin. Adding support to that idea, he says, when the team stopped cells from making CHD4 by genetically disrupting the gene, the accompanying proteins were no-shows after exposure to hydrogen peroxide or the laser. Presumably, Baylin says, the mechanism exists to shut down genes in damaged regions while cells repair DNA. However, he says, the repair team may stick around in some genes, keeping them turned off even after DNA repair is finished or ongoing. The type of gene that is kept turned off could be linked to cancer, notes the team. The researchers found that eight genes most likely to be already methylated and thus turned off in colon cancer cells are thought to be potential tumor suppressors. Further investigation showed that these genes were also already enriched with CHD4. When researchers prevented cells from making CHD4, these genes lost their methylation and became reactivated, able to produce proteins that prevented the spread of cancer cells. Checking the Cancer Genome Atlas, a database funded by the National Institutes of Health that catalogs genetic mutations thought to be responsible for cancer, the investigators found that a significant subset of colon, lung and other cancers -- between 30 and 40 percent -- had much higher levels of CHD4 than healthy tissues. Curious as to how CHD4 is drawn to damaged DNA, Xia, Baylin and their colleagues looked for other factors that might attract CHD4 to the DNA damage site. They found that CHD4 interacts directly with an enzyme called 8-oxoguanine glycosylase (OGG1), which removes guanine -- one of the units that makes up DNA -- when it becomes damaged. When the researchers removed this enzyme from cells, CHD4 failed to arrive at sections of damaged DNA. When the researchers color-stained the DNA of colon cancer cells to find the most likely locations of OGG1, they found it at the locations of the eight tumor suppressor genes that are often turned off when cancer occurs. Finally, the researchers performed a series of experiments to examine the behavior of two sets of colon cancer cells: one set with a characteristically high amount of CHD4, and one in which the researchers had used genetic techniques to reduce levels of this protein. The researchers found that the unmodified colon cancer cells readily moved around in petri dishes, penetrated other cell membranes there, and migrated from one area to another in live mice to create new tumors -- the hallmarks of metastases. However, when the researchers tried the same experiments with the cells in which CHD4 had been knocked down, they'd lost all these characteristic cancer cell abilities. "Taken together," Baylin says, "our experiments suggest that CHD4 and the resulting methylation is a really important phenomenon associated with the cause of colon and probably many other cancer types." Consequently, he says, finding ways to reduce the amount of CHD4 in tumors could be one way to treat cancer. Additionally, he says, tracking high levels of OGG1, which attracts CHD4, might be useful for doctors to gauge risk of cancer recurrence. Other researchers who participated in this study include Yi Cai, Yang W. Zhang, Huili Li, Cynthia A. Zahnow, Wenbing Xie, and Ray-Whay Chiu Yen of Johns Hopkins, and Feyruz V. Rassool from the University of Maryland Greenebaum Comprehensive Cancer Center. The research was supported by grants from the National Institutes of Health's National Institute of Environmental Health Sciences (RO1 ES011858), the Hodson Trust, and the National Natural Science Foundation of China (No.81522031, No.81272652). The study was also supported in part by internal funds from the National Center for Toxicological Research, U.S. Food and Drug Administration.


News Article | May 10, 2017
Site: www.eurekalert.org

Using gene sequencing tools, scientists from Johns Hopkins Medicine and the University of British Columbia have found a set of genetic mutations in samples from 24 women with benign endometriosis, a painful disorder marked by the growth of uterine tissue outside of the womb. The findings, described in the May 11 issue of the New England Journal of Medicine, may eventually help scientists develop molecular tests to distinguish between aggressive and clinically "indolent," or non-aggressive, types of endometriosis. "Our discovery of these mutations is a first step in developing a genetics-based system for classifying endometriosis so that clinicians can sort out which forms of the disorder may need more aggressive treatment and which may not," says Ie-Ming Shih, M.D., Ph.D., the Richard W. TeLinde Distinguished Professor in the Department of Gynecology & Obstetrics at the Johns Hopkins University School of Medicine and co-director of the Breast and Ovarian Cancer Program at the Johns Hopkins Kimmel Cancer Center. Endometriosis occurs when tissue lining the uterus forms and grows outside of the organ, most often into the abdomen. The disease occurs in up to 10 percent of women before menopause and half of those with abdominal pain and infertility problems. In the 1920s, Johns Hopkins graduate and trained gynecologist John Sampson first coined the term "endometriosis" and proposed the idea that endometriosis resulted when normal endometrial tissue spilled out through the fallopian tubes into the abdominal cavity during menstruation. The new study, Shih says, challenges that view. The presence of the unusual set of mutations they found in their tissue samples, he says, suggests that while the origins of endometriosis are rooted in normal endometrial cells, acquired mutations changed their fate. For reasons the researchers say are not yet clear, the mutations they identified have some links to genetic mutations found in some forms of cancer. They emphasize that although abnormal tissue growth in endometriosis often spreads throughout the abdominal cavity, the tissue rarely becomes cancerous except in a few cases when ovaries are involved. For the study, Shih and his colleagues sequenced -- or figured out the genetic alphabet -- a part of the genome known as the exome, which contains all of the genes that can be expressed and make proteins. Specifically, they sequenced the exome of both normal tissue and endometriosis tissue removed during laparoscopic biopsies on 24 women, some with more than one abnormal endometrial growth. All had deep infiltrating endometriosis, the type that typically causes pain and infertility. Seven of the 24 women were from Japan; the rest were patients at Lenox Hill Hospital-Northwell Health in New York City. The use of samples from Japanese women was selected because endometriosis before menopause occurs more often in Asian women (13-18 percent) than in Caucasian women (6-10 percent), Shih says. The scientists looked for mutations, or abnormal changes in the DNA, and filtered out normal variations in genes that commonly occur among humans. Of the 24 women, 19 had one or more mutations in their endometriosis tissue that were not present in their normal tissue. The type and number of mutations varied per endometriosis lesion and between each of the women. The most common mutations, occurring in five of the women, occurred in genes including ARID1A, PIK3CA, KRAS and PPP2R1A, all known for controlling cell growth, cell invasion and DNA damage repair. Mutations in these genes have been associated with one of the deadliest types of ovarian cancer, called clear cell carcinoma. Nickolas Papadopoulos, Ph.D., professor of oncology and pathology at the Johns Hopkins Kimmel Cancer Center, led the team that completed the first sequencing of the clear cell ovarian cancer genome in 2010. "We were surprised to find cancer-linked genes in these benign endometriosis samples because these lesions do not typically become cancer," says Papadopoulos, whose Ludwig Center laboratories performed the sequencing. "We don't yet understand why these mutations occur in these tissues, but one possibility is that they could be giving the cells an advantage for growth and spread." In an additional group of endometriosis samples biopsied from 15 women at the University of British Columbia, the scientists looked specifically for mutations in the KRAS gene, whose expression signals proteins that spur cell growth and replication. They found KRAS mutations in five of the 15 patients. The scientists make clear that their sequencing studies may have missed mutations in some of the samples. Their data do not at this point reveal the aggressiveness of the lesions. However, Shih says, he and his team are working on additional studies to determine if the mutations correlate with patients' outcomes. He says a molecular test that sorts lesions as more or less aggressive has the potential to help doctors and patients decide how to treat and monitor the progression and control of the disease. "We may also be able to develop new treatments for endometriosis that use agents that block a gene-related pathway specific to a person's disease," says Shih. Women with endometriosis are typically prescribed anti-hormonal treatments that block estrogen to shrink lesions. When the disease occurs in the ovaries and forms a large cyst, which increases the risk of developing ovarian cancer, the lesion is usually surgically removed. Other scientists involved in the research include M.S. Anglesio, A. Ayhan, T.M. Nazeran, M. Noë, H.M. Horlings, A. Lum, S. Jones, J. Senz, T. Seckin, J. Ho, R.-C. Wu, V. Lac, H. Ogawa, B. Tessier?Cloutier, R. Alhassan, A. Wang, Y. Wang, J.D. Cohen, F. Wong, A. Hasanovic, N. Orr, M. Zhang, M. Popoli, W. McMahon, L.D. Wood, A. Mattox, C. Allaire, J. Segars, C. Williams, C. Tomasetti, N. Boyd, K.W. Kinzler, C.B. Gilks, L. Diaz, T.-L. Wang, B. Vogelstein, P.J. Yong, and D.G. Huntsman. Funding for the studies was provided by the Richard W. TeLinde Gynecologic Pathology Research Program at The Johns Hopkins University, the Virginia and D.K. Ludwig Fund for Cancer Research, the Ephraim and Wilma Shaw Roseman Foundation, the Endometriosis Foundation of America, the National Institutes of Health and National Cancer Institute (grants P50-CA62924, CA06973, GM07184, GM07309, CA09243, CA57345, P30-CA006973, CA215483, and UO1-CA200469), the Gray Family Ovarian Clear Cell Carcinoma Research Resource, the Canadian Cancer Society (grant 701603), the Canadian Institutes of Health Research (IHD-137431 and MOP-142273), the Canadian Foundation for Innovation (John R. Evans Leaders Fund) and British Columbia Knowledge Development Fund, the Women's Health Research Institute (Nelly Auersperg Grant), and the Canadian Foundation for Women's Health (General Research Grant), the BC Women's Hospital and Health Centre Foundation, The BC Cancer Foundation and the VGH and UBC Hospital Foundation, David and Darrell Mindell, Peter and Shelley O'Sullivan, the Jemini Foundation, the Vancouver Coastal Health Research Institute, the Dr. Chew Wei Memorial Professorship in Gynecologic Oncology, the Canada Research Chairs program (Research Chair in Molecular and Genomic Pathology), and the Dutch Cancer Society translational research fellowship (KWF 2013-5869).


PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE:BMY) today announced that more than 80 presentations, including 16 oral presentations and seven poster discussions, highlighting data from Company-sponsored studies, collaborations and investigator-sponsored research evaluating its oncology compounds across 20 types of cancer, will be featured at the American Society of Clinical Oncology (ASCO) Annual Meeting 2017 in Chicago from June 2-6. Results to be presented represent the breadth of the Company’s Oncology research portfolio, including monotherapy and combination studies of Opdivo (nivolumab) and Yervoy (ipilimumab), as well as studies of Empliciti (elotuzumab) and Sprycel (dasatinib). The Company will also present updates from its robust investigational pipeline, including proof-of-concept efficacy data for its anti-lymphocyte activation gene-3 (LAG-3) monoclonal antibody in combination with Opdivo and pharmacokinetic, pharmacodynamic and safety data on its investigational glucocorticoid-induced tumor necrosis factor receptor-related gene (GITR) agonist alone and for the first time, in combination with Opdivo in advanced solid tumors. Several presentations will report data from clinical collaborations supportive of the Company’s efforts to advance understanding of the potential role for Opdivo in combination with novel mechanisms of action for several tumor types, including the first presentation of data evaluating the safety and efficacy of Opdivo in combination with epacadostat, Incyte’s selective IDO1 enzyme inhibitor. Presentations featuring translational medicine research underscore Bristol-Myers Squibb’s scientific leadership in driving understanding of how a patient’s tumor biology can potentially guide treatment decisions. Data from research on the Company’s medicines to be presented during the meeting include: At Bristol-Myers Squibb, patients are at the center of everything we do. Our vision for the future of cancer care is focused on researching and developing transformational Immuno-Oncology (I-O) medicines for hard-to-treat cancers that could potentially improve outcomes for these patients. We are leading the scientific understanding of I-O through our extensive portfolio of investigational compounds and approved agents. Our differentiated clinical development program is studying broad patient populations across more than 35 types of cancers with 14 clinical-stage molecules designed to target different immune system pathways. Our deep expertise and innovative clinical trial designs position us to advance I-O/I-O, I-O/chemotherapy, I-O/targeted therapies and I-O/radiation therapies across multiple tumors and potentially deliver the next wave of therapies with a sense of urgency. We also continue to pioneer research that will help facilitate a deeper understanding of the role of immune biomarkers and how patients’ individual tumor biology can be used as a guide for treatment decisions throughout their journey. We understand making the promise of I-O a reality for the many patients who may benefit from these therapies requires not only innovation on our part but also close collaboration with leading experts in the field. Our partnerships with academia, government, advocacy and biotech companies support our collective goal of providing new treatment options to advance the standards of clinical practice. The II-ON, formed in 2012, is a global peer-to-peer collaboration between Bristol-Myers Squibb and academia advancing the science of Immuno-Oncology (I-O) through a series of preclinical, translational and biology-focused research objectives. The research in the collaboration is focused on three fundamental scientific pillars: understanding the mechanisms of resistance to immunotherapy; identifying patient populations likely to benefit from immunotherapy; and exploring novel combination therapies that may enhance anti-tumor response through complementary mechanisms of action. The II-ON facilitates the translation of scientific research findings into drug discovery and development, with the goal of introducing new treatment options into clinical practice. In addition to Bristol-Myers Squibb, the II-ON currently comprises 15 leading cancer research institutions, including: Clinica Universidad Navarra, Columbia University Medical Center, Dana-Farber Cancer Institute, The Earle A. Chiles Research Institute (Providence Health & Services), Institut Gustave Roussy, Istituto Nazionale per lo Studio e la Cura dei Tumori “Fondazione G. Pascale”, Bloomberg-Kimmel Institute for Cancer Immunotherapy at the Johns Hopkins Kimmel Cancer Center, Memorial Sloan Kettering Cancer Center, National Cancer Center Japan, The Netherlands Cancer Institute, Peter MacCallum Cancer Centre, The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, University College London, The University of Chicago and West German Cancer Center/University Hospital Essen. Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that is designed to uniquely harness the body’s own immune system to help restore anti-tumor immune response. By harnessing the body’s own immune system to fight cancer, Opdivo has become an important treatment option across multiple cancers. Opdivo’s leading global development program is based on Bristol-Myers Squibb’s scientific expertise in the field of Immuno-Oncology and includes a broad range of clinical trials across all phases, including Phase 3, in a variety of tumor types. To date, the Opdivo clinical development program has enrolled more than 25,000 patients. The Opdivo trials have contributed to gaining a deeper understanding of the potential role of biomarkers in patient care, particularly regarding how patients may benefit from Opdivo across the continuum of PD-L1 expression. In July 2014, Opdivo was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world. Opdivo is currently approved in more than 60 countries, including the United States, the European Union and Japan. In October 2015, the company’s Opdivo and Yervoy combination regimen was the first Immuno-Oncology combination to receive regulatory approval for the treatment of metastatic melanoma and is currently approved in more than 50 countries, including the United States and the European Union. OPDIVO® (nivolumab) as a single agent is indicated for the treatment of patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. OPDIVO® (nivolumab) as a single agent is indicated for the treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma. OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the treatment of patients with unresectable or metastatic melanoma. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. OPDIVO® (nivolumab) is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO. OPDIVO® (nivolumab) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy. OPDIVO® (nivolumab) is indicated for the treatment of patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and post-transplantation brentuximab vedotin. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. OPDIVO® (nivolumab) is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy. OPDIVO® (nivolumab) is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. YERVOY can result in severe and fatal immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY. Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests (LFTs), adrenocorticotropic hormone (ACTH) level, and thyroid function tests at baseline and before each dose. OPDIVO can cause immune-mediated pneumonitis. Fatal cases have been reported. Monitor patients for signs with radiographic imaging and for symptoms of pneumonitis. Administer corticosteroids for Grade 2 or more severe pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In patients receiving OPDIVO monotherapy, fatal cases of immune-mediated pneumonitis have occurred. Immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated pneumonitis occurred in 6% (25/407) of patients. In Checkmate 205 and 039, pneumonitis, including interstitial lung disease, occurred in 4.9% (13/263) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 3.4% (9/263) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=8). OPDIVO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO monotherapy for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon re-initiation of OPDIVO. When administered with YERVOY, withhold OPDIVO and YERVOY for Grade 2 and permanently discontinue for Grade 3 or 4 or recurrent colitis. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated colitis occurred in 26% (107/407) of patients including three fatal cases. In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 (7%) patients. Across all YERVOY-treated patients in that study (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis. OPDIVO can cause immune-mediated hepatitis. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 immune-mediated hepatitis. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated hepatitis occurred in 13% (51/407) of patients. In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5x the ULN or total bilirubin elevations >3x the ULN; Grade 3-5) occurred in 8 (2%) patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4%. In a separate Phase 3 study of YERVOY 3 mg/kg, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported. OPDIVO can cause immune-mediated hypophysitis, immune-mediated adrenal insufficiency, autoimmune thyroid disorders, and Type 1 diabetes mellitus. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency, thyroid function prior to and periodically during treatment, and hyperglycemia. Administer hormone replacement as clinically indicated and corticosteroids for Grade 2 or greater hypophysitis. Withhold for Grade 2 or 3 and permanently discontinue for Grade 4 hypophysitis. Administer corticosteroids for Grade 3 or 4 adrenal insufficiency. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 adrenal insufficiency. Administer hormone-replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. Withhold OPDIVO for Grade 3 and permanently discontinue for Grade 4 hyperglycemia. In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients. In patients receiving OPDIVO with YERVOY, hypophysitis occurred in 9% (36/407) of patients. In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994) of patients. In patients receiving OPDIVO with YERVOY, adrenal insufficiency occurred in 5% (21/407) of patients. In patients receiving OPDIVO monotherapy, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 9% (171/1994) of patients. Hyperthyroidism occurred in 2.7% (54/1994) of patients receiving OPDIVO monotherapy. In patients receiving OPDIVO with YERVOY, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (89/407) of patients. Hyperthyroidism occurred in 8% (34/407) of patients receiving OPDIVO with YERVOY. In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients. In patients receiving OPDIVO with YERVOY, diabetes occurred in 1.5% (6/407) of patients. In a separate Phase 3 study of YERVOY 3 mg/kg, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3-4) occurred in 9 (1.8%) patients. All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. 6 of the 9 patients were hospitalized for severe endocrinopathies. OPDIVO can cause immune-mediated nephritis. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grades 2-4 increased serum creatinine. Withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 increased serum creatinine. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated nephritis and renal dysfunction occurred in 2.2% (9/407) of patients. OPDIVO can cause immune-mediated rash, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some cases with fatal outcome. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4 rash. For symptoms or signs of SJS or TEN, withhold OPDIVO and refer the patient for specialized care for assessment and treatment; if confirmed, permanently discontinue. In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated rash occurred in 22.6% (92/407) of patients. In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3-5) occurred in 13 (2.5%) patients. 1 (0.2%) patient died as a result of toxic epidermal necrolysis. 1 additional patient required hospitalization for severe dermatitis. OPDIVO can cause immune-mediated encephalitis. Evaluation of patients with neurologic symptoms may include, but not be limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Withhold OPDIVO in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out other causes. If other etiologies are ruled out, administer corticosteroids and permanently discontinue OPDIVO for immune-mediated encephalitis. In patients receiving OPDIVO monotherapy, encephalitis occurred in 0.2% (3/1994) of patients. Fatal limbic encephalitis occurred in one patient after 7.2 months of exposure despite discontinuation of OPDIVO and administration of corticosteroids. Encephalitis occurred in one patient receiving OPDIVO with YERVOY (0.2%) after 1.7 months of exposure. Based on the severity of adverse reaction, permanently discontinue or withhold treatment, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. Across clinical trials of OPDIVO the following clinically significant immune-mediated adverse reactions occurred in <1.0% of patients receiving OPDIVO: uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), myositis, myocarditis, rhabdomyolysis, motor dysfunction, vasculitis, and myasthenic syndrome. OPDIVO can cause severe infusion reactions, which have been reported in <1.0% of patients in clinical trials. Discontinue OPDIVO in patients with Grade 3 or 4 infusion reactions. Interrupt or slow the rate of infusion in patients with Grade 1 or 2. In patients receiving OPDIVO monotherapy, infusion-related reactions occurred in 6.4% (127/1994) of patients. In patients receiving OPDIVO with YERVOY, infusion-related reactions occurred in 2.5% (10/407) of patients. Complications, including fatal events, occurred in patients who received allogeneic HSCT after OPDIVO. Outcomes were evaluated in 17 patients from Checkmate 205 and 039, who underwent allogeneic HSCT after discontinuing OPDIVO (15 with reduced-intensity conditioning, 2 with myeloablative conditioning). Thirty-five percent (6/17) of patients died from complications of allogeneic HSCT after OPDIVO. Five deaths occurred in the setting of severe or refractory GVHD. Grade 3 or higher acute GVHD was reported in 29% (5/17) of patients. Hyperacute GVHD was reported in 20% (n=2) of patients. A steroid-requiring febrile syndrome, without an identified infectious cause, was reported in 35% (n=6) of patients. Two cases of encephalitis were reported: Grade 3 (n=1) lymphocytic encephalitis without an identified infectious cause, and Grade 3 (n=1) suspected viral encephalitis. Hepatic veno-occlusive disease (VOD) occurred in one patient, who received reduced-intensity conditioned allogeneic HSCT and died of GVHD and multi-organ failure. Other cases of hepatic VOD after reduced-intensity conditioned allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor blocking antibody before transplantation. Cases of fatal hyperacute GVHD have also been reported. These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT. Follow patients closely for early evidence of transplant-related complications such as hyperacute GVHD, severe (Grade 3 to 4) acute GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other immune-mediated adverse reactions, and intervene promptly. Based on their mechanisms of action, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with an OPDIVO- or YERVOY- containing regimen and for at least 5 months after the last dose of OPDIVO. It is not known whether OPDIVO or YERVOY is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from an OPDIVO-containing regimen, advise women to discontinue breastfeeding during treatment. Advise women to discontinue nursing during treatment with YERVOY and for 3 months following the final dose. In Checkmate 037, serious adverse reactions occurred in 41% of patients receiving OPDIVO (n=268). Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. In Checkmate 066, serious adverse reactions occurred in 36% of patients receiving OPDIVO (n=206). Grade 3 and 4 adverse reactions occurred in 41% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of patients receiving OPDIVO were gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%). In Checkmate 067, serious adverse reactions (73% and 37%), adverse reactions leading to permanent discontinuation (43% and 14%) or to dosing delays (55% and 28%), and Grade 3 or 4 adverse reactions (72% and 44%) all occurred more frequently in the OPDIVO plus YERVOY arm (n=313) relative to the OPDIVO arm (n=313). The most frequent (≥10%) serious adverse reactions in the OPDIVO plus YERVOY arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.6%), colitis (10% and 1.6%), and pyrexia (10% and 0.6%). In Checkmate 017 and 057, serious adverse reactions occurred in 46% of patients receiving OPDIVO (n=418). The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. In Checkmate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO (n=406). The most frequent serious adverse reactions reported in ≥2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. In Checkmate 205 and 039, among all patients (safety population [n=263]), adverse reactions leading to discontinuation (4.2%) or to dosing delays (23%) occurred. The most frequent serious adverse reactions reported in ≥1% of patients were infusion-related reaction, pneumonia, pleural effusion, pyrexia, rash and pneumonitis. Ten patients died from causes other than disease progression, including 6 who died from complications of allogeneic HSCT. Serious adverse reactions occurred in 21% of patients in the safety population (n=263) and 27% of patients in the subset of patients evaluated for efficacy (efficacy population [n=95]). In Checkmate 141, serious adverse reactions occurred in 49% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory tract infections, and sepsis. In Checkmate 275, serious adverse reactions occurred in 54% of patients receiving OPDIVO (n=270). The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration. In Checkmate 037, the most common adverse reaction (≥20%) reported with OPDIVO (n=268) was rash (21%). In Checkmate 066, the most common adverse reactions (≥20%) reported with OPDIVO (n=206) vs dacarbazine (n=205) were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO plus YERVOY arm (n=313) were fatigue (59%), rash (53%), diarrhea (52%), nausea (40%), pyrexia (37%), vomiting (28%), and dyspnea (20%). The most common (≥20%) adverse reactions in the OPDIVO (n=313) arm were fatigue (53%), rash (40%), diarrhea (31%), and nausea (28%). In Checkmate 017 and 057, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=418) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. In Checkmate 025, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=406) vs everolimus (n=397) were asthenic conditions (56% vs 57%), cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%), constipation (23% vs 18%), decreased appetite (23% vs 30%), back pain (21% vs 16%), and arthralgia (20% vs 14%). In Checkmate 205 and 039, among all patients (safety population [n=263]) and the subset of patients in the efficacy population (n=95), respectively, the most common adverse reactions (≥20%) were fatigue (32% and 43%), upper respiratory tract infection (28% and 48%), pyrexia (24% and 35%), diarrhea (23% and 30%), and cough (22% and 35%). In the subset of patients in the efficacy population (n=95), the most common adverse reactions also included rash (31%), musculoskeletal pain (27%), pruritus (25%), nausea (23%), arthralgia (21%), and peripheral neuropathy (21%). In Checkmate 141, the most common adverse reactions (≥10%) in patients receiving OPDIVO were cough and dyspnea at a higher incidence than investigator’s choice. In Checkmate 275, the most common adverse reactions (≥ 20%) reported in patients receiving OPDIVO (n=270) were fatigue (46%), musculoskeletal pain (30%), nausea (22%), and decreased appetite (22%). In a separate Phase 3 study of YERVOY 3 mg/kg, the most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%). Checkmate 067 - advanced melanoma alone or in combination with YERVOY; Checkmate 037 and 066 - advanced melanoma; Checkmate 017 - squamous non-small cell lung cancer (NSCLC); Checkmate 057 - non-squamous NSCLC; Checkmate 025 - renal cell carcinoma; Checkmate 205/039 - classical Hodgkin lymphoma; Checkmate 141 - squamous cell carcinoma of the head and neck; Checkmate 275 - urothelial carcinoma. Please see U.S. Full Prescribing Information for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY. About the Bristol-Myers Squibb and Ono Pharmaceutical Co., Ltd. Collaboration In 2011, through a collaboration agreement with Ono Pharmaceutical Co., Ltd (Ono), Bristol-Myers Squibb expanded its territorial rights to develop and commercialize Opdivo globally except in Japan, South Korea and Taiwan, where Ono had retained all rights to the compound at the time. On July 23, 2014, Bristol-Myers Squibb and Ono further expanded the companies’ strategic collaboration agreement to jointly develop and commercialize multiple immunotherapies – as single agents and combination regimens – for patients with cancer in Japan, South Korea and Taiwan. Empliciti is an immunostimulatory antibody that specifically targets Signaling Lymphocyte Activation Molecule Family member 7 (SLAMF7), a cell-surface glycoprotein. SLAMF7 is expressed on myeloma cells independent of cytogenetic abnormalities. SLAMF7 also is expressed on Natural Killer cells, plasma cells and at lower levels on specific immune cell subsets of differentiated cells within the hematopoietic lineage. Empliciti has a dual mechanism-of-action. It directly activates the immune system through Natural Killer cells via the SLAMF7 pathway. Empliciti also targets SLAMF7 on myeloma cells, tagging these malignant cells for Natural Killer cell-mediated destruction via antibody-dependent cellular toxicity. On November 30, 2015, the U.S. Food and Drug Administration (FDA) approved Empliciti in combination with lenalidomide and dexamethasone in patients with multiple myeloma who have received one to three prior therapies. On May 11, 2016, the European Commission approved Empliciti in combination with lenalidomide and dexamethasone in patients with multiple myeloma who have received at least one prior therapy. The safety and efficacy of Empliciti is being evaluated by other health authorities. Bristol-Myers Squibb and AbbVie are co-developing Empliciti, with Bristol-Myers Squibb solely responsible for commercial activities. EMPLICITI™ (elotuzumab) is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received one to three prior therapies. Please see the full Prescribing Information for EMPLICITI. Sprycel was first approved by the FDA in 2006 for the treatment of adults with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP) who are resistant or intolerant to prior therapy including imatinib. At that time, Sprycel was also approved for adults with Ph+ acute lymphoblastic leukemia (ALL) who are resistant or intolerant to prior therapy. Sprycel is approved and marketed worldwide for these indications in more than 60 countries. Sprycel is also an FDA-approved treatment for adults with newly diagnosed CP Ph+ CML (since October 2010). Sprycel received accelerated FDA approval for this indication. Additional country approvals for this indication total more than 50. SPRYCEL® (dasatinib) is indicated for the treatment of adults with: Treatment with SPRYCEL is associated with severe (NCI CTC Grade 3/4) thrombocytopenia, neutropenia, and anemia, which occur earlier and more frequently in patients with advanced phase CML or Ph+ ALL than in patients with chronic phase CML. Myelosuppression was reported in patients with normal baseline laboratory values as well as in patients with pre-existing laboratory abnormalities. SPRYCEL caused thrombocytopenia in human subjects. In addition, dasatinib caused platelet dysfunction in vitro. In all CML or Ph+ ALL clinical studies, ≥grade 3 central nervous system (CNS) hemorrhages, including fatalities, occurred in <1% of patients receiving SPRYCEL. Grade 3 or greater gastrointestinal hemorrhage, including fatalities, occurred in 4% of patients and generally required treatment interruptions and transfusions. Other cases of ≥grade 3 hemorrhage occurred in 2% of patients. SPRYCEL may cause fluid retention. After 5 years of follow-up in the randomized newly diagnosed chronic phase CML study (n=258), grade 3/4 fluid retention was reported in 5% of patients, including 3% of patients with grade 3/4 pleural effusion. In patients with newly diagnosed or imatinib resistant or intolerant chronic phase CML, grade 3/4 fluid retention occurred in 6% of patients treated with SPRYCEL at the recommended dose (n=548). In patients with advanced phase CML or Ph+ ALL treated with SPRYCEL at the recommended dose (n=304), grade 3/4 fluid retention was reported in 8% of patients, including grade 3/4 pleural effusion reported in 7% of patients. After 5 years of follow-up in the randomized newly diagnosed chronic phase CML trial (n=258), the following cardiac adverse events occurred: Monitor patients for signs or symptoms consistent with cardiac dysfunction and treat appropriately. SPRYCEL may increase the risk of developing PAH, which may occur any time after initiation, including after more than 1 year of treatment. Manifestations include dyspnea, fatigue, hypoxia, and fluid retention. PAH may be reversible on discontinuation of SPRYCEL. In vitro data suggest that dasatinib has the potential to prolong cardiac ventricular repolarization (QT interval). Cases of severe mucocutaneous dermatologic reactions, including Stevens-Johnson syndrome and erythema multiforme, have been reported in patients treated with SPRYCEL. TLS has been reported in patients with resistance to prior imatinib therapy, primarily in advanced phase disease. Based on limited human data, SPRYCEL can cause fetal harm when administered to a pregnant woman. Hydrops fetalis, fetal leukopenia and fetal thrombocytopenia have been reported with maternal exposure to SPRYCEL. Transplacental transfer of dasatinib has been measured in fetal plasma and amniotic fluid at concentrations comparable to those in maternal plasma. No data are available regarding the presence of dasatinib in human milk, the effects of the drug on the breastfed infant or the effects of the drug on milk production. However, dasatinib is present in the milk of lactating rats. SPRYCEL is a CYP3A4 substrate and a weak time-dependent inhibitor of CYP3A4. The safety data reflects exposure to SPRYCEL at all doses tested in clinical studies including 324 patients with newly diagnosed chronic phase CML and 2388 patients with imatinib resistant or intolerant chronic or advanced phase CML or Ph+ ALL. The median duration of therapy in all 2712 SPRYCEL-treated patients was 19.2 months (range 0–93.2 months). Median duration of therapy in: In the newly diagnosed chronic phase CML trial, after a minimum of 60 months of follow-up, the cumulative discontinuation rate for 258 patients was 39%. In the overall population of 2712 SPRYCEL-treated patients, 88% of patients experienced adverse reactions at some time and 19% experienced adverse reactions leading to treatment discontinuation. Among the 1618 SPRYCEL-treated patients with chronic phase CML, drug-related adverse events leading to discontinuation were reported in 329 (20.3%) patients. Among the 1094 SPRYCEL-treated patients with advanced phase CML or Ph+ ALL, drug-related adverse events leading to discontinuation were reported in 191 (17.5%) patients. Patients ≥65 years are more likely to experience the commonly reported adverse reactions of fatigue, pleural effusion, diarrhea, dyspnea, cough, lower gastrointestinal hemorrhage, and appetite disturbance, and more likely to experience the less frequently reported adverse reactions of abdominal distention, dizziness, pericardial effusion, congestive heart failure, hypertension, pulmonary edema and weight decrease, and should be monitored closely. Please see the full Prescribing Information for SPRYCEL. Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol-Myers Squibb, visit us at BMS.com or follow us on LinkedIn, Twitter, YouTube and Facebook. This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding the research, development and commercialization of pharmaceutical products. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Among other risks, there can be no guarantee that any of the oncology compounds mentioned in this release will receive regulatory approval for an additional indication. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb's business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb's Annual Report on Form 10-K for the year ended December 31, 2016, in our Quarterly Reports on Form 10-Q and our Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.


News Article | May 16, 2017
Site: www.biosciencetechnology.com

Using gene sequencing tools, scientists from Johns Hopkins Medicine and the University of British Columbia have found a set of genetic mutations in samples from 24 women with benign endometriosis, a painful disorder marked by the growth of uterine tissue outside of the womb. The findings, described in the May 11 issue of The New England Journal of Medicine, may eventually help scientists develop molecular tests to distinguish between aggressive and clinically “indolent,” or non-aggressive, types of endometriosis. “Our discovery of these mutations is a first step in developing a genetics-based system for classifying endometriosis so that clinicians can sort out which forms of the disorder may need more aggressive treatment and which may not,” said Ie-Ming Shih, M.D., Ph.D., the Richard W. TeLinde Distinguished Professor in the Department of Gynecology & Obstetrics at the Johns Hopkins University School of Medicine and co-director of the Breast and Ovarian Cancer Program at the Johns Hopkins Kimmel Cancer Center. Endometriosis occurs when tissue lining the uterus forms and grows outside of the organ, most often into the abdomen. The disease occurs in up to 10 percent of women before menopause and half of those with abdominal pain and infertility problems. In the 1920s, Johns Hopkins graduate and trained gynecologist John Sampson first coined the term “endometriosis” and proposed the idea that endometriosis resulted when normal endometrial tissue spilled out through the fallopian tubes into the abdominal cavity during menstruation. The new study, Shih said, challenges that view. The presence of the unusual set of mutations they found in their tissue samples, he says, suggests that while the origins of endometriosis are rooted in normal endometrial cells, acquired mutations changed their fate. For reasons the researchers say are not yet clear, the mutations they identified have some links to genetic mutations found in some forms of cancer. They emphasize that although abnormal tissue growth in endometriosis often spreads throughout the abdominal cavity, the tissue rarely becomes cancerous except in a few cases when ovaries are involved. For the study, Shih and his colleagues sequenced — or figured out the genetic alphabet — a part of the genome known as the exome, which contains all of the genes that can be expressed and make proteins. Specifically, they sequenced the exome of both normal tissue and endometriosis tissue removed during laparoscopic biopsies on 24 women, some with more than one abnormal endometrial growth. All had deep infiltrating endometriosis, the type that typically causes pain and infertility. Seven of the 24 women were from Japan; the rest were patients at Lenox Hill Hospital-Northwell Health in New York City. The use of samples from Japanese women was selected because endometriosis before menopause occurs more often in Asian women (13–18 percent) than in Caucasian women (6-10 percent), Shih says. The scientists looked for mutations, or abnormal changes in the DNA, and filtered out normal variations in genes that commonly occur among humans. Of the 24 women, 19 had one or more mutations in their endometriosis tissue that were not present in their normal tissue. The type and number of mutations varied per endometriosis lesion and between each of the women. The most common mutations, occurring in five of the women, occurred in genes including ARID1A, PIK3CA, KRAS and PPP2R1A, all known for controlling cell growth, cell invasion and DNA damage repair. Mutations in these genes have been associated with one of the deadliest types of ovarian cancer, called clear cell carcinoma. Nickolas Papadopoulos, Ph.D., professor of oncology and pathology at the Johns Hopkins Kimmel Cancer Center, led the team that completed the first sequencing of the clear cell ovarian cancer genome in 2010. “We were surprised to find cancer-linked genes in these benign endometriosis samples because these lesions do not typically become cancer,” said Papadopoulos, whose Ludwig Center laboratories performed the sequencing. “We don't yet understand why these mutations occur in these tissues, but one possibility is that they could be giving the cells an advantage for growth and spread.” In an additional group of endometriosis samples biopsied from 15 women at the University of British Columbia, the scientists looked specifically for mutations in the KRAS gene, whose expression signals proteins that spur cell growth and replication. They found KRAS mutations in five of the 15 patients. The scientists make clear that their sequencing studies may have missed mutations in some of the samples. Their data do not at this point reveal the aggressiveness of the lesions. However, Shih said, he and his team are working on additional studies to determine if the mutations correlate with patients’ outcomes. He says a molecular test that sorts lesions as more or less aggressive has the potential to help doctors and patients decide how to treat and monitor the progression and control of the disease. “We may also be able to develop new treatments for endometriosis that use agents that block a gene-related pathway specific to a person’s disease,” said Shih. Women with endometriosis are typically prescribed anti-hormonal treatments that block estrogen to shrink lesions. When the disease occurs in the ovaries and forms a large cyst, which increases the risk of developing ovarian cancer, the lesion is usually surgically removed. Image: Endometriosis in the peritoneal tissue (left) forming a scar. Under microscopy, it is composed of glands and surrounding stroma with chronic inflammation and fibrosis.


News Article | March 24, 2017
Site: www.techtimes.com

A person who sticks to a healthy lifestyle — doesn't smoke, doesn't eat processed foods, stays fit with regular workouts, steers clear from carcinogens — and who has no known family history of the disease can get the big C. Scientists at Johns Hopkins Kimmel Cancer Center shed light on this topic with their new study suggesting that random, unpredictable DNA copying errors account for nearly 66 percent, or at least two-thirds, of the mutations that cause cancer. It also found that 29 percent is due to environmental factors or lifestyle, and 5 percent is due to hereditary DNA mutations. The study used a novel mathematical model based on DNA sequencing and worldwide epidemiologic data. According to researchers, their findings back up the theory of an earlier Cancer Research UK study saying that 42 percent of cancers can be avoided with a healthy lifestyle. "It is well-known that we must avoid environmental factors such as smoking to decrease our risk of getting cancer. But it is not as well-known that each time a normal cell divides and copies its DNA to produce two new cells, it makes multiple mistakes," Cristian Tomasetti, Ph.D., one of the study's authors, said. Brain and prostate cancer are the two types of cancer that are found largely attributable to random DNA mistakes. This was seen in over 95 percent of the cases examined by the researchers. Environmental factors still played a huge role in other forms of cancer, such as lung cancer. In the study, it caused 65 percent of lung cancer cases, leaving the remaining 35 percent to DNA copying errors. "Even if, as this study suggests, most individual cancer mutations are due to random chance, the researchers admit that the cancers they cause may still be preventable," Professor Mel Greaves, director of the Centre for Evolution and Cancer at The Institute of Cancer Research in London, said. Dr. Bert Vogelstein, a coauthor of the study, said that adhering to a healthy lifestyle and staying away from carcinogens is still imperative to lower one's risk for cancer mutation. While it is true that no mutation can be avoided and that cancer can happen even in a perfect environment, Dr. Vogelstein believes that early detection should be the ultimate focus. The latest cancer study was published on March 24 in the journal Science. © 2017 Tech Times, All rights reserved. Do not reproduce without permission.

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