生物治疗临床新技术国际研讨会

中国·天津

2015.10.20~21

主办单位：

天津市干细胞开发应用协会                    

支持单位：

中国医师协会、中华医学会科学普及分会、中华医学会北京分会

会议背景：

生物治疗研究近30年来取得飞速发展，为癌症患者带来了新的希望。生物治疗领域目前已经成为最令人瞩目、最鼓舞人心的焦点，是未来临床治疗的重要发展方向。国务院出台《“十二五”国家战略性新兴产业发展规划》，生物产业位列七大战略性新兴产业之一。生物治疗的发展，依赖创新性治疗技术的发展，依靠科研人员、临床医生和企业紧密结合，围绕临床关键问题与技术难点，深入开展创新性研究，不断丰富理论基础并推动新技术发展与转化。

CAR-T，嵌合抗原受体T细胞，是目前较为有效的恶性肿瘤的治疗方式之一。在急性白血病和非霍奇金淋巴瘤的治疗上有着显著的疗效，被认为是最有前景的肿瘤治疗方式。正如所有的技术一样，CAR-T技术也经历一个漫长的演化过程，正是在这一系列的演化过程中，CAR-T技术逐渐走向成熟。

本次研讨会以天津市干细胞开发应用协会作为主办单位，中国医师协会作为支持单位，天津市外专局立项审批，顺昊细胞生物技术(天津)股份有限公司为主要赞助单位。

本次研讨会旨在交流最新科研进展，推广能解决降低CART细胞临床应用的副作用，增加其在临床应用的有效性，更大程度解决脱靶效应、肿瘤免疫逃逸引起的复发和转移等问题的新技术，讨论疗效更确切的过继性免疫细胞治疗方法，给肿瘤治疗带来新的希望。

大会分为三个学术板块

1、细胞生物治疗新技术(如CAR-T)基础研究最新成果

2、细胞生物治疗新技术临床应用进展

3、细胞生物治疗新技术推广国际动向

大会议程

会议时间：2015年10月20日~2015年10月21日

地点：天津滨海圣光皇冠假日酒店

地址：天津市东丽区空港经济区中心大道55号

会议日程暂定为：

10月19日  星期一 下午 报到

10月20日  星期二 上午 9:00-9:40 开幕式

10：00-12:00专家公开学术报告

学术板块： 细胞生物治疗新技术临床应用进展

星期二 下午 13：30-16:00专家公开学术报告

学术板块： 细胞生物治疗新技术(如CAR-T)基础研究最新成果

16：30-18:00国内外专家高峰论坛

10月21日  星期三 上午 9:00-12:00专家公开学术报告

学术板块： 细胞生物治疗新技术推广国际动向

国际专家简介及宣讲大纲：

Dr. Lawrence Lamb:

抗异体骨髓移植并发症的T细胞治疗技术及临床研究，阿拉巴马大学医学院(临床治疗研究教授，血液学、肿瘤学专家)

报告题目及大纲：γδ T作为癌症免疫治疗的应用

Lawrence S. Lamb, Jr., MN, PhD

药学教授

阿拉巴马大学伯明翰分校

伯明翰，亚拉巴马州，美国

人类γδT细胞已经被证明可以杀灭多种肿瘤细胞，但直到最近，它们实际应用于癌症治疗的疗效已经发展缓慢。小型临床试验通过利用体外扩增活化的自体Vγ9Vδ2 T细胞来抑制单核细胞培养的甲羟戊酸途径，由此导致代谢产物如异戊烯焦磷酸(IPP)的积累。唑来膦酸的胺基和白介素2的结合导致Vγ9Vδ2 T细胞受刺激，进而在培养过程中出现选择性增殖。这种方法很简单，使用药品制剂可以很便捷的应用于任何cGMP的功能细胞标准培养。然而，这种增殖获得的Vγ9Vδ2 + T细胞表型在培养过程中一般在体内都具有短暂的寿命和持续性。因此，频繁的输注必须维持一个有效的细胞毒性反应。另外，循环持续的、具有肿瘤反应性的Vδ1 +γδT细胞已经被证明与同种异体骨髓移植患者的长期生存有关。在这份报告中，我们将讨论有关于使用各种γδT细胞扩增手段获得的γδT细胞对血液系统恶性肿瘤和高级别胶质瘤的反应的经验。我们还将讨论γδ基因修饰T细胞作为一个平台提供治疗的潜力，这将扩大抗肿瘤反应和这个领域未来的发展。

原文：

Application of γδ T cells as a platform for cancer immunotherapy

Lawrence S. Lamb, Jr., MN, PhD

Professor of Medicine

University of Alabama at Birmingham

Birmingham, AL, USA

Human γδ T cells have been shown to kill a variety of tumor cells, but until recently their practical application in cancer therapy has been slow to evolve. Small clinical trials have been conducted using ex vivo expanded/activated autologous Vγ9Vδ2 T cells using a method designed to inhibit the mevalonate pathway in cultured mononuclear cells, thereby resulting in the accumulation of metabolites such as isopentenyl pyrophosphate (IPP). The combination of the aminobisphosphonate Zoledronate with IL-2 results in the stimulation of Vγ9Vδ2 T cells which then undergo selective proliferation in culture. The method is straightforward, uses pharmaceutical grade reagents, and can easily be applied in any standard cGMP-capable cell manufacturing facility. However, expanded Vγ9Vδ2+ T cells progress to the effector phenotype in culture and generally have a short lifespan and persistence in vivo. As such, the frequent multiple infusions would be required to maintain an effective cytolytic response. Alternatively, persistence of circulating, tumor-reactive Vδ1+ γδ T cells has been shown to correlate with long-term survival in allogeneic bone marrow transplant patients. In this presentation, we will discuss previous experience with the γδ T cell response to hematologic malignancies and high-grade glioma using various means of γδ T cell expansion. We will also discuss the potential for gene modification γδ T cell use as a platform for delivery of therapies that will amplify the anti-tumor response and the future development of this worl.

Dr. Stephen Haley:

与抗原识别/诊断及癌细胞治疗相关的T细胞治疗专家，现职为丹麦Immundex公司(国际著名生物技术公司)副总裁，Immundex北美公司运营总负责人。

报告题目及大纲： T细胞分析在疫苗和治疗中的发展

Stephen T. Haley, 博士

Immudex公司副总裁

疫苗对于传染病的预防是人类公共健康的一个巨大成功。传统疫苗依赖于抗体介导的免疫，很少依赖于细胞免疫。然而，到目前为止的21世纪艾滋病，肺结核，疟疾等传染病仍然是巨大的难题，所有这些疾病的免疫抵抗需要细胞介导的免疫应答。目前，许多开发现在的疫苗仍然仅仅依靠抗体的测定来指导病情并作为保护的措施。

最近公开的各种癌症免疫疗法的研究表明，人的免疫系统能够被调控来治疗和预防疾病的。检查点抑制剂疗法旨在通过从持续进行的反应中“消除开关”，以加强现有的T细胞应答。我们如何衡量成功的免疫干预?传统分析如酶联免疫斑点已经使用多年，但仍有一些问题，如在他们系统中的分析是否得当，或者作为T细胞反映的描述是否精确。

许多类型的T细胞有不同的分析方法并尝试融入疫苗进行治疗，但开发过程证明令人沮丧。随着研究的选择和发展，T细胞将会引起巨大的注意力。

T cell assays in vaccine and therapeutic development

Stephen T. Haley, PhD

Vice President, Immudex

Vaccines for the prevention of infectious disease are humanity's single greatest public health success. Classical vaccinology relies on antibody mediated immunity with little attention given to associated cell mediated immunity. However, the infectious disease burden thus far in the 21st century is dominated by HIV, tuberculosis, and malaria. Immune resistance to all of these is thought to require a cell mediated immune response. Yet many developing 21st century vaccines still rely solely on measurements of antibody to guide development and as correlates of protection.

The much publicized recent successes of various cancer immunotherapies are demonstration that the human immune system can be manipulated for treatment of disease as well as prevention. Checkpoint inhibitor therapies are designed to enhance existing T cell responses by “removing the brakes” from an ongoing response. How do we measure the success of immunological intervention? Classical assays such as Elispot have been utilized for many years and few question if the appropriateness of the assay(s) in their system or if the results are an accurate depiction of the T cell response.

Many types of T cell assays exist and attempts at integration into the vaccine and/or therapeutic development processes have proven frustrating. It is our contention that T cell correlates will be defined when the necessary attention is given to assay selection and development.

Dr. H. Trent Spencer:

美国艾默里大学医学院骨科学系骨科副教授，亚特兰大儿童医院基因治疗科主任。Dr. H.T.Spencer的主要领域涉及白血病和实体肿瘤的细胞基因治疗及研究，血友病的基因治疗。目前他在血友病细胞基因治疗方面的几项临床试验已完成，其治疗方法将正式启动使用。

报告题目及大纲：

新型抗癌嵌合T细胞受体的细胞免疫疗法的研究

嵌合抗原受体(CARS)是用来通过选定细胞表面抗原来改变T细胞的。利用T细胞基因工程表达肿瘤特异性的嵌合抗原受体，抗肿瘤免疫可以在没有预先存在的肿瘤靶向免疫细胞的患者体内建立。最近临床试验结果趋向于扩大CARS技术的应用，但这项研究仍然被癌细胞靶抗原/受体对的有效性限制。作为一种手段，以提高识别的靶抗原，并产生独特的单链结合结构域结构，我们使用七鳃鳗免疫系统独特性来试验。七鳃鳗具有可变淋巴细胞受体适应性免疫系统(VLR)作为免疫效应，这自然是单链结构，因此能够与高亲和力和特异性的结合。我们开发了一个包含的小鼠B细胞白血病B细胞受体特异性(BCL)的可变淋巴细胞受体，用它克隆到一个CAR载体上，并用它来产生高滴度的慢病毒。T细胞持续表达了2个月CAR，超过85%的细胞存活，表达CAR的T细胞表现出了强大的活力。此外，转染的NK-92细胞和Gd T细胞表达的vlr-car能识别和杀死细胞的靶向效应bcl细胞的比率低，为1:1，30%靶细胞具有杀伤力。采用B细胞来实验的一组未发现杀伤现象。我们扩展了一些包括对神经母细胞瘤细胞和T细胞特异性抗原分子的研究，他们的功能类似于BCL控制的CAR。总的来说，这些结果表明，VLRs可以提供一个独特而有效的方法来激活CAR-T细胞，他们可以引领我们激活对抗人类肿瘤抗原的VLR-CARS。

Creation of novel anticancer chimeric T cell receptors for cellular immunotherapeutics

Chimeric antigen receptors (CARs) are used to redirect T cells toward selected cell surface antigens. Using T cells genetically engineered to express cancer-specific CARs, anti-tumor immunity can be established in patients with no pre-existing tumor targeted immunocompetent cells. Results from recent clinical trials have driven efforts to expand the application of CAR technologies, but this approach remains limited by the availability of cancer cell target antigens/receptor pairs. As a means to increase the identification of target antigens and generate unique single chain binding domain structures, we used unique aspects of the immune system of lampreys. Lampreys possess an adaptive immune system with variable lymphocyte receptors (VLRs) as immune effectors, which are naturally single chain structures and are capable of binding with high affinity and specificity. We developed a VLR containing CAR specific for the B-cell receptor of a murine B-cell leukemia (BCL), cloned it into a CAR cassette, and used it to generate high-titer lentivirus. Transduced T cells demonstrated persistent CAR expression for over 2 months with over 85% cell viability, and CAR expressing T cells demonstrated robust activation. Furthermore, transduced NK-92 cells and gd T cells expressing the VLR-CAR demonstrated an ability to recognize and kill BCL cells at target to effector ratios as low as 1:1, with 30% target cell killing. No killing was observed with a control B cell line. We have expanded these studies to include VLRs against neuroblastoma and T cell specific antigens, which function similarly to the BCL-directed CAR. Collectively, these results show that VLRs can provide both a unique and effective method for activating CAR T-cells, which led us to generate VLR-CARs against human tumor antigens.

Dr. Antonio DiStasi：

阿拉巴马大学医学院教授，大学附属医院血液与肿瘤科骨髓移植与细胞治疗项目组临床医生，为自杀基因治疗及急性髓细胞性白血病CAR-T细胞治疗专家。

报告题目及大纲：

基于免疫治疗方法制定调节T细胞功能的策略

Dr.Antonio Di Stasi 副教授 伯明翰阿拉巴马大学 美国

摘要 过继T细胞治疗能产生深远的抗肿瘤作用，包括异基因造血干细胞移植(allo-HSCT)后供体淋巴细胞输注(DLI)，或离体培养肿瘤浸润T细胞(TIL)疗法， 或最近使用较多的T细胞受体(TCR)疗法重新输注T细胞，或嵌合抗原受体T细胞(CAR)疗法。细胞疗法并不是没有风险的。在造血干细胞产品中的供体T细胞或供体淋巴细胞输注与移植物抗宿主病有着潜在联系。改造的T细胞可导致脱靶毒性效应以及细胞因子释放综合征。不像小分子物质或生物制剂,细胞疗法是长期过程, 甚至有无限半衰期, 因为毒性是不断进展的，这就一个安全开关来消除所输注细胞的副作用，并且急需阻止毒性。自杀基因是一个基因编码分子，可以选择性破坏过继转移细胞，自杀基因加入细胞治疗产物会导致基因修饰细胞选择性切除，阻止临近细胞或组织的伤害。“理想”的自杀基因可以不可逆转消除“所有”和“唯一”不必要毒性的细胞，确保基因修饰细胞程序的安全。临床证实造血干细胞移植后，患者接受Caspase-9自杀基因修饰的供体淋巴细胞 (DLI),可有条件地消除移植物抗宿主病,同时保留移植物抗肿瘤(GVT)效应。另外，目前我们正在设计一种方案有选择性地针对白血病相关抗原与CART细胞共表达抑制性的嵌合抗原受体来介导正常的造血细胞的抗原表达，同时可诱导的Caspase9来消除副作用，或在异基因造血干细胞移植前清除T细胞。

个人简介

Dr.Antonio Di Stasi，医学副教授，就职单位涉及骨髓移植和细胞疗法项目，执行临床和转化研究活动。他的首要研究集中在临床前验证过继性t细胞免疫治疗恶性血液病，主要是关于T细胞的基因改造，使T细胞表达嵌合人工肿瘤相关抗原受体，和加入可诱导的Caspase9自杀基因来保证细胞安全的方法，包括异基因造血干细胞移植(allo-HSCT)后供体淋巴细胞输注(DLI)。作为博士后研究员，Dr. Di Stasi成功完成临床前转化项目，涉及嵌合抗原受体细胞毒性t细胞的生成，重新定位到淋巴瘤表面的CD30分子。基于肿瘤分泌与CCR4结合的TARC趋化因子，为了克服免疫环境的排斥，T细胞高表达CCR4趋化因子受体。这个变化使得体内淋巴瘤模型发生抗癌活性，不久将被应用到临床I期实验。Dr. Di Stasi带领团队对可诱导的Caspase9自杀基因进行临床试验;为了增强抗病毒和抗癌免疫力，单倍体相同的供者T细胞给予异基因造血干细胞移植的患者。该技术可及时消除由输注ic9二聚分子后引起移植物抗宿主病的这些患者输入体内的供者T细胞。目前，该技术在美国及海外若干个临床I/II期研究中被研究，有可能将减少移植物抗宿主病发病率和死亡率。UAB大学正在进行临床I期，其患者经历过异基因造血干细胞移植。

Title: Devising strategies to modulate the function of T-cell based immunotherapy approaches.

Dr. Antonio Di Stasi

Assistant Professor

University of Alabama at Birmingham,

USA

Abstract

Adoptive T-cell therapy can exert a profound anti-tumor effect, given as donor lymphocyte infusion (DLI) after allogeneic hematopoietic stem cell transplantation (allo-HSCT), or consisting of tumor infiltrating lymphocyte (TILs) expanded ex-vivo, or more recently by infusing T-cells redirected by the means of a T-cell-receptor (TCR) or a chimeric antigen receptor (CAR). Cellular therapies are not without risks. Donor T-cells within the HSC product or infused post-transplant as DLI have been associated with potentially fatal graft-versus-host-disease (GVHD), whereas administration of engineered T-cells has also resulted in on/off target toxicities as well as a cytokine release syndrome.

Unlike small molecules or biologics, cell therapies have a very long, or even an indefinite half-life, therefore since toxicity can be progressive a safety switch is needed in order to eliminate the infused cells in case of adverse events, and novel strategies to prevent toxicities are strongly needed. A suicide gene is a genetically encoded molecule that allows selective destruction of adoptively transferred cells. Suicide gene addition to cellular therapeutic products can lead to selective ablation of gene-modified cells, preventing collateral damage to contiguous cells and/or tissues. The ‘ideal’ suicide gene would ensure the safety of gene modified cellular applications by granting irreversible elimination of ‘all’ and ‘only’ the cells responsible for the unwanted toxicity. We have clinically validated a novel inducible Caspase9 suicide gene (iC9) in patients receiving suicide gene modified DLI after haploidentical-HSCT, and currently validating the ability to conditionally eliminate GVHD whilst retaining graft-versus-tumor (GVT). Additionally, we are devising a strategy to selectively target leukemia associated antigens with CAR T-cells co-expressing an inhibitory CAR directed to an antigen expressed on normal hematopoietic cells, whilst also incorporating the iC9 suicide gene to abate serious adverse events, and/or eliminate the infused T-cells before allo-HSCT rescue.

Biography

Dr. Di Stasi is Assistant Professor of Medicine in the Bone Marrow Transplantation and Cell Therapy Program Unit, where he performs both clinical and translational research activities. His primary research focus involves the pre-clinical validation of adoptive T-cell immunotherapy strategies for hematologic malignancies, primarily regarding genetic modification of T-cells with chimeric artificial receptors targeting tumor associated antigens, and the incorporation of a novel inducible Caspase9 suicide gene to grant safety of cellular approaches, including donor lymphocytes infused after allogeneic hematopoietic stem cell transplantation (allo-HSCT).

As post-doctoral fellow Dr. Di Stasi successfully completed a pre-clinical translational projects involving the generation of chimeric antigen receptor cytotoxic T-cells redirected to target the CD30 molecule on the surface of Hodgkin lymphoma (HL). To overcome the hostile immune-environment to T-cells he over-expressed the CCR4 chemokine receptor in the T-cells, based on the tumor's secretion of the chemokine TARC which is bound by CCR4. This modification increased migration and anti-tumor activity in an in vivo HL model, and will soon be tested in a phase-I clinical trial. Dr. Di Stasi also led a team to clinically test a novel inducible Caspase9 (iC9) suicide gene; haploidentical donor T-cells were administered to patients after allo-HSCT, in order to boost anti-viral and anti-cancer immunity. This technology allowed prompt elimination of infused donor T-cells in patients who developed graft versus host disease (GVHD) after infusion of the iC9 dimerizer molecule, AP1903.

This technology is currently investigated in several phase I/II clinical studies in the US and abroad, and has the potential to reduce the morbidity and mortality burden of GVHD, and UAB is now compiling a phase-I clinical

trial for patients undergoing matched related allo-HSCT.

主办及支持单位介绍:

天津市干细胞开发应用协会

天津市干细胞研究与应用协会(Tianjin Association for Stem Cell Research and Application，简写：TASCRA)。成立于2014年7月，受天津市社团局直属管理。主要业务范围为干细胞相关科学研究的交流;相关生物治疗技术和制剂的研发项目的申报合作;临床应用研究及推广;

规范相关企业的竞争模式;召集国内外相关科研单位、杰出个人及相关企业召开交流研讨学会;协助政府相关部门制定行业标准等。旨在保持天津干细胞科研在生物医药领域具有国际领先性，推广干细胞生物技术的临床应用和产业化，规范干细胞相关企业的良性发展和有序竞争，搭建科研与临床之间的桥梁，加强科研院所之间的合作，推动相关科研成果市场化进程，促进生物技术行业标准的建立。大力发展天津的生物医药产业，突破常规治疗手段，为危害人类健康的重大难治性疾病提供新的治疗途径，造福社会，造福人民!

中国医师协会

中国医师协会是经国家民政部登记注册，由执业医师、执业助理医师及单位会员自愿组成的全国性、行业性、非营利性的群众团体，是国家一级协会，是独立的法人团体。本会的宗旨是发挥行业服务、协调、自律、维权、监督、管理作用，团结和组织全国医师遵守国家宪法、法律、法规和政策，弘扬以德为本，救死扶伤人道主义的职业道德，努力提高医疗水平和服务质量，维护医师的合法权益，未我国人民的健康和社会主义建设服务。

中国医师协会是在我国加入WTO和医疗卫生事业深化改革的新形势下应运而生的。这标志着我国医师队伍的管理，将由目前单一的卫生行政管理模式，逐步过渡到卫生行政管理和行业自律协同管理的模式。今后，医师协会将会在行业管理中发挥越来越大的作用，推进我国医师队伍向国际化的管理模式迈出坚实的步伐。

中华医学会

中华医学会是中国医学科学技术工作者自愿组成并依法登记成立的学术性、公益性、非营利性法人社团，是党和国家联系医学科技工作者的桥梁和纽带，是发展中国医学科学技术事业的重要社会力量。

中华医学会(Chinese Medical Association)成立于1915年。现有83个专科分会，50万名会员，下设部门16个，法人实体机构3个，另与解放军军事医学科学院合办医学图书馆1个。

全国共有会员25万人。各地市县分会 386个、专科学会65个、学组139个。出版中华系列杂志417种，并办有学会机关报《中华医学信息导报》。学会设学术会务部、编辑出版部、继续教育部、对外联络部、科技咨询部、图书信息中心等办事机构。

台湾也设有医学会，出版两种刊物：《台湾医学会杂志》(月刊，1901年始刊)和《台湾医学会继续教育版》(月刊，始刊于1989年)。香港有香港医学会，为独立的组织，与中华医学会有杂志交换。澳门有中华医学会澳门分会。

国内专家：

大会主席：

王建祥：中国医学科学院血液病医院教授、北京大学教授、中国医学科学院北京协和医学院血液病医院·血液学研究所副所院长、主任医师、白血病诊疗中心(血二科)主任，教授、博士生导师

大会副主席 :王立祥，黎功

大会形象大使 :郎永淳

邀请院士：

吴祖泽 中国科学院院士、实验血液学家、军事放射医学研究所所长

陈 虎 中国人民解放军307医院CTC肿瘤生物治疗中心主任

付小兵 中国工程院院士、中国人民解放军总医院、全军创伤修复重点实验室主任

拟邀演讲嘉宾

段海峰 中国人民解放军军事医学科学院教授

韩为东 中国人民解放军总医院、免疫学研究室/生物治疗病区主任

胡亮钉 中国人民解放军307医院造血干细胞移植科副主任

胡显文 中国人民解放军军事医院科学院教授

任秀宝 天津肿瘤医学生物治疗科主任

王立生 军事医学科学院放射与辐射学研究所 研究员

夏建川 中山大学肿瘤医院生物治疗科主任

张 斌 中国人民解放军307医院CTC肿瘤生物治疗中心副主任

钱 程 第三军医大学病理研究所生物治疗研究室主任、肿瘤生物治疗研究室主任

杨 林 苏州大学教授、唐仲英血液学研究中心特聘教授、美国MD安德森癌症研究中心兼职教授

唐晓义：军事医学科学院细胞与基因治疗中心

朱军：主任医师，博士研究生导师

王昭：北京友谊医院血液内科主任

赵明：湖南长沙肿瘤医院免疫生物治疗中心主任

黄晓军：北京大学人民医院血液病研究所所长、主任医师、博导

韩伟：中国科学院合肥物质科学研究院医学物理与技术中心，辐射生物医学研究室主任

陈海旭：解放军总医院南楼临床部老年医学研究所，衰老及相关疾病研究北京市重点实验室，转化医学平台负责人

李军：解放军第二炮兵总医院临床输血治疗中心主任

杨超：解放军第二炮兵总医院临床输血治疗中心、干细胞库副主任

裴海云：军事医学科学院全军干细胞与再生医学研究室博士

畅继武，天津市医科大学第二附属医院肿瘤免疫研究室主任

陈军：天津医科大学总医院肺部肿瘤外科行政主任、天津市肺癌研究所副所长。

部分已经确定的国内专家演讲题目：

韩卫东：《CART临床试验在中国》

段海峰：《基于免疫激活的肿瘤治疗策略》

杨林：《CAR-T治疗技术在实体肿瘤治疗上的挑战与机遇》

钱程：《CAR-T细胞治疗癌症的新策略》

胡显文：《慢性非传染疾病治疗性抗体药物的研究进展》

夏建川：《体细胞免疫治疗联合肿瘤常规治疗的基本原则》

陈军：《EGFR-TKIs获得性耐药的研究进展》

注：

本次会议交流语言为汉语和英语，会场会配备同声传译和专业翻译。

International Seminar of New Clinical Techniques of Biotherapy

China · Tianjin

Oct. 20 -21, 2015

Organized by:

                    Tianjin Association for Stem Cell Research and Application

Supported by:

                   Chinese Medical Doctor Association, Science Popularization Branch of Chinese Medical Association, Beijing Branch of Chinese Medical Association

Background

In the last 30 years, biotherapy study had a rapid development, and brought new hope for cancer patients. At present, biotherapy has become one of the most impressive and inspiring focuses of medical science, and is an important development direction of clinical treatment in future. In the Development Plan on National Strategic Emerging Industries during the 12th Five-year Planning Period issued by the State Council, bioindustry is one of the seven strategic emerging industries. Development of biotherapy depends on development of innovative treatment techniques and close cooperation of researchers, clinical doctors and enterprises. Based on such cooperation, profound innovative studies can be conducted on key issues and technical difficulties in clinical practice so as to continuously enrich theoretical foundation and promote development and transformation of new techniques.

CAR-T (Chimeric Antigen Receptor T-Cell Immunotherapy), is one of the relatively effective therapies for malignant tumor. It has remarkable curative effect for acute leukaemia and non-Hodgkin lymphoma, and has been considered as the most promising tumor therapy. Similar as all other techniques, CAR-T also experienced a long evolution process, and became more and more mature during such process.

This Seminar is organized by Tianjin Association for Stem Cell Research and Application, supported by Chinese Medical Doctor Association, initiated and approved by Tianjin Administration of Foreign Expert Affairs, and mainly sponsored by Shunho Cell Biotechnology (Tianjin) Co., Ltd..

This Seminar aims to exchange the latest progress in scientific research, to popularize the new techniques that can reduce the side effect of CART cell therapy, improve its effectiveness in clinical use, and solve the problems of palindromia and metastasis caused by off-target effect and tumor immune escape, to discuss about adoptive immunotherapy that has better curative effect, and to bring new hope to tumor treatment.

This Seminar has three academic themes:

1. Latest achievements in fundamental study on new cell biotherapy techniques (such as CAR-T);

2. Progress in clinical application of new cell biotherapy techniques;

3. International trend in popularization of new cell biotherapy techniques.

Agenda

Time: Oct. 20, 2015 to Oct. 21, 2015

Place: Tianjin Binhai Shengguang Crowne Plaza Hotel

Address: No. 55 Central Road, Tianjin Airport Economic Area, Dongli District, Tianjin

The temporarily determined agenda is as follows:

October 19  Monday  Afternoon:  Check-in

October 20  Tuesday  Morning  9:00-9:40: Opening ceremony

10:00-12:00: Public academic reports of experts

Academic theme: Progress in clinical application of new cell biotherapy techniques

Tuesday  Afternoon  13:30-16:00: Public academic reports of experts

Academic theme: Latest achievements in fundamental study on new cell biotherapy techniques (such as CAR-T)

16:30-18:00: Summit forum of domestic and overseas experts

October 21  Wednesday  Morning  9:00-12:00: Public academic reports of experts

Academic theme: International trend in popularization of new cell biotherapy techniques

Introduction of international experts and preach outline:

Dr. Lawrence Lamb:

Application of γδ T cells as a platform for cancer immunotherapy

Lawrence S. Lamb, Jr., MN, PhD

Professor of Medicine

University of Alabama at Birmingham

Birmingham, AL, USA

Human γδ T cells have been shown to kill a variety of tumor cells, but until recently their practical application in cancer therapy has been slow to evolve. Small clinical trials have been conducted using ex vivo expanded/activated autologous Vγ9Vδ2 T cells using a method designed to inhibit the mevalonate pathway in cultured mononuclear cells, thereby resulting in the accumulation of metabolites such as isopentenyl pyrophosphate (IPP). The combination of the aminobisphosphonate Zoledronate with IL-2 results in the stimulation of Vγ9Vδ2 T cells which then undergo selective proliferation in culture. The method is straightforward, uses pharmaceutical grade reagents, and can easily be applied in any standard cGMP-capable cell manufacturing facility. However, expanded Vγ9Vδ2+ T cells progress to the effector phenotype in culture and generally have a short lifespan and persistence in vivo. As such, the frequent multiple infusions would be required to maintain an effective cytolytic response. Alternatively, persistence of circulating, tumor-reactive Vδ1+ γδ T cells has been shown to correlate with long-term survival in allogeneic bone marrow transplant patients. In this presentation, we will discuss previous experience with the γδ T cell response to hematologic malignancies and high-grade glioma using various means of γδ T cell expansion. We will also discuss the potential for gene modification γδ T cell use as a platform for delivery of therapies that will amplify the anti-tumor response and the future development of this worl.

Dr. Stephen Haley:

T cell assays in vaccine and therapeutic development

Stephen T. Haley, PhD

Vice President, Immudex

Vaccines for the prevention of infectious disease are humanity's single greatest public health success. Classical vaccinology relies on antibody mediated immunity with little attention given to associated cell mediated immunity. However, the infectious disease burden thus far in the 21st century is dominated by HIV, tuberculosis, and malaria. Immune resistance to all of these is thought to require a cell mediated immune response. Yet many developing 21st century vaccines still rely solely on measurements of antibody to guide development and as correlates of protection.

The much publicized recent successes of various cancer immunotherapies are demonstration that the human immune system can be manipulated for treatment of disease as well as prevention. Checkpoint inhibitor therapies are designed to enhance existing T cell responses by “removing the brakes” from an ongoing response. How do we measure the success of immunological intervention? Classical assays such as Elispot have been utilized for many years and few question if the appropriateness of the assay(s) in their system or if the results are an accurate depiction of the T cell response.

Many types of T cell assays exist and attempts at integration into the vaccine and/or therapeutic development processes have proven frustrating. It is our contention that T cell correlates will be defined when the necessary attention is given to assay selection and development.

Dr. H. Trent Spencer:

Creation of novel anticancer chimeric T cell receptors for cellular immunotherapeutics

Chimeric antigen receptors (CARs) are used to redirect T cells toward selected cell surface antigens. Using T cells genetically engineered to express cancer-specific CARs, anti-tumor immunity can be established in patients with no pre-existing tumor targeted immunocompetent cells. Results from recent clinical trials have driven efforts to expand the application of CAR technologies, but this approach remains limited by the availability of cancer cell target antigens/receptor pairs. As a means to increase the identification of target antigens and generate unique single chain binding domain structures, we used unique aspects of the immune system of lampreys. Lampreys possess an adaptive immune system with variable lymphocyte receptors (VLRs) as immune effectors, which are naturally single chain structures and are capable of binding with high affinity and specificity. We developed a VLR containing CAR specific for the B-cell receptor of a murine B-cell leukemia (BCL), cloned it into a CAR cassette, and used it to generate high-titer lentivirus. Transduced T cells demonstrated persistent CAR expression for over 2 months with over 85% cell viability, and CAR expressing T cells demonstrated robust activation. Furthermore, transduced NK-92 cells and gd T cells expressing the VLR-CAR demonstrated an ability to recognize and kill BCL cells at target to effector ratios as low as 1:1, with 30% target cell killing. No killing was observed with a control B cell line. We have expanded these studies to include VLRs against neuroblastoma and T cell specific antigens, which function similarly to the BCL-directed CAR. Collectively, these results show that VLRs can provide both a unique and effective method for activating CAR T-cells, which led us to generate VLR-CARs against human tumor antigens.

Dr. Antonio DiStasi：

Title: Devising strategies to modulate the function of T-cell based immunotherapy approaches.

Dr. Antonio Di Stasi

Assistant Professor

University of Alabama at Birmingham,

USA

Abstract

Adoptive T-cell therapy can exert a profound anti-tumor effect, given as donor lymphocyte infusion (DLI) after allogeneic hematopoietic stem cell transplantation (allo-HSCT), or consisting of tumor infiltrating lymphocyte (TILs) expanded ex-vivo, or more recently by infusing T-cells redirected by the means of a T-cell-receptor (TCR) or a chimeric antigen receptor (CAR). Cellular therapies are not without risks. Donor T-cells within the HSC product or infused post-transplant as DLI have been associated with potentially fatal graft-versus-host-disease (GVHD), whereas administration of engineered T-cells has also resulted in on/off target toxicities as well as a cytokine release syndrome.

Unlike small molecules or biologics, cell therapies have a very long, or even an indefinite half-life, therefore since toxicity can be progressive a safety switch is needed in order to eliminate the infused cells in case of adverse events, and novel strategies to prevent toxicities are strongly needed. A suicide gene is a genetically encoded molecule that allows selective destruction of adoptively transferred cells. Suicide gene addition to cellular therapeutic products can lead to selective ablation of gene-modified cells, preventing collateral damage to contiguous cells and/or tissues. The ‘ideal’ suicide gene would ensure the safety of gene modified cellular applications by granting irreversible elimination of ‘all’ and ‘only’ the cells responsible for the unwanted toxicity. We have clinically validated a novel inducible Caspase9 suicide gene (iC9) in patients receiving suicide gene modified DLI after haploidentical-HSCT, and currently validating the ability to conditionally eliminate GVHD whilst retaining graft-versus-tumor (GVT). Additionally, we are devising a strategy to selectively target leukemia associated antigens with CAR T-cells co-expressing an inhibitory CAR directed to an antigen expressed on normal hematopoietic cells, whilst also incorporating the iC9 suicide gene to abate serious adverse events, and/or eliminate the infused T-cells before allo-HSCT rescue.

Biography

Dr. Di Stasi is Assistant Professor of Medicine in the Bone Marrow Transplantation and Cell Therapy Program Unit, where he performs both clinical and translational research activities. His primary research focus involves the pre-clinical validation of adoptive T-cell immunotherapy strategies for hematologic malignancies, primarily regarding genetic modification of T-cells with chimeric artificial receptors targeting tumor associated antigens, and the incorporation of a novel inducible Caspase9 suicide gene to grant safety of cellular approaches, including donor lymphocytes infused after allogeneic hematopoietic stem cell transplantation (allo-HSCT).

As post-doctoral fellow Dr. Di Stasi successfully completed a pre-clinical translational projects involving the generation of chimeric antigen receptor cytotoxic T-cells redirected to target the CD30 molecule on the surface of Hodgkin lymphoma (HL). To overcome the hostile immune-environment to T-cells he over-expressed the CCR4 chemokine receptor in the T-cells, based on the tumor's secretion of the chemokine TARC which is bound by CCR4. This modification increased migration and anti-tumor activity in an in vivo HL model, and will soon be tested in a phase-I clinical trial. Dr. Di Stasi also led a team to clinically test a novel inducible Caspase9 (iC9) suicide gene; haploidentical donor T-cells were administered to patients after allo-HSCT, in order to boost anti-viral and anti-cancer immunity. This technology allowed prompt elimination of infused donor T-cells in patients who developed graft versus host disease (GVHD) after infusion of the iC9 dimerizer molecule, AP1903.

This technology is currently investigated in several phase I/II clinical studies in the US and abroad, and has the potential to reduce the morbidity and mortality burden of GVHD, and UAB is now compiling a phase-I clinical

trial for patients undergoing matched related allo-HSCT.

Introduction of organizer and supporters:

TianjinAssociation for Stem Cell Research and Application

Tianjin Association for Stem Cell Research and Application (TASCRA), established in July 2014 and directly subordinate to Tianjin Administration of Social Organizations, is mainly engaged in: exchanging scientific research achievements on stem cells; declaring and jointly implementing biotherapy and biological preparation development projects; conducting clinical application research and popularizing the research achievements; normalizing competition modes of related enterprises; convening seminars of related domestic and overseas research institutes, outstanding individuals and enterprises; assisting relevant government departments in setting industrial standards; and so on. It aims to keep the scientific research on stem cell in Tianjin internationally leading in the field of biological medicine, promote clinical application and industrialization of stem cell biotechnology, standardize virtuous development and ordered competition of stem cell related enterprises, build a bridge between scientific research and clinical practice, strengthen cooperation among research institutes, promote commercialization of research fruits, and facilitate establishment of industrial standards on biotechnology. It makes efforts to develop the biomedicine industry of Tianjin, to break through routine treatment means, to provide new curative approaches for significant refractory human diseases, and to bring benefits to the people and the society.

Chinese Medical Doctor Association

Chinese Medical Doctor Association is a national, industrial and non-profit organization registered at the Ministry of Civil Affairs of China, consisting of practicing doctors, practicing assistant doctors and organization members. It is a national Class I association and an independent corporate body. The tenet of this Association is to bring into play the functions of industrial service, coordination, self-discipline, right protection, supervision and administration, to unite and organize doctors in the whole country and ensure their compliance with the Constitution, laws, regulations and policies of China, to carry forward humanitarian spirit and professional ethics of doctors, to improve medical treatment level and medical service quality, to maintain legal rights and benefits of doctors, and to make contribution to the health of the people and the socialist construction.

Chinese Medical Doctor Association was established under the new background of China’s entry into WTO and deepened reform of medical and health services. Its establishment indicates that the management of doctors in China will gradually transit from the current mode of management by administrative organs only to the mode of management by administrative organs together with self-discipline of the industry. In future, this Association will play a more and more important role in industrial management, and drive a solid step toward international management mode of doctors in China.

Chinese Medical Association

Chinese Medical Association is an academic, public and non-profit corporate body registered according to law. Consisting of persons engaged in medical sciences and technologies, it is a bridge and tie between the Party/country and such persons, and is important social force for the development of medical sciences and technologies in China.

Established in 1915, this Association has 83 specialized branches, 500,000 members, 16 departments, 3 subordinate corporate bodies, and 1 medical library jointly run with Academy of Military Medical Sciences of PLA.

It has totally 250,000 members in the whole country, and has 386 branch associations of city/county level, 65 specialized branch associations, and 139 academic teams. It publishes 417 academic journals, and runs its official newspaper named China Medical News. Its departments and offices include Academic Conference Department, Edit and Publication Department, Continued Education Department, External Liaison Department, Science and Technology Consultation Department, Book Information Center, and so on.

There is a medical association in Taiwan, which publishes two journals, respectively Journal of Taiwan Medical Association (a monthly journal started in 1901) and Continued Education Journal of Taiwan Medical Association (a monthly journal stated in 1989). There is a medical association in Hong Kong too, which is an independent organization and has journal exchange with China Medical Association. China Medical Association has a branch association in Macao.

Domestic experts:

Chairman of the Seminar:

Wang Jianxiang: A professor of Blood Disease Hospital of China Academy of Medical Sciences, a professor of Peking University, deputy director and chief physician of Hematology Research Institute of Blood Disease Hospital of Peking Union Medical College of China Academy of Medical Sciences, director of Leukaemia Center (Blood Disease Department II) of the Blood Disease Hospital of Peking Union Medical College, professor and doctoral supervisor.

Vice chairman of the Seminar: Wang Lixiang, Li Gong

Image ambassador of the Seminar: Lang Yongchun

Academicians invited:

Wu Zuze, academician of Chinese Academy of Sciences, expert in experimental hematology, director of Institute of Radiation Medicine of Academy of Military Medical Sciences;

Chen Hu, director of CTC Tumor Biotherapy Center of No. 307 Hospital of PLA;

Fu Xiaobing, academician of Chinese Academy of Engineering, director of Wound Healing Lab of General Hospital of PLA;

Lecturers to be invited:

Duan Haifeng, professor of Academy of Military Medical Sciences of PLA;

Han Weidong, director of Immunology Research Center and Biotherapy Section of General Hospital of PLA;

Hu Liangding, deputy director of Hematopoietic Stem Cell Transplantation Department of No. 307 Hospital of PLA;

Hu Xianwen, professor of Academy of Military Medical Sciences of PLA;

Ren Xiubao, director of Biotherapy Department of Tianjin Cancer Hospital;

Wang Lisheng, researcher of Radiation Medicine Research Institute of Academy of Military Medical Sciences;

Xia Jianchuan, director of Biotherapy Department of Sun Yat-Sen University Cancer Hospital;

Zhang Bin, deputy director of CTC Tumor Biotherapy Center of No. 307 Hospital of PLA;

Qian Cheng, director of Biotherapy Lab of Institute of Pathology of The Third Military Medical University, director of Cancer Biotherapy Lab of the same Institute;

Yang Lin, professor of Suzhou University, distinguished visiting professor of Hematology Center of Cyrus Tang Medical Institute, part-time professor of MD Anderson Cancer Center in USA;

Tang Xiaoyi, member of Cell and Gene Therapy Center of Academy of Military Medical Sciences;

Zhu Jun, chief physician, doctoral supervisor;

Wang Zhao, director of Hematology Internal Medicine Department of Hunan Changsha Cancer Hospital;

Zhao Ming: director of Immune Biotherapy Center of Hunan Changsha Cancer Hospital

Huang Xiaojun, director of Blood Disease Research Institute of People’s Hospital of Peking University, chief physician, doctoral supervisor;

Chang Jiwu, The Tumor Immunology Research Laboratory of The Second Affiliated Hospital of Tianjin Medical University;

Han Wei, Center of Medical Physics and Technology Hefei Institutes of Physical Science, C.A.S;

Chen Haixu, The General Hospital of PLA Beijing 100853 Department of Geriatrics Research Institute;

Li Jun, Cent for Clinical Transfusion Therapy of the Second Artillery General Hospital of PLA;

Yang Chao, Cent for Clinical Transfusion Therapy of the Second Artillery General Hospital of PLA;

Pei Haiyun, Research Office of Stem Cell and Regenerative Medicine of Academy of Micitary Medical Sciences.

Titles of lectures of some domestic experts:

Han Weidong: CART Clinical Test in China;

Duan Haifeng: Immune Activation Based Cancer Treatment Strategies;

Yang Lin: Challenges and Opportunities in Application of CAR-T Therapy for Solid Tumor;

Qian Cheng: New Strategies of Cancer Treatment with CAR-T Cell Therapy;

Hu Xianwen: Research Progress on Therapy Antibody Drugs for Chronic Non-infectious Diseases;

Xia Jianchuan: Basic Rules in Routine Treatment of Combination Tumors using Somatic Cell Immune Therapy.

Note: Chinese and English will be used at this Seminar, and simultaneous interpreting and professional translation services will be provided at the meeting place.