University of Texas MD Anderson Cancer Center, USA
Eliminating TKI-induced MSC-mediated drug resistance in BCR-ABL+ ALL
Xiaoping Sun completed his MD at Zhejiang Medical University, Hangzhou, China in 1984, and his PhD at Catholic University of Nijmegen, The Netherlands and Shanghai Institute of Cell Biology, Chinese Academy of Sciences, Shanghai, China in 1994. He received postdoctoral fellowship training at the Salk Institute for Biological Studies, La Jolla, California, USA from 1994 to 1998. His medical residency in anatomical and clinical pathology was completed at Northwestern University Medical School, Chicago, Illinois, USA in 2002 and his hematopathology fellowship at The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA in 2003. He then became an assistant professor, and subsequently associated professor and professor in the Department of Laboratory Medicine at UT MD Anderson. Besides his patient care clinical service in the core lab at UT MD Anderson, he runs a research lab that works on leukemogenesis, leukemia progression and drug resistance, B-cell acute lymphoblastic leukemia, and B cell development.
Tyrosine kinase inhibitors (TKIs) are used as a frontline therapy for BCR-ABL–positive (BCR-ABL+) acute lymphoblastic leukemia (ALL). However, resistance to TKI therapy arises rapidly, and its underlying molecular mechanisms are poorly understood. We identified a novel cascade of events initiated by TKIs and traversing through mesenchymal stem cells (MSCs) to leukemic cells, leading to resistance. MSCs exposed to TKIs acquired a new functional status with the expression of genes encoding for chemo-attractants, adhesion molecules, and pro-survival growth factors, and this priming enabled leukemic cells to form clusters underneath the MSCs. This cluster formation was associated with the protection of ALL cells from therapy as leukemic cells switched from BCR-ABL signaling to alternative surviving signaling such as IL-7R/JAK signaling in the MSC milieu.
To eliminate the TKIs’ off-target effects on mesenchymal stem/stromal cells (MSCs) and the alternative survival signaling in leukemic cells, we screened a large library of clinically relevant compounds and demonstrated that p38 MAPK inhibitor SB203580 and glucocorticoid receptor agonist dexamethasone could abolish the imatinib-induced MSC–mediated survival support to BCR-ABL–positive ALL cells and prevent BCR-ABL TKI resistance. These findings provide a strong rationale for integrating p38 MAPK inhibitors into current induction and/or maintenance therapy to eliminate TKI resistance and to improve therapeutic outcomes in patients with BCR-ABL–positive ALL.
University of Texas MD Anderson Cancer Center, USA
Biomarkers that have prognostic and therapeutic importance for inflammatory breast cancer
Yun Gong received MD degree in 1984 and then finished her post-graduate Pathology training in 1989 at Zhejiang Medical University in China. She then worked as a post-doctor and Research Associate in the Shanghai Institute of Cell Biology, Chinese Academy of Sciences; Catholic University of Nijmegen, The Netherlands; and The Scripps Research Institute, La Jolla, California. From 1998 to 2002, she received her residency training in Anatomic and Clinical Pathology at Northwestern University Medical School in Chicago, followed by one-year cytopathology fellowship training at MD Anderson Cancer Center. From 2003, she became a faculty member at the Dept. of Pathology, MD Anderson Cancer Center, and currently is a Full Professor. She has numerous publications in the fields of breast cancer research and cytopathology (120 peer-review articles, 18 invited articles, 6 book chapters and 1 book, 118 abstracts). She is an important collaborator of two IBC research projects that were funded by Susan G. Komen Promise Grant. She is a Guest Editor of Breast Diseases: Year Book of Oncology since 2011, a member of the study section of MD Anderson Institutional Research Grant Program, and was a reviewer for NCI/NIH on Business Innovation Research Contract Proposals in 2009 and 2013.
Inflammatory breast cancer (IBC) is rare but the most lethal type of breast cancer. IBC is often associated with early metastasis and resistance to conventional therapies. Understanding biological insights that underlie the aggressive behavior of IBC and identifying novel therapeuticstrategies are highly desirable for improvement of clinical outcome in patients with IBC. This presentation will cover the clinic-pathologic significance of some important biomarkers expression in a cohort of IBC that have long-term clinical follow-up and treatment information. Our results indicated that EZH2 and PD-L1 (clone 28-8) expression status may be used to identify a subset of patients who have a relatively worse prognosis. Targeting EZH2 also may provide a novel strategy for improving the clinical outcome of patients with IBC. In addition, Androgen Receptor expression was significantly associated with lymphovascular invasion. Additional information and discussion will be presented.
Baylor College of Medicine, USA
Sepin-1, a novel separase inhibitor for the treatment of refractory breast cancers
Pati is a highly accomplished cancer biologist who is an internationally recognized leader in the field of chromosomal cohesion and Separation and its role in carcinogenesis. He has a highly impressive track record not only in basic biology of chromosomal cohesion and separation, but devising novel and innovative approaches to target the cohesin pathway for treating refractory human cancers. He is widely recognized nationally and internationally as a creative and innovative scientist and is specifically recognized for his identification and targeting of the cohesin-protease, Separase for cancer therapy. Separase, an enzyme important for resolving chromosomal cohesion, is a novel oncogene and promoter of aneuploidy and tumorigenesis that Professor Pati demonstrated is an ideal target for cancer therapy. His laboratory was first to show that Separase is an oncogene and aneuploidy promoter. In a series of publications in high impact journals, Professor Pati and his colleagues demonstrated that overexpression of Separase in mouse models not only induces aneuploidy but also results in tumorigenesis.
Separase, an enzyme that resolves chromosomal cohesion during cell division, is an oncogene. Separase is overexpressed in multiple human tumors of breast, bone and brain. Separase is overexpressed in >60% of breast cancer (BC) specimens, 50% of triple-negative BC (TNBC) tumors, and >80% of luminal-B BC tumors. Separase overexpression strongly correlates with aneuploidy, a high incidence of relapse, metastasis, and a lower 5-year overall survival rate. In mouse models, Separase overexpression has been shown to induce aneuploidy, genomic instability, mammary tumorigenesis, and intratumor heterogeneity.
Knockdown of Separase inhibits the growth of Separase overexpressing mammary tumor cells but have no effect on cells with normal Separase level. Using a high throughput screen, we have identified a small molecule Separase inhibitor (Sepin-1) which selectively curtails the growth of Separase-overexpressing TNBC tumor cells. Sepin-1 inhibits growth of breast tumor cells with IC50s ranging from 10-30µM, and thus represents a lead candidate to target breast tumors that overexpress Separase. Sepin-1 is well tolerated with no significant toxicity or side effect up to a dose of 80mg/kg in mice. Studies using patient-derived orthotopic xenografts of TNBC render significant survival advantages for Sepin-1 treated mice. Sepin-1 inhibits the growth of Separase-overexpressing human TNBC xenografts in mice in a Separase-dependent manner, and in the same assay, Sepin-1 had no appreciable effect on TNBC tumors with low-Separase expression, suggesting the specificity and efficacy of this compound in targeting tumors addicted to Separase overexpression.
These results suggest that inhibition of Separase represents a new line of therapy to treat breast tumors addicted to Separase overexpression. We have recently developed a highly effective Sepin-1 analog with one order magnitude higher activity using medicinal chemistry approaches. Investigational New Drug (IND) enabling studies including the pharmacokinetics, pharmacodynamics and toxicity in animal models are currently in progress to bring Sepin compounds to the clinics for phase-I clinical trial. Blocking the overexpressed Separase activity as a strategy to eliminate and/or sensitize resistant cancer cells to chemotherapy is a new therapeutic approach, and if successful, will significantly impact breast cancer treatment. Furthermore, developing anti-cancer therapeutics that target chromosome instability is a new field of research.(Supported by the Cancer Prevention and Research Institute of Texas Grant # DP150064, and Department of Defense Award W81XWH-15-1-0122 awarded to D. Pati)
Accelerating vaccine process development and manufacturing: Innovative approaches and challenges
Anissa Boumlic-Courtade, PhD is Associate Director for the vaccine initiative in EMEA with Merck. Dr. Boumlic-Courtade joined Merck in 2009 (formerly Millipore) after research experience in various institute including Pasteur Institute of Athens and the CNRS (National Center for Research, France). She has held various positions focused on downstream processing, virus safety, and monoclonal antibody and vaccine process development and manufacturing. Dr. Anissa Boumlic-Courtade holds a M. Sc. in Biotechnology Engineering from the Ecole Supérieure de Biotechnologie(ESBS) de Strasbourg (France) and a PhD in Molecular Biology & Biochemistry specialized in Virology from the University of Strasbourgco-directed with the University of Thessaly (Greece)
Preventable diseases vaccines save millions of lives but are not always delivered when needed to a large fraction of the population. In addition, there are a number of infectious diseases that still remain without cure or vaccine. Innovations in process development and manufacturing are unavoidable to enable release of existing and novel vaccines and their delivery where and when they are mostly needed. This presentation will outline where innovative approaches and technologies while developing and/or optimizing the process and at manufacturing scale can accelerate clinical phases and compress the time to market of highly needed vaccines. Furthermore, using case studies like Ebola and influenza outbreaks, challenges will also be highlighted in pandemic situations and approaches will be discussed on how to alleviate roadblocks and be better prepared to manufacture vaccines in urgent situations.
Sheik Mohammad Fazle Akbar
Toshiba General Hospital, Japan
Therapeutic vaccination: A new and novel therapeutic approach for chronic hepatitis B
Sheikh Mohammad Fazle Akbar has graduated in Medicine and Surgery from Bangladesh in 1980 and received his PhD in Medical Sciences from Japan in 1993. Being a post-graduate fellow from 1994-1996, he has worked as full Faculty Member at the Graduate School of Medicine, Ehime University, Japan from 1996-2008. In 2008, he has joined Toshiba General Hospital, Tokyo, Japan as Principal Investigator. He has worked to elucidate pathogenesis of chronic liver diseases and hepatocellular carcinoma; subsequently developed therapeutic vaccine for HBV transgenic mice and presently he has been conducting pilot studies and clinical trials in patients with CHB with Therapeutic Vaccines for last one decade to optimize a safe, effective and clinical viable regimen of this approach in CHB patients. He has authored more than one hundred scientific articles in peer-reviewed journals.
There is no curative therapy that can block progression of hepatitis B virus (HBV)-induced liver diseases and their complications although HBV has infected 2 billion people, established chronic infection in about 240-370 million patients, inducing cirrhosis of liver and hepatocellular carcinoma and responsible for about one million annual death. On the basis of studies in benches with HBV transgenic mice (HBV TM), that expressed HBV-related viral particles and antigens, a unique immune therapeutic strategy was developed for patients with chronic hepatitis B (CHB) that used both HBsAg and HBcAg (NASVAC) in higher doses (200-400 micrograms) for 15 times via nasal and injection routes in CHB patients. The safety and efficacy of NASVAC were compared with those of pegylated interferon (Peg-IFN), the gold standard of HBV therapy, in a phase III clinical trial in 160 patients with CHB. At end of treatment (EOT) and during follow up, it appears that NASVAC is better than Peg-IFN regarding antiviral, liver protection, and arrest of fibrosis in CHB patients. NASVAC induced both HBsAg and HBcAg-specific immunities in CHB patients and HBcAg-specific immunity played a cardinal role for therapeutic effect of NASVAC. Based on our studies for treatment of CHB patients, an inference was developed that support that antigen-specific immunity may be safe and effective for broad range of patients and this exposed an area of tackling liver diseases due to HCV, liver cirrhosis, autoimmunity, and HCC by using antigen-specific immune therapy. Also, its use may be expanded to cancer therapy.
Vaxeal Group, Switzerland
High therapeutic efficacy of a new cancer vaccine against the tumor associated antigen survivin
AHMED BOUZIDI is the Chief Executive Officer Of Vaxeal Group, Vevey, Switzerland. He is also a Board Member of vaccines Europe - Brussels, Belgium. Ahmed Bouzidi is the founder of Vaxeal. He founded and managed SEDAC-Therapeutics inc., a leading biotech pioneer in peptide-based therapeutic vaccines (exit by Leveraged Buy Out), and Biophysiomics inc. (acquired by Chengdu Kuachang Science & Technology, China). He is a board member of Vaccines Europe and of the European Biopharmaceutical Enterprises (EBE-biopharma), and is a Senior Associate of the Royal Society of Medicine. He held previously senior advisory positions with Chinese pharmaceutical companies and public institutions, and worked 10 years as senior researcher at the LFB. He holds a Master degree in Animal Biology (University of Lille, France), a PhD in Cellular Biology, and a MBA in Finance (University of New Hampshire, USA)
The tumor antigen survivin is an ideal target for therapeutic vaccine, as it is over-expressed in almost all type of tumors but undetectable in normal tissues. To optimize vaccination efficiency, wedesign a new survivin(SVX-1) vaccine composed of three long synthetic peptides containing several CD4 and CD8 T-cell epitopes.
The immunogenicity of the SVX-1 vaccine was assessed in humans and the therapeutic efficacy was tested in relevant mouse tumor models.
Studies in healthy individuals predicted a high T-cell immunogenicity of SVX-1 vaccine in human, irrespective of the individual’s HLA types. We then demonstrated the high therapeutic efficacy of the SVX-1 vaccine against various established murine tumor models, associated with its capacity to generate both specific cytotoxic CD8+ and multifunctional Th1 CD4+ T-cell responses but also effective memory T-cell responses for long-term protection against relapses. Treatment with SVX-1 vaccine also strongly increased the tumor infiltration of both CD4+ and CD8+ T cells over Treg cells therefore tipping the balance toward a strong immune response. Additionally, high frequencies of spontaneous T cell precursors specific to SVX peptides, which could be potentially boostedby the SVX-1 vaccine, were found in the peripheral blood of various cancer patients.
This new SVX-1 vaccine showed great promise in our preclinical studies. In humans, the immunogenicity of the SVX-1 vaccine, irrespective of their HLA types, and the high frequencies of spontaneous T cell precursors observed in various cancer patients strongly support its development in clinical trials.
The choice of the antigen to incorporate in a cancer vaccine is crucial and as such survivin appears an ideal candidate because it is a near universally over-expressed tumor antigen in human cancers. Vaccine strategy targeting survivin showed encouraging effects that need to be optimized. We developed a new survivin (SVX-1)-based vaccine strategy composed of three long peptides containing both promiscuous CD4+ and CD8+ T cell epitopes. This vaccine allowed to generate both CD4+ and CD8+ specific T cell responses leading to strong therapeutic efficacy in various tumor models. Importantly, the SVX-1 vaccine was immunogenic in healthy donors irrespective of HLA types. Additionally, high frequency of spontaneous T-cell precursors specific to SVX-1 vaccine was observed in the peripheral blood of various cancer patients, demonstrating the absence of tolerance against survivin epitopes. This new SVX-1 vaccine thus holds great promise as a future candidate for clinical trials.
The Catholic University of Korea, South Korea
Current Status of Cancer Screening in Korea
Won-Chul Lee did his BM, Ms and Doctor of medicine from Catholic university of Korea. He is currently working as an advicer committee, Quality control of national cancer screening program at National Cancer Center of Korea. Previously, he worked as a Dean of Graduate School of Public Health at The Catholic University of Korea. He was also a Chairman, Board of Directors at The Korean Society for Preventive Medicine and also played the role of a Representative of Korea, ICSN (International Cancer Screening Network)
Cancer is the leading cause of death in Korea. So Cancer control is one of the most important issues.10-year plan for cancer control was started in 1996 in Korea. Now the Third Term Comprehensive Plan for Cancer Control (2016-2020) at the national level is being implemented.Cancer screening is actively being performed for cancer control.In Korea, Cancer screening is provided by two tracks. One is National Cancer Screening Program and the other is screening from private sector.National cancer screening program was started in 1999. The Program provides targeted population for five cancers- stomach, liver, colorectal, breast and cervix.Stomach cancer screening is provided for over 40 yrs old, every 2 yrs using endoscopy or UGIS. For Breast, over 40 yrs old, every 2 yrs using Mammography. For Cervix, over 20 yrs old, every 2 yrs using Pap Smear. For colorectal cancer screening, over 50 yrs old, every 1 yr using immunochemical FOBT. Liver Cancer screening is provided only for high risk group using Sonography and AFP every 6 months for over 40 yrs old.The clinical guideline for cancer screeningwas revised using GRADE by National Cancer Center in 2015.For the subjects below 50% of income, the cost for screening is free. And For the subjects over 50% of income, the cost is subsidized by 90% from the National Health Insurance, so subjects only pay for 10% of the cost.The average lifetime screening rate of the five major cancers by survey in 2016 was 79.7%, and the average cancer screening rates with recommendation was 63.5%. The screening rate for all cancers increased 1.64 times from 2004 to 2016.To promote the quality control of national cancer screening program, several efforts are being performed. The Basic Medical Screening Law was enacted from 2009.The National Screening Advisory Board was established based on this Law. Cancer stage shift is now appearing from 5 targeted cancers. Especially for colorectal cancer, 5-yr survival rate of Korea is estimated to 72.8%, which is the highest on among OECD countries. The trends in 2006-2015 of age-standardized mortality rate of stomach and liver cancers have shown the largest decrease compared to other cancers in Korea. Colon and rectum cancers also have shown a decrease in mortality. Since 1999, the incidence of cervix began to decrease and the incidences of colorectal cancer began to decrease since 2011. The National Screening Program has severalstrength; 1) All the related data are gathered in one system, the National Health Insurance Corporation, 2) National Cancer Registry is collecting cancer incidence data, 3) every subject has own unique ID, 4) So all the data related can be linked using the unique ID.Private sector of the cancer screening is prevalent although data collection from private sector is almost impossible. The benefit and harm of the screening from private sector will be discussed.
Ministry of Health, Swaziland
How much does preclinical data contribute to decisions to do vaccine trials?
Rufaro Kashangura is a 33 year old female doctor currently working in Swaziland under the ministry of health. She graduated with a bachelor of medicine and Bachelor of surgery (MBChB) in 2005 at the University of Zimbabwe. In 2011, she enrolled for a Masters in Clinical Epidemiology which she graduated in December 2013 with Cum Laude. Her thesis was a systematic review of animal studies on the efficacy of MVA85A vaccine against Tuberculosis challenge in animals; a vaccine that was recently tried in infants in South Africa. It was later published in 2015 in the International Journal of epidemiology in 2015. She is currently working on a systematic review on the efficacy of the same vaccine in humans. When she is not glued to the computer she likes cooking and fundraising for the less privileged.
The existing Bacillus Calmette–Guerin (BCG) vaccination provides partial protection against tuberculosis (TB). The modified vaccinia Ankara virus-expressing antigen85A (MVA85A) aims to boost BCG immunity. We evaluated the animal evidence supportingthe testing of MVA85A in humans.
Our protocol included in vivo preclinical studies of the MVA85A boosterwith BCG compared with BCG alone, followed by a TB challenge. We used standardmethods for systematic review of animal studies, and summarized mortality, measuresof pathology and lung bacterial load. The comprehensive literature search was toSeptember 2014. Two independent investigators assessed eligibility and performed dataextraction. We assessed study quality and pooled bacteria load using random effectmeta-analysis.
We included eight studies in 192 animals. Three experiments were in mice,two in guinea pigs, two in macaques and one in calves. Overall, study quality was lowwith no randomization, baseline comparability was not described and blinding not reported.For animal death (including euthanasia due to severe morbidity), studies were underpowered,and overall no benefit demonstrated. No difference was shown for lung pathologymeasured on an ordinal scale or bacterial load. The largest mortality trial carried out inmacaques had more deaths in the MVA85A vaccine group, and was published after atrial in South Africa had started recruiting children.
This independent assessment of the animal data does not provide evidenceto support efficacy of MVA85A as a BCG booster. More rigorous conduct and reportingof preclinical research are warranted, and we believe the results of studies should bepublicly available before embarking on trials in humans, irrespective of the findings.