Opening Remarks...Closing Remarks Session III Session II Session I Opening Remarks 2 3 Stem cell...

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37 抄録集 [主催]公益財団法人先端医療振興財団 臨床研究情報センター(TRI) [共催]Caladrius Biosciences, Inc. [協賛]ミルテニーバイオテク株式会社、日立化成株式会社 [後援]文部科学省、厚生労働省、国立研究開発法人日本医療研究開発機構(AMED)

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Page 1: Opening Remarks...Closing Remarks Session III Session II Session I Opening Remarks 2 3 Stem cell therapy has been attracting attention for its regenerative potency. Bone marrow-derived

36 37抄録集

[主催]公益財団法人先端医療振興財団 臨床研究情報センター(TRI)[共催]Caladrius Biosciences, Inc.[協賛]ミルテニーバイオテク株式会社、日立化成株式会社[後援]文部科学省、厚生労働省、国立研究開発法人日本医療研究開発機構(AMED)

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Stem cell therapy has been attracting attention for its regenerative potency. Bone marrow-derived CD34 antigen-positive (CD34+) cells are a well-characterized population of stem cells which have traditionally been used in clinic to reconstitute the hematopoietic system after radiation or chemotherapy. In 1997, Asahara et al first identified human endothelial progenitor cells (vascular stem cells) in peripheral blood CD34+ cell fraction. In animal models of ischemic vascular diseases, CD34+ cells induce therapeutic angiogenesis by direct incorporation of the cells into the expanding vasculature and paracrine secretion of angiogenic growth factors developing microvasculature. Recent research also revealed that enhancement of microcirculation by CD34+ cell therapy contributes to tissue regeneration in non-vascular diseases. Based on these preclinical achievements, phase I/II clinical trials have explored the usefulness of CD34+ cells in the treatment of patients with ischemic conditions such as peripheral, coronary and cerebral artery diseases and those with non-vascular diseases including dilated cardiomyopathy, unhealing fracture (nonunion) and liver cirrhosis. Some of the clinical projects for CD34+ cell therapy are already at the pivotal stage aiming pharmaceutical approval by global regulatory agencies. This international symposium is held to introduce such clinical development of CD34+ cell therapy in various fields of medicine. Distinguished researchers from USA, UK, Germany, Slovenia and Russia as well as domestic renowned researchers will demonstrate the latest achievements and the future perspectives of this therapeutic modality for intractable diseases. We hope all the participants would share the exact knowledge about this regenerative medicine product awaiting fast provision to the Japanese and international patients.

Opening Remarks Contents

Opening Remarks

Atsuhiko Kawamoto(Translational Research Informatics Center)

Contents

Opening Remarks

Atsuhiko Kawamoto (Translational Research Informatics Center) ………………………………………………………… 2

Session I

CD34+ Cell Therapy for Ischemic Tissue Repair: Two Decades of EvidenceDouglas W Losordo (Caladrius Biosciences, Inc.) …………………………………………………………………………………… 6

CD34+ Cell Therapy for Chronic Heart Failure: Clinical Experience in More than 300 CasesBojan Vrtovec (Ljubljana University Medical Centre) ………………………………………………………………………………… 8

Induction of Cardiac Regeneration is Linked to a Response Signature of CD133 and SH2B3– Outcome Analysis of the Randomized Phase III PERFECT TrialGustav Steinhoff (Rostock Medical University) ……………………………………………………………………………………… 10

CD34+ stem cell therapy for Ischemic StrokeSoma Banerjee (Imperial College Healthcare NHS Trust, UK) ………………………………………………………………… 12

[Discussant]Nobuyuki Ohara (Kobe City Medical Center General Hospital) ………………………………………………………………… 14

Session II

CD34+ Cell Therapy for Critical Limb Ischemia Atsuhiko Kawamoto (Translational Research Informatics Center) ………………………………………………………… 18

Highly Effective CD34 Cell Therapy on Critical Limb Ischemia in Hemodialysis PatientsShuzo Kobayashi (Shonan Kamakura General Hospital) ………………………………………………………………………… 20

The use of adipose tissue stem cells in the treatment of patients with critical limb ischemia (CLI)Andrei Kalinin (Central Clinical Hospital with Outpatient Health Center of the Business Administration for the President of the Russian Federation)………………………………………………… 22

Session III

CD34+ Cell Therapy for Liver Cirrhosis Toru Nakamura (Kurume University School of Medicine) ……………………………………………………………………… 26

Autologous Transplantation of CD34+ Cells for Patients with Fracture NonunionTomoyuki Matsumoto (Kobe University School of Medicine) ……………………………………………………………… 26

Closing Remarks

Masanori Fukushima (Translational Research Informatics Center) ……………………………………………………… 30

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CD34+ Cell Therapy for Ischemic Tissue Repair: Two Decades of Evidence Douglas W Losordo (Caladrius Biosciences, Inc., USA)

CD34+ Cell Therapy for Chronic Heart Failure: Clinical Experience in More than 300 Cases Bojan Vrtovec (Ljubljana University Medical Centre, Slovenia)

Induction of Cardiac Regeneration is Linked to a Response Signature of CD133 and SH2B3 – Outcome Analysis of the Randomized Phase III PERFECT Trial Gustav Steinhoff (Rostock Medical University, Germany)

CD34+ stem cell therapy for Ischemic Stroke Soma Banerjee (Imperial College Healthcare NHS Trust, UK)

[Discussant] 尾原 信行 (神戸市立医療センター中央市民病院)

13:00 - 13:05 Opening Remarks

▲ 川本 篤彦 (臨床研究情報センター)

13:05 - 15:25 Session I

CD34陽性細胞、CD133陽性細胞による心血管・脳血管再生治療[座長] 川本 篤彦 (臨床研究情報センター)

慢性重症下肢虚血に対するCD34陽性細胞治療 川本 篤彦 (臨床研究情報センター)

血液透析患者における重症下肢虚血に対するCD34陽性細胞治療の高い有効性 小林 修三 (湘南鎌倉総合病院)

The use of adipose tissue stem cells in the treatment of patients with critical limb ischemia (CLI) Andrei Kalinin (Central Clinical Hospital of the Presidential Administration of Russia, Russia)

15:35 - 16:50 Session II

17:00 - 17:50 Session III

CD34陽性細胞、脂肪幹細胞による末梢血管再生治療[座長] 横井 宏佳 (福岡山王病院)

肝硬変に対するCD34陽性細胞療法 中村 徹 (久留米大学)

偽関節患者に対する自家末梢血CD34陽性細胞移植 松本 知之 (神戸大学)

CD34陽性細胞による組織再生治療[座長] 小林 修三 (湘南鎌倉総合病院)

17:50 - 18:00 Closing Remarks

▲ 福島 雅典 (臨床研究情報センター)

2017.9.9 (Sat)(受付開始12:30)13:00-18:00

虎ノ門ヒルズフォーラム 4F[Hall B]〒105-6305 東京都港区虎ノ門1-23-3 (銀座線「虎ノ門駅」1番出口 徒歩約5分)

[主催] 公益財団法人先端医療振興財団 臨床研究情報センター(TRI)[共催] Caladrius Biosciences, Inc.[協賛] ミルテニーバイオテク株式会社、日立化成株式会社[後援] 文部科学省、厚生労働省、国立研究開発法人日本医療研究開発機構(AMED)

[お問い合わせ]

CD34 陽性細胞が変える再生医療の世界─治験実施による早期実用化を目指して

日 時

場 所

Clinical Application of CD34-Positive Cells for Cardiac, Cerebral, Vascular, Bone and Liver Regeneration

参加申込▲

http://www.tri-kobe.org

7th World Centenarian Initiative

350名定 員

[参加無料]日英同時通訳あり

〈事前登録が必要です〉

〒650-0047 神戸市中央区港島南町1-5-4  E-Mail: [email protected]

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オンライン参加登録事務局

International Symposium

Session I

CD34+/CD133+ Cells for Cardiac and Cerebrovascular Diseases

Moderator : Atsuhiko Kawamoto    (Translational Research Informatics Center)

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Abstract

Profile

Chief Medical Officer, Senior Vice President Clinical, Medical and Regulatory Affairs, Caladrius Biosciences, Inc., New York, NY, USA, Adjunct Professor of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL USA, Clinical Professor of Medicine, New York University Langone Medical Center, New York, NY

As the population ages and the acute mortality from cardiovascular disease decreases, a large population of patients is emerging who have symptomatic chronic ischemic cardiac and vascular disease, many of whom remain severely symptomatic despite exhausting conventional medical therapy and mechanical revascularization. Mounting evidence suggests that microvascular insufficiency plays a significant role in the pathophysiology of ischemia. Recognizing this problem, investigators have worked to understand the biology of the vascular system and harness this information to develop new treatments for patients with ischemic diseases. With this end in mind, the science of therapeutic angiogenesis has been evolving for over two decades. Pre-clinical and early clinical data provide evidence that CD34+ cells may be employed therapeutically for repair of ischemic tissue. Preclinical studies have provided evidence for safety and the potential therapeutic potency of freshly isolated CD34+ cells. Clinical trials involving over 700 patients have been completed providing data supporting the feasibility, safety and efficacy of CD34+ cell therapy for treatment of advanced cardiovascular disease. Accordingly, the goal of ischemic tissue repair appears within reach and is entering a pivotal clinical trial in Japan for patients with critical limb ischemia.

The evolution of the strategy of CD34+ cell based ischemic tissue repair will require an ongoing dialogue between clinicians, scientists, regulators, industry and payors to take full advantage of advances in our understanding of the biology of these processes and thereby drive their appropriate application to patients who are disabled with their condition and have exhausted conventional medical and surgical therapies.

Dr. Losordo is the Chief Medical Officer and Senior Vice President of Clinical, Medical and Regulatory Affairs of Caladrius Biosciences, Inc, Clinical Professor of Medicine at the New York University Langone Medical Center and Adjunct Professor of Medicine at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.Dr. Losordo’s career has been dedicated to patient care and to the development of novel therapeutics aimed at the reversal or repair of chronic conditions such as heart failure, critical limb ischemia, cancer, diabetes and autoimmune disease. A native of Brooklyn, NY, he received his medical degree from the University of Vermont. Dr. Losordo completed an internship, residency and fellowship at St. Elizabeth’s Medical, Boston, Massachusetts, where he subsequently joined the faculty, working with the late Jeff Isner to develop a program in gene therapy and cell-based tissue repair. Dr. Losordo’s group has executed the full “translational medicine” paradigm: identifying potential therapeutic approaches in the laboratory, investigating these strategies in pre-clinical/IND-enabling models and designing and executing first-in-human and proof-of-concept clinical trials as the study sponsor/IND-holder. His work has included developing VEGF gene therapy for myocardial ischemia and diabetic neuropathy, CD34+ cell therapy for refractory angina, critical limb ischemia, severe claudication and coronary microvascular dysfunction and regulatory T cell therapy for autoimmune disease. Two of these candidates advanced to phase 3. At Caladrius Dr. Losordo has initiated a phase 2 study of autologous regulatory T cell therapy for new onset type 1 diabetes in children and recently received Japanese PMDA agreement on a study of CD34 cell therapy for critical limb ischemia targeting conditional approval under the new Japanese regulatory rules governing regenerative therapies. In addition to his own work Dr. Losordo has also mentored numerous scientists and physician-scientists from around the world who now have their own independent programs in translational research.

CD34+ Cell Therapy for Ischemic Tissue Repair: Two Decades of Evidence

Douglas W Losordo

Caladrius Biosciences, Inc.

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Chronic heart failure represents a major healthcare burden with troubling morbidity and mortality rates. The most frequent cause of advanced chronic heart failure is non-ischemic dilated cardiomyopathy (DCM), which accounts for 50% of all heart transplantations. There is increasing evidence that heart failure progression in DCM is not only a consequence of injury to the myocytes, but also results from decreased myocardial perfusion. In these patients, coronary flow reserve is often impaired both globally and regionally due to defective vascularization and impaired vasculogenesis and angiogenesis. In our clinical studies in non-ischemic DCM we were able to demonstrate that that CD34+ cell therapy results in significant improvement in myocardial perfusion as assessed by SPECT, which is associated with improved left ventricular function. Furthermore, we have shown that transplantation of CD34+ cells may reverse heart failure progression in DCM, which results in improved 5-year survival rate. These effects demonstrate a significant dose-dependency and appear to be particularly prominent when CD34+ cells are administered via transendocardial route. Thus, the focus of our current research is to investigate the effects of repetitive transendocardial CD34+ cell therapy in patients with non-ischemic DCM.

Bojan Vrtovec received his MD and PhD at Univeristy of Ljubljana School of Medicine. He completed his postgraduate training in the field of advanced heart failure and heart transplantation at Texas Heart Institute, Stanford University and Columbia University. Currently he is serving as a medical director of Advanced Heart Failure and Transplantation Programme at University Medical Center Ljubljana, and as a full professor of cardiovascular medicine at University of Ljubljana School of Medicine. His research interests include clinical aspects of stem cell therapy for heart failure, heart transplantation and mechanical circulatory support.

CD34+ Cell Therapy for Chronic Heart Failure: Clinical Experience in More than 300 Cases

Bojan Vrtovec

Ljubljana University Medical Centre

Slovenia

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AbstractObjective: The phase III clinical trial PERFECT was designed to assess clinical safety and efficacy of intramyocardial CD133+ bone marrow stem cell treatment combined with CABG for induction of cardiac regeneration. Design: Multicentre, double-blinded, randomised placebo controlled trial. Setting: The study was conducted across six centres in Germany October 2009 through March 2016 and stopped due slow recruitment after positive interim analysis in March 2015. Participants: Post-infarction patients with chronic ischemia and reduced LVEF (25-50%). Interventions: Eighty-two patients were randomised to two groups receiving intramyocardial application of 5mL placebo or a suspension of 0·5-5x106 CD133+. Outcome: Primary endpoint was delta (∆) LVEF at 180 days (d) compared to baseline measured in MRI. Findings (prespecified): Safety (n=77): 180d survival was 100%, MACE n=2, SAE n=49, without difference between placebo and CD133+. Efficacy (n=58): The LVEF improved from baseline LVEF 33·5% by +9·6% at 180d, p=0·001 (n=58). Treatment groups were not different in ∆LVEF (ANCOVA: Placebo +8·8% vs. CD133+

+10·4%, ∆CD133+ vs placebo +2·6 %, p=0·4). Findings (posthoc): Responders (R) classified by ∆LVEF >5% after 180d were sixty percent of the patients (35/58) in both treatment groups. ∆LVEF in ANCOVA was +17·1% in (R) vs. non-responders (NR) (∆LVEF 0%, n=23). NR were characterized by a preoperative response signature in peripheral blood with reduced CD133+ EPC (RvsNR: p=0·005) and thrombocytes (p=0·004) in contrast to increased Erythropoeitin (p=0·02), and SH2B3 mRNA expression (p=0·073). Actuarial computed mean survival time was 76.9 ± 3.32 months (R) vs. +72.3 ± 5.0 months (NR), HR 0.3 [Cl 0.07-1.2]; p=0.067. Using a machine learning algorithm, 20 biomarker response parameters were identified allowing preoperative discrimination with an accuracy of 80% (R) and 84% (NR) after 10-fold cross-validation.Interpretation: The PERFECT trial analysis demonstrates that the regulation of induced cardiac repair is linked to the circulating pool of CD133+ EPC and thrombocytes, associated with SH2B3 gene expression. Based on these findings, responders to cardiac functional improvement may be identified by a peripheral blood biomarker signature. Heart function improvement is dependent on circulating endothelial progenitor cells.

Conclusion: 1. Heart function improvement is dependent on circulating endothelial progenitor cells.2. Suppression of bone marrow response is associated to SH2B3 gene expression.3. Peripheral blood angiogenesis response can be predicted by a biomarker signature.

Gustav Steinhoff, M.D., is a professor of cardiac surgery and head of the German Reference and Translation Center for cardiac stem cell therapy at the University of Rostock, Germany. Born 1958, graduated for medicine at Erasmus University Rotterdam in 1984, trained for residency in general surgery, vascular surgery, thoracic, and cardiac surgery, Prof. And head cardiac surgery in Rostock since 2000. He performed the worldwide first intramyocardial stem cell therapy in 2001 and is a leading expert and pioneer in regenerative medicine. Publications 300, H-F. 48. He installed and completed The Phase III multicentre randomized GCP trial PERFECT as a pioneering project to develop highly standardarized molecular clinical research and advanced stem cell transplantation trials.

Induction of Cardiac Regeneration is Linked to a Response Signature of CD133 and SH2B3– Outcome Analysis of the Randomized Phase III PERFECT Trial

Gustav Steinhoff

Rostock Medical University

Session I

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Abstract

Session I

There is a major unmet need for treatments that can reduce tissue injury progression, and enhance functional recovery in stroke. Stem cell therapy offers the promise of a novel reparative strategy for acute brain injury. Its basis stems from the observation that certain parts of the adult brain are capable of regeneration. However, whilst the regenerative capacity of certain parts of the brain has been demonstrated, it is clear that this endogenous neuroreparative process is unable to overcome the devastating damage to the brain tissue that occurs after acute, severe stroke.

Cell-based therapies have the potential to open up new avenues of treatment in this arena. Targets for stem cell therapy include neuroprotective approaches, which are aimed at protecting the at-risk tissue during the acute phase of stroke, as well as neuroreparative approaches, which may involve direct replacement of damaged brain tissue or, alternatively, promote endogenous repair processes of the brain.

CD34+ cells are a subset of bone marrow mononuclear cells which act as the main endogenous source of haematopoietic and endothelial cell precursors. There are several lines of evidence suggesting that they might act as a potentially useful therapy in acute stroke. In this talk, I will be concentrating on CD34+ stem cell use, and discussing the evidence from basic science and human studies, to date.

Dr. Soma Banerjee is a Consultant Physician and Specialist in Stroke Medicine at Imperial College Healthcare NHS Trust, where she is the Head of Department. She was elected to become a Fellow of the Royal College of Physicians in 2017.Her clinical practice involves all aspects of the hyperacute treatment of stroke and early rehabilitation. Her research interest lies in stem cell therapy for the treatment of stroke, and she completed an MD Research degree investigating the use of CD34+ stem cells for acute ischemic stroke. She will be presenting on this aspect at the symposium.

CD34+ stem cell therapy for Ischemic Stroke

Soma Banerjee

Imperial College Healthcare NHS Trust, UK

UK

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Advantages•  Pluripotent•  Immortalinvitro•  Highlyexpandable

Disadvantages•  Ethicalissues•  Insufficientavailability•  Unknownriskoftumour

formaBon

EmbryonicStemCells AdultStemCells

Advantages•  MulBpotent•  PotenBalforInduced

Pluripotency•  Suitableforautologousand

allogeneicuse

Disadvantages•  Immunosuppression

requiredforallograZing•  Certaintypesdifficultto

obtainegneuralstemcells•  Expansion&Potencyissues

Ra9onaleinStroke

•  EvidenceofNeurogenesisinHumanBrain

•  Neurogenesisin

Stroke

Hirsch MC. interBRAIN: Springer 2004

TypesofStemCells

•  ClassifiedbySource&Potency

– EmbryonicStemCells(pluripotent)– AdultStemCells(mulBpotent)–  InducedPluripotentStemCells

– Autologous-‘selftoself’VsAllogeneic–‘one-to-many’

Presenta9onOutline•  StemCells•  RaBonaleinStroke

•  Evidence&RaBonaleforCD34+stemcells

•  Imperialtrial•  Challenges&FutureDirecBons

MyBackground

•  ConsultantinStrokeMedicine•  InterestedinthetranslaBonofStemcelltherapytothebedside,for

strokepaBents•  ImperialCollegegroup:Completed1stUK-basedclinicaltrialof

stemcellsforthetreatmentofacute,severestrokepaBents

FinancialDisclosures•  IhavereceivedhonorariafromBMS/Pfizerasaninvitedspeaker

•  Nootherdisclosures

CD34+stemcelltherapyforIschemicStroke

DrSomaBanerjeeConsultantPhysicianinStrokeMedicine

CharingCrossandStMary’sHospitalsImperialCollegeHealthcareNHSTrust

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Translational Research Informatics CenterFoundation for Biomedical Reseach and Innovation

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[Discussant]

Nobuyuki Ohara

Kobe City Medical Center General Hospital

Japan

Education and Work Experience2017-present Chief, Department of Neurology, Comprehensive Stroke Center, Kobe City Medical Center General Hospital2014-2016 Attending, Department of Vascular Neurology National Hospital Organization, Osaka Minami Medical Center2013-2014 Visiting scholar, Department of Neurology, Stroke Center, David Geffen School of Medicine at University of California, Los Angeles2010-2013 Chief, Department of Neurology and Cerebrovascular Center, Osaka Neurological Institute2008-2010 Attending, Department of Neurology and Stroke Center, Osaka University Hospital2005-2008 Senior Residency, Department of Neurology, Kobe City Medical Center General Hospital2003-2005 Residency, Kobe City Medical Center General Hospital

Licensures and Certificates1) Unrestricted Physician’s License in Japan (#436732)2) Board Certified Member of the Japanese Society of Internal Medicine (#32526)3) Fellow of the Japanese Society of Internal Medicine (#21599)4) Board Certified in Clinical Neurology (#4382)5) Japanese Society of Neuro-endovascular Therapy, Specialist Certificate (#572)6) Board Certified in Stroke Medicine (#20110077)

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Translational Research Informatics CenterFoundation for Biomedical Reseach and Innovation

Session II

CD34+/Adipose Stem Cells for Peripheral Arterial Disease (PAD)

Moderator : Hiroyoshi Yokoi (Fukuoka Sanno Hospital)

ProfileEducation and TrainingGRADUATE: 1980-1986 M.D., Kanazawa University, Ishikawa, JapanPOST GRADUATE: 1986-1987 Internship: 1st Department of Internal Medicine Kanazawa University Hospital, Ishikawa 1987-1991 Residency: 1st Department of Internal Medicine Kanazawa University Hospital, Ishikawa

Appointments and PositionsCURRENT POSITION: Director, Cardiovascular Medicine Center, Fukuoka Sanno Hospital Director, Cardiovascular Medicine Center, Takagi Hospital Professor, International University of Health and WelfarePRIOR POSITION: Director, Department of Cardiology, Kokura Memorial Hospital

Memberships in Professional and Scientific SocietiesMember The Society of Japanese CirculationMember The Japanese Society of Internal MedicineMember The Japanese College of CardiologyFellow The Japanese Association of Cardiac RehabilitationFellow Japanese Association of Cardiovascular Intervention and TherapeuticsFellow Japanese Society of Limb Salvage and Podiatric MedicineFellow Japanese Society for Foot CareFellow Japan Endovascular Treatment ConferenceFellow Japan Society for Clinical PathwayFellow Kyushu Regional Office of Japanese Circulation SocietyFellow Alliance for Revolution and Interventional Cardiology Advancement

Editorial Board2008-present Journal of Cardiology Cases

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Current Position TitleVice Director, Translational Research Informatics Center (TRI)Unit Director, Unit of Regenerative Medicine, Institute of Biomedical Research and Innovation (IBRI) HospitalGroup Leader, Vascular Regeneration Research Group, IBRI Research CenterFoundation for Biomedical Research and Innovation (FBRI)Research and Professional Experience1987: M.D., Nara Medical University, Kashihara, Japan1992: Ph.D., Nara Medical University Graduate School1995-1998: Assistant Professor, Coronary Care Unit, Nara Medical University1998-1999: Assistant Professor, Department of Cardiology, Nara Medical University 1999-2003: Postdoctoral Research Fellow, Division of Cardiovascular Research, St. Elizabeth’s Medical Center,

Boston, MA, USA2003-2010: Senior Researcher, Vascular Regeneration Research Group, IBRI Research Center, FBRI, Kobe, Japan2010-present: Unit Director, Unit of Regenerative Medicine, IBRI Hospital, FBRI2013-present: Group Leader, Vascular Regeneration Research Group, IBRI Research Center, FBRI2015-present: Vice Director, TRI, FBRIResearch InterestCardiology, Cell Therapy, Clinical Trial, Regenerative Medicine, Vascular Medicine

AbstractCD34+ stem cell is an endothelial progenitor cell-enriched fraction in bone marrow (BM) and peripheral blood (PB) mononuclear cells. CD34+ cells can be mobilized from BM into PB by administration of granulocyte colony stimulating factor (G-CSF). Based on these findings, since 1990s, transplantation of BM, G-CSF-mobilized PB or non-mobilized PB mononuclear cells has been applied in patients with critical limb ischemia (CLI) for vascular regeneration. Although these therapies have been approved as the Advanced Medical Treatments in Japan, they have never been pharmaceutically approved or covered by insurance due to lack of validated clinical data complying with good clinical practice (GCP). We have performed a series of clinical trials regarding intramuscular transplantation of G-CSF-mobilized CD34+ cells in patients with CLI. Initial phase I/IIa study was performed in 17 no-option patients with CLI. All patients were free from death and major amputation for 1 year. CLI-free ratio serially increased up to 88% at 1 year. Rest pain scale, total and pain-free walking distances, toe brachial pressure index, transcutaneous partial oxygen pressure and ulcer size significantly improved by week 12 compared with baseline. Long-term study revealed the sustained efficacy for 4 years. Next, we performed a phase II study of G-CSF-mobilized CD34+ cell therapy in 11 CLI patients, which was the first investigator-led, GCP-complied clinical trial in the field of regenerative medicine in Japan. Promising results in the initial pilot study were almost reproduced in this validated clinical trial. Since 2014, in addition to the pharmaceuticals and medical devices, a novel review category, “regenerative medicine products” was created in the amended Pharmaceutical Affairs Law in Japan. Under this law, conditional pharmaceutical approval may be considered after relatively small-sized clinical trial for “regenerative medicine products”. We are preparing for a phase II/III, multicenter and randomized clinical trial under GCP, aiming the conditional approval. We have already agreed with the Pharmaceuticals and Medical Devices Agency (PMDA) regarding the overall study design and endpoints. Hopefully, the study will start in the fourth quarter of 2017.

Session II

CD34+ Cell Therapy for Critical Limb Ischemia

Atsuhiko Kawamoto

Translational Research Informatics Center

Japan

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Abstract

Session II

Background: Peripheral arterial disease (PAD) is highly prevalent in hemodialysis (HD) patients. Furthermore, critical limb ischemia (CLI) has strong impact on mortality in HD patients. However, satisfactory effect has not been achieved by several kinds of therapies including revascularization treatment in HD patients with CLI. Method: Prospective phase 1/2 interventional clinical trial of autologous granulocyte colony stimulating factor (G-CSF)-mobilized CD34+ cell transplantation in HD patients with no optional CLI was conducted in our hospital. We used peripheral blood (PB)-derived CD34+ cells instead of whole PBMNCs. This was the first clinical trial in which selected CD34+ cells were used in terms of pre-specified subjects only for HD patients with CLI. After 5 days’ G-CSF 5 µg/kg/day subcutaneous injection, peripheral blood-derived mononuclear cells were collected. The CD34+ cells were separated using anti-CD34 monoclonal antibody labeled magnetic beads, and were injected intramuscularly in ischemic lower limbs. Primary endpoint was safety, and secondary endpoint was the efficacy of CD34 cell therapy.Result: Six patients (4 in Rutherford category 5, and 2 in Rutherford category 4) were registered and treated. The number of injected CD34+ cells were 0.78-14.1 × 105/kg/limb. There was no serious adverse event related to cell therapy. As to the efficacy, resting pain in 2 patients (Rutherford category 4) completely resolved, and 3 out of 5 intractable ulcers (ulcer size ≤ 30 mm) completely healed within 3 months after treatment. Limb ischemia represented by skin perfusion pressure (SPP) improved at one month after treatment (38.0 ± 16.5 mmHg to 55.1± 7.5 mmHg, p<0.05), and remained to be above 40 mmHg during 12 months follow-up period. Six minutes’ walking distance also significantly improved. At the end of 12 months’ follow-up period, the rate of changes from CLI stage to non-CLI stage was 71% (5 out of 7 limbs). Furthermore, 1-year amputation-free survival rate was 100%. Conclusion: Autologous G-CSF-mobilized CD34+ cell transplantation was safe, feasible, and extremely effective for HD patients with CLI.

I am very active as a councilor for several scientific and medical professional societies: Japanese Society of Nephrology, Japanese Society of Internal Medicine, Japanese Society for Dialysis Therapy, Japanese Society of Acute Blood Purification, and Japanese Society of Hypertension. Also, I am on the Board of Directors of the Japanese Society of Artificial Organs and Engineering and President of the Japanese Society of Foot Care Medicine. I obtained my MD degree in 1980 and postgraduate training that led to a PhD degree in 1986 from Hamamatsu University School of Medicine in Hamamatsu, Japan. I was working as visiting assistant professor in the Department of Pathology, University of Texas. Currently, I am Chairman of Internal Medicine, Chief of Kidney & Dialysis Center and Deputy Executive Director of the Shonan Kamakura General Hospital, Kamakura, Japan. I am author of more than 200 research papers and I continue to be active in clinical research. Recently, we are qualified for the 2nd Class cell therapy by the Ministry of Health, Labor and Welfare, aiming to treat limb ischemia with autologous CD34. Moreover, we obtained the certification of the eligibility of state-of–the-art medicine with LDL-apheresis for the patients with diabetic nephropathy with massive proteinuria. By establishing these innovative clinical medicines, we have been appointed as outstanding reviewer of the committee of PMDA (Pharmaceuticals and Medical Devices Agency).Since June the 1st 2017, I have worked as Standing Director of Tokusyukai Medical Group (the third biggest medical group in the world), Representative for Foreign Medical Affairs & Cutting-Edge Technology, and Acting Executive Director of Shonan Kamakura General Hospital.

Highly Effective CD34 Cell Therapy on Critical Limb Ischemia in Hemodialysis Patients

Shuzo Kobayashi

Shonan Kamakura General Hospital

Japan

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Rate of Changes from CLI stage to non-CLI stage

71% (5 out of 7 limb)

1 year amputation-free rate (AFS)

100% (7 out of 7 limbs)

Change of 6 minutes’ total walking distance

250

350

300

200

(m)

(mean±SD, *p<0.05 vs. pre)

400

* * * *

pre 1 3 6 12 (months)

Change of ulcer size (Rutherford 5) (mm)

10

30

20

Case 2

Case 3

Case 4

Case6 Lt

Case6 Rt

EVT

EVT

pre 1 3 6 12 (months)

Peripheral blood WBC count and CD34+ cell count before and after 5 days’ G-CSF S.C. injection in HD patients.

WBC (/μL)

CD34+ cell (/μL)

baseline 5th day

baseline 5th day

G-CSF 5 μg/kgBW was injected s.c. for 5 days. Data were expressed as mean±SD.

10000

20000

30000

40000

1

2

3

4

0.37

2.80

5700

26480

cases

1 2 3 4 5 6 6’

79 77 70 57 68 74

4 5 5 5 4 5 5

(yr) Ulcer

0

15 (Rt)

6 (Rt)

22 (Rt)

0

20 (Rt)

35 (Lt)

age Rutherford category

Apheresis Product

(CD34+ cell)

(mm)

1.19x107

9.63x106

3.43x107 1.12x108

1.70x107

2.88x107

Climimax product

(CD34+ cell)

8.9X106

5.44x106

2.61x107

8.68x107

1.31x107

9.58x106

Injected CD34+ Cells

(x105/kg/Limb)

1.6

0.95

42

13.3

2.0

0.72

0.72

Prognosis after major amputation

(Aulivola B et al. Arch Surg 2004, 139; 395-399)

Prognosis according to renal function

1year survival

5year survival

Normal renal function

75.4% 42.2%

HD 51.9% 14.4%

Uremia is the major risk.

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AbstractCritical limb ischemia is caused by a severe damage of lower extremity arteries and is characterized by rest pain and trophic changes. According to some authors, critical ischemia leads to amputation in 25-30% of cases (North Shore Medical Center, Salem, MA, USA). The effectiveness of conducting reconstructive surgery is achieved only in 40-50% of cases. (J. Vascular and Endovascular Surgery)In spite of the amount of research done on the use of stem cells in various human pathology, including critical ischemia, cell therapy has not been widely applied yet. Adipose tissue is one of the effective sources enriched by progenitor cells, the number of which is much higher than the number of the progenitor cells in the bone marrow and other tissues. Adipose tissue derived stromal cells (ATDSC) are produced as a result of special processing of adipose tissue. ATDSC contains various populations of stem cells-predecessors.The present clinical study presents the experience of using adipose tissue derived stromal cells in eight patients with critical ischemia of the lower extremities. The inclusion criteria was the inability to perform revascularization in patients with critical lower limb ischemia in atherosclerotic lesions (atherosclerotic peripheral artery disease) (three patients with rest pain, and five patients with trophic changes in the limbs).All patients had a complex examination, including contrast angiography, duplex ultrasound (DU) arteries / extremities with the dimension of ABI in the dynamics of Transcutaneous oxygen tension (TcPo2) lower extremities (in dynamics), as well, a questionnaire was used to assess quality of life (SF-36).Contrast angiography of the extremities was performed to determine the possibility of a reconstructive operation. In the absence of the ability to perform open surgery or endovascular procedures, these patients were included in the study. The effectiveness of the treatment was controlled by means of the ABI, TcPo2, as well as evaluation of quality of life.The results of the study were observed from 6 months to 12 months. There were no adverse reactions after ATDSC administration.The progression of critical ischemia was indicated in one patient within one month after inclusion in the study. The patient underwent amputation of the limb at the hip level. Analysis of the progression of ischemia in this patient showed initially low rates of TcPo2, ABI, and the presence of the expressed trophic disorders on the foot.The remaining seven patients saved their limbs. Rest pain was relieved, existing trophic disorders significantly decreased. The complete epithelialization was indicated in two patients.The dynamics of changes in ABI and TcPo2 in seven patients are presented in the table below:

Before After 1 m After 6 m After 12 mABI 0,11±0,21 0,24±0,14 0,38±0,18 0,41±0,26

TcPO2 (mmHg) 6,2±0,21 12,7±0,34 30,14±0,22 32,08±0,19

Conclusions: the results can be considered satisfactory, despite the limited experience of the use of autologous stem cells in critical ischemia. The use of ATDSC in critical limb ischemia is a safe and effective method. A significant increase in indicators of ABI and TcPo2 in the first 6 months, and clinical symptoms demonstrate the positive effect of this method. It is important to continue the research for more reliable results.

My name is Andrei Kalinin. I was born in 1973. I graduated from Russian State Medical University in 1997. After graduation, I was a resident in the Cardiovascular Surgery program at the A.V. Vishnevsky Institute of Surgery. I gained my post-graduate degree at the same Institute during the next three years. I wrote my dissertation in 2002 which centered on Cardiovascular Surgery.From 2002 to 2012 I worked as a surgeon in the division of Vascular Surgery at the A.V. Vishnevsky Institute of Surgery under the guidance of academician A.V. Pokrovsky. In 2012 I obtained the qualification of Cardio-Vascular Surgeon of the Highest qualification category. I have been working in the Central Clinical Hospital of the Presidential Administration of Russia as Head of the Department of Vascular Surgery since 2012.I specialize in all types of reconstructive vascular surgery for diseases of the abdominal aorta, arteries of upper and lower extremities, brachiocephalic arteries, and all kinds of operations in venous pathology.In my surgical operations we use advanced technology, including minimally invasive techniques: EVAR for aneurysms of the aorta, hybrid surgery for lesions of lower limb arteries and aorta. I actively participate in research work. I have more than 20 scientific articles in leading publications. I also take an active part in Russian and foreign conferences specifically devoted to problems of vascular diseases and present results of my work at conferences.

Session II

The use of adipose tissue stem cells in the treatment of patients with critical limb ischemia (CLI)

Andrei Kalinin

Central Clinical Hospital with Outpatient Health Center of the Business Administration for the President of the Russian Federation

Russia

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Translational Research Informatics CenterFoundation for Biomedical Reseach and Innovation

Session III

CD34+ Cells for Tissue Regeneration

Moderator : Shuzo Kobayashi    (Shonan Kamakura General Hospital)

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CD34+ Cell Therapy for Liver Cirrhosis

Toru Nakamura

Kurume University School of Medicine

Education2001 Ph.D. Kurume University School of Medicine1997 M.D. Kurume University School of Medicine

Professional Training and Employment2003-present Assistant, Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine2001-2003 Resident in Internal Medicine, Kurume University1997-2001 Kurume University Graduate School of Medicine1997 Passed the examination of National Board

Membership in Medical SocietieThe Japanese Society of Internal MedicineThe Japanese Society of GastroenterologyThe Japanese Society of Hepatology

Background: Liver cirrhosis (LC) is a leading cause of morbidity and mortality worldwide. In patients with decompensated disease, ascites decreases quality of life (QOL) and is a poor prognostic factor. The only curative treatment for end-stage liver cirrhotic patients is liver transplantation. However, there are only a limited number of donor livers available for patients. Preclinical studies in rodent models of chronic liver fibrosis have shown that transplantation of peripheral blood (PB)-CD34+ cells leads to hepatic regeneration and a reduction of liver fibrosis by suppressing hepatic stellate cell activity and increasing matrix metalloproteinase activity. Based on these findings, we conducted a prospective clinical trial to evaluate the safety and efficacy of autologous granulocyte colony-stimulating factor (G-CSF)-mobilized PB-CD34+ cell transplant in patients with decompensated LC. Methods: The inclusion criteria were the following: Patients with decompensated LC, aged from 20 to 75 years, serum albumin of less than 3.0 g/dL, total bilirubin of less than 5.0 mg/dL, and no viable hepatocellular carcinoma on CT or MRI. The exclusion criteria were the following: Patients with creatinine of more than 2.0 mg/dL, PT-INR of more than 2.4, and liver tumors or other cancer. Patients were admitted for liver function tests, full blood count, coagulation profile, tumor marker levels, and ultrasound (US). Seventeen patients were included and ten patients were treated. Patients included in the study received a daily subcutaneous injection of G-CSF 10 µg/kg/day for 5 days, to mobilized bone marrow derived CD34+ stem cells. Leukapheresis was performed on day 4 and 5. In the treated patients, CD34+ cells were infused via the hepatic artery. Patients were divided into three groups according to the amount of CD34+ cell collection. All the patients were followed up every 4 weeks, and laboratory data were analyzed for 24 weeks. Results: G-CSF treatment and leukapheresis were well tolerated, and no serious adverse events were observed. After 24 weeks, serum albumin level was significantly increased in patients who had received middle (1×106cells/kg) or high (2×106cells/kg) doses of CD34+ cells compared with baseline. Doppler US showed a significant increase in hepatic blood flow velocity and blood flow volume after CD34+ cell therapy. The average Child–Pugh score, which were used to evaluate the hepatic reserve function, of all treated patients at week 24 was not significantly different from baseline. Conclusions: CD34+ cell therapy is feasible, safe and effective in slowing the decline of hepatic reserve function.

Session III

Japan

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Japan

Autologous Transplantation of CD34+ Cells for Patients with Fracture Nonunion

Tomoyuki Matsumoto

Kobe University School of Medicine

Abstract

Medical School4/1994–3/2000 Medical Doctor, Kobe University School of Medicine

Clinical Training6/2000–5/2001 Kobe University Hospital6/2001–11/2006 Wadayama Hospital, Hyogo Rehabilitation Center Hospital, Hyogo Emergency Medical Center,

Rokko Hospital

Graduate4/2003–9/2006 Doctoral, Kobe University School of Medicine (6/2004–3/2006) Stem Cell Translational Research, Institute of Biomedical Research and Innovation/RIKEN Center

for Developmental Biology

Postgraduate12/2006–11/2008 Postdoctoral and Fellowship, Department of Orthopaedic Surgery University of Pittsburgh Medical

Center/Stem Cell Research Center 12/2008-7/2010 Clinical Staff, Kobe University Hospital 8/2010-3/2017 Assistant Professor, Kobe University Hospital4/2017- present Associate Professor/Lecture, Kobe University Hospital

Failures in fracture healing are caused due to many factors, in which severe skeletal injuries consisting of fractures with a compromised blood supply result in either delayed unions or established nonunions. An essential requirement for these fractures is to restore the local blood flow. One emerging strategy in the regeneration and repair of bone and surround tissue is the use of stem cells. We have proved the first proof-of-principle that elucidate the healing potential of CD34+ cells for fracture nonunion. As a series of preclinical studies, we first demonstrated that systemic infusion of human circulating CD34+ cells into immunodeficient rats with non-healing fracture contributes to fracture healing. Next, we attempted local transplantation of CD34+ cells with atelocollagen gel, a bio-absorbable scaffold, in the same animal model and demonstrated the similar effect at the lower dose compared with the systemic administration. Based on the in vitro experiments and pre-clinical study using in vivo animal experiments, we started clinical trial of autologous transplantation of granulocyte colony-stimulating factor (G-CSF) mobilized peripheral blood CD34+ cells for patients of tibial or femoral nonunion. Based on these scientific backgrounds, we started phase I/IIa clinical trial: autologous local transplantation of G-CSF mobilized peripheral blood CD34+ cell for patients with the tibial or femoral nonunion. Inclusion criteria are (1)patient with tibial or femoral fracture, (2) patient with non-infectious nonunion, (3) 20 to 69 year-old patient, (4) patient with informed consent by writing. After leukoapheresis following 5 days G-CSF injection, patient receives magnet sorting of CD34+ cells. Treatment is conventional surgery for nonunion combined with autologous transplantation of G-CSF mobilized peripheral blood CD34+ cells suspended with atelocollagen gel. Radiological fracture healing at week 12, the primary endpoint of this study, was achieved in 5 cases out of 7 patients (71.4%). Both of 2 cases without fracture healing at week 12 had femoral fractures in which cases ultimately radiological healing was finally observed at week 19 and 36. The interval between the cell transplantation and union, the secondary endpoint, was 12.6 ± 5.4 (range 8 to 24) weeks for clinical healing and 16.1±10.2 (range 8 to 36) weeks for radiological healing. Promising outcomes in this phase I/IIa clinical trial encourage the application of the CD34+ cells for nonunion as a novel therapeutic modality. To further elucidate the safety and efficacy of CD34+ cell transplantation for bone fracture healing, multicenter clinical trial has been started. 65

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KOBE UNIVERSITY

Clinical Application of CD34-Positive Cells (September 9, 2017)、Tokyo

Comparison with Historical control

CD34+ cells Historical control

number 7 11 Gender(male/female) 6/1 9/2

Age 34 (20-45) 37 (21~56)

Femur/Tibia 2/5 4/7

Healing rate at 12 weeks (%)

5/7 (71.1%) 2/11 (18.1%)

Duration to heal (week)

16.1 (8~38) 29.1 (12~44)

Kuroda R, Matsumoto T, et al. Stem Cell Transl Med 2015

KOBE UNIVERSITY

Clinical Application of CD34-Positive Cells (September 9, 2017)、Tokyo

Autologous transplantation of peripheral blood CD34+ cells for patients with nonunion

:PhaseⅠ/Ⅱ Clinical trial

KOBE UNIVERSITY

Clinical Application of CD34-Positive Cells (September 9, 2017)、Tokyo

Locally transplanted CD34+ cells were dose-dependently contributed to fracture healing via enhancing angiogenesis and osteogenesis.

Mifune Y, Matsumoto T, Kuroda R, et al. Stem Cells 2008

GM-PB CD34+ cell

Local administration

103

104

105

More than 104 cells / rat

Osteoblast

Endothelial cell

Series of experiments (2)

KOBE UNIVERSITY

Clinical Application of CD34-Positive Cells (September 9, 2017)、Tokyo

Human peripheral blood CD34+ cells, which were systemically transplanted, recruited to the fracture site and contribute to local environment by enhancing angiogenesis and osteogenesis.

Matsumoto T, Mifune Y, Kuroda R, et al. Am J Pathol 2006

callus

Blood vessel CD34+ cell

CD34+ cell

bone marrow

bridging callus

osteoblast

cortical bone

Osteogenesis Vasculogenesis

endothelial cell

VEGF capillary

CD34+

hCD31/SMA

hOsteocalcin

Series of experiments (1)

KOBE UNIVERSITY

Clinical Application of CD34-Positive Cells (September 9, 2017)、Tokyo

Human peripheral blood CD34+ cells Immunodeficient rat unfracture model

ref) Kokubu T, J Orthop Res, 2003

Transplantation

Isolectin B4 Osteocalcin

Truidine blue Laser Doppler

Xray

Methods of experimental study

KOBE UNIVERSITY

Clinical Application of CD34-Positive Cells (September 9, 2017)、Tokyo

Autologous Transplantation of CD34+ Cells for Patients with Fracture Nonunion

Tomoyuki MASTUMOTO, Takahiro NIIKURA, Ryosuke KURODA

Department of Orthopaedic Surgery, Kobe University Graduste School of Medicine

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Twelve years have passed since we organized the consensus meeting for vascular regenerative therapy in March 2005 at Yokohama. However vascular regenerative therapy is not yet put into daily clinical practice to date. The major reason is that the clinical trial focusing on responsible cellular fraction of regenerating blood vessel has not been conducted with appropriate endpoint. This is likewise in the clinical trial using growth factor other than cell preparations, such as HGF producing vector, bFGF, etc. In latter cases, cellular process induced by such factor has not well been understood and thereby appropriate clinical trial was not designed. Nevertheless, due to steady efforts by researchers, the crucial effect of CD34 cell therapy has been proven by well-designed clinical trials, and finally we could forecast its cell therapy to be disseminated. Today you should find specific data supporting its outcome, and should feel confident that lower limb amputation or death caused by critical limb ischemia (CLI) should be dramatically reduced hereafter. Furthermore, CD34 indication is not limited to CLI but also to patients with non-union, liver cirrhosis, stroke, etc. They will also receive clinical benefit from CD34 cellular therapy in the very near future.

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• Director and Chairman, Translational Research Informatics Center (TRI), Foundation for Biomedical Research and Innovation (FBRI)

• Professor Emeritus, Kyoto University• Program Officer, Rare / Intractable Disease Project of Japan, AMED (Japan Agency for Medical Research and

Development)• Board of Director, CDISC (Clinical Data Interchange Standards Consortium)

With comprehensive experience spanning over the past quarter-century as a medical oncologist at Aichi Cancer Center and Kyoto University Hospital, Dr. Fukushima has engaged in the practice and dissemination of standard cancer treatment and reform of Japan’s medical care system, and is active to date contributing to building up the infrastructure of clinical trial, particularly focusing on translational research. He was in charge of supervising the national translational research promotion programs conducted by the government of Japan, and currently, assuming the Board of Director for CDISC, and Program Officer of Rare / Intractable Disease Project of Japan, aiming to contribute to the standardization and harmonization of global data sharing in clinical trials; ultimately for the disease control over the world.

Profile

Closing Remarks

Masanori Fukushima (Translational Research Informatics Center)

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