原启生物首个靶向肝癌CAR T 细胞产品亮相ASCO，临床数据令人振奋

美国东部时间2021年6月4日，原启生物科技（上海）有限责任公司（简称“原启生物”） 联合浙江大学附属丽水市中心医院和上海长征医院在2021年美国临床肿瘤学会（ASCO）年会上首次公布其评估靶向GPC3的CAR-T药物（Ori-CAR-001）治疗复发/难治性肝细胞癌（hepatocellular carcinoma，HCC）的最新临床研究数据（Abstract ID: 4095）。该研究的初步数据显示，Ori-CAR-001在GPC3阳性复发/难治性患者中表现出良好安全性和有效性。

细胞疗法在实体瘤领域的重大突破

截至2021年3月10日，本研究共纳入11例接受细胞输注的复发受试者，均为化疗、TACE以及靶向药物治疗无效的晚期肝癌患者。按照巴塞罗那分期标准进行评估，除1例为B期（中期），其余10例全部为C期（晚期）。所有受试者都有多处的转移病灶，其中6例（54%）受试者有肺部等远端转移。除2例受试者未接受评估退组外，在 9例可评价的患者中，4例获得部分缓解（PR）, 3例获得疾病稳定（SD），2例获得疾病进展（PD）。治疗的客观缓解率达44.44%，疾病控制率达77.78%。

其中，受试者007的PR缓解时间超过6个月，肿瘤体积减少超过80%。截止日前该患者的缓解周期已超过8个月，仍在持续随访中。另一名疗效显著的受试者012是一位弥漫型、巨块型晚期的肝癌患者，曾接受过 12次以上的TACE治疗，在放疗及靶向治疗无效后加入本研究。回输28天后MRI结果显示最大肿瘤直径从133mm减少至9mm，缩小超过93%。目前，该受试者在回输3个月后评估，MRI扫描结果显示此肿瘤几乎消失。相应地，回输28天后其AFP （甲胎蛋白，诊断原发性肝癌特异性的肿瘤标志物）水平从>80000降至1148.9ng/ml，回输3个月后降至746.7ng/ml （其正常值是在0-40ng/ml以内），展示了Ori-CAR-001在晚期肝癌治疗的显著有效性。

Barcelona Clinic Liver Cancer，BCLC，欧洲肝病协会制定的肝癌临床分期系统，帮助评估病人的患病情况提供准确治疗方案和预测患者预后，主要分为0、A、A1、A2、A3、A4、B、C、D期。

安全性良好

在已回输的11例患者中，Ori-CAR-001显示出了良好的安全性和耐受性。9例患者观察到了细胞因子释放综合征（CRS），其中7例发生1-2级CRS，2例经静脉回输出现4级CRS，给予类固醇激素和托珠单抗治疗后恢复正常。没有观察到神经毒性。

对于Ori-CAR-001治疗晚期难治/复发型肝癌在探索性临床研究中获得的结果，该临床项目的PI之一的国家重点研发计划首席科学家, 浙江省影像诊断与介入微创研究重点实验室主任纪建松教授表示：“复发/难治肝细胞癌目前没有有效治疗手段，细胞治疗实体瘤由于受到肿瘤微环境等因素影响难以突破。而原启生物的Ori-CAR-001细胞治疗复发/难治性肝细胞癌客观缓解率达到了44%，疾病控制率达到了77%，是目前已上市药物无法企及的兼具安全可控和良好抗肿瘤活性的效果。基于前期良好的疗效和安全性数据，Ori-CAR-001细胞药物有望成为晚期肝细胞癌患者新的治疗选择，这让我们对其未来的研究前景充满信心，也对中国的创新药感到自豪。”

原启生物联合创始人、首席科学官何晓文博士表示：“肿瘤免疫细胞治疗在血液肿瘤上已经有非常好的治疗效果，未来在实体瘤治疗这个更大的临床需求上，原启生物将不断探索，希望能为众多的晚期病人和临床医生带来更有效的细胞免疫治疗方案”。

关于Ori-CAR-001

Ori-CAR-001细胞是靶向GPC3的高干性嵌合抗原受体T细胞，拟用于治疗难治性/复发性的肝细胞癌（HCC）。Ori-CAR-001采用的 GPC3 CAR结构是由抗GPC3的scFv形式人源化抗体、CD8 绞链区、跨膜区、4-1BB 共刺激域、CD3z胞内激活域、以及通过T2A同时表达的Ori2新元件构成，经慢病毒感染T细胞后在适于记忆性T细胞的培养工艺下扩增制成。与传统的CAR-T细胞比较，

Ori-CAR-001有明显更高的记忆干细胞比例，抵抗免疫负环境，可显著提高CAR-T细胞的扩增和维持，从而提高其抗肿瘤功效。

值得注意的是，本次会议除了在研究中初步证实CAR-T治疗HCC的安全性和有效性，原启生物与研究者们同时进行了转化医学的相关研究，对给药方式、给药剂量、PK/PD（药代动力学/药效动力学）、生物标志物进行探索，推进了细胞治疗实体肿瘤应用和发展。

目前，原启生物将在已有的数据基础上进一步探索相关临床研究，国家药品监督管理局（NPMA）的新药注册临床试验（IND）申请正在同步准备中。

关于美国临床肿瘤协会

美国临床肿瘤学会 (ASCO) 是全球领先的肿瘤专业学术组织，有来自100 多个国家超过40000名会员，其旨是预防癌症及改善癌症服务，促进研究成果转化到临床应用。一年一度的ASCO年会汇聚了全球临床肿瘤学研究的精英，被公认为全球最重要的肿瘤学术会议。

关于原启生物

原启生物科技（上海）有限责任公司（原称“上海原能细胞医学技术公司”自2021年5月25日起正式更名）成立于2015年，在2019年底获得启明创投近亿元的Pre-A轮独家投资，2020年底完成超过2亿元人民币的A轮融资。在启明创投支持下，原启生物作为原能细胞集团生物创新药研发资产分拆独立，未来将聚焦于肿瘤免疫治疗领域的新产品开发.

原启生物立足于自主创新，投入巨资构建了协同增效的四个创新型产品研发技术平台：Ori™Ab抗体开发与优化技术平台、Ori™CAR高记忆性CAR-T结构技术平台、Ori™TIL细胞高效扩增培养技术平台和Ori™UCAR通用型CAR-T技术平台。

关于Ori™Ab—抗体发现技术平台

建有1011全人源抗体噬菌体展示库和1012纳米抗体库及抗体工程的技术平台，已产生一系列自主创新且性能优越的抗体侯选药物及CAR-T细胞靶点抗体。

关于Ori™CAR技术平台

在新颖且专有的CAR结构内插入了独特的信号激活域，成倍提升记忆性免疫细胞扩增效率，有效抵抗实体肿瘤的免疫负环境，增强CAR-T的功效和持久性，高效抑制肿瘤和预防复发。

关于Ori™TIL—细胞高效扩增培养技术平台

高倍率提升TIL细胞扩增数量，质量属性和工艺参数突破行业瓶颈，有效确保TIL疗法的临床效果和安全保障，年轻态TIL细胞增强肿瘤杀伤活性。

关于Ori™UCAR技术平台

高效协同抗体技术、Ori技术和基因编辑和细胞分化技术等平台优势，以实现未来CAR-T产品的通用性及便捷性，同时有效降低使用成本。

OriginCell Therapeutics Presents Positive Results of GPC3 CAR-T in HCC Trial

at the 2021 ASCO Annual Meeting

On June 4, 2021 (EDT), OriginCell Therapeutics (Shanghai) Co., Ltd. ("OriginCell”), together with Lishui Central Hospital affiliated to Zhejiang University and Shanghai Changzheng Hospital, presented the updated data from the on-going trial of Ori-CAR-001, a GPC3 CAR-T cell therapy for the treatment of relapsed/refractory hepatocellular carcinoma (HCC), at the 2021 annual meeting of American Society of Clinical Oncology. Preliminary results from the study show promising safety and efficacy of Ori-CAR-001 in patients with GPC3-positive relapsed/refractory HCC.

Session type: Poster Session

Abstract Title: An armored GPC3-directed CAR-T for refractory or relapsed hepatocellular carcinoma in China: A phase I trial

Date and time: 06/04/2021, 9:00 AM (EDT)

Abstract ID: 4095

Link: https://meetinglibrary.asco.org/record/199036/abstract

A breakthrough Cell Therapy against Solid Tumors

As of March 10, 2021, a total of 11 patients were enrolled into this study. All subjects had advanced HCC and had failed prior lines of treatment including chemotherapy, TACE, and targeted therapies. All subjects had BCLC stage C (late stage) HCC except for one subject with stage B (mid stage). All subjects had multiple lesions, of which 6 (54%) had distant metastasis. Two subjects dropped out early and were not evaluable. Among the 9 evaluable subjects, 4 achieved partial response (PR), 3 achieved stable disease (SD), and 2 had disease progression (PD). The objective response rate was 44.4%, and the disease control rate reached 77.8%. A partial response lasting for more than 6 months was observed in Subject 007 at the time of data cutoff, whose tumor volume was reduced by more than 80% one month post cell therapy infusion. (As of June 2021, this subject had exceeded 8 months of disease control, follow-up is still ongoing). Good tumor response was also seen in Subject 012, who has advanced and diffuse massive HCC and joined the study after failing in radiotherapy, targeted drug and 12 times of TACE.

Barcelona Clinic Liver Cancer (BCLC) is a liver cancer staging system developed by the European Association for the Study of Liver, to help assess patients’ conditions, select the right therapies for the right patients, and predict patients’ prognosis. The BCLC system classifies HCC mainly as stages of 0, A, A1,A2,A3,A4, B, C,and D.

On day 28 post infusion with CAR-T cells, the target tumor lesion decreased from 133mm in diameter at baseline to 9mm, a reduction of more than 93%. Currently, the subject is being evaluated for month 3 post CAR-T cell infusion, MRI scan showed near complete tumor response. In addition, AFP level (alpha-fetoprotein, a specific tumor marker for primary liver cancer) decreased from a baseline value of >80,000/ng/ml to 1148.9 ng/ml on month 1, and to 746.7 ng/ml at month 3 post infusion (normal range <40ng/ml), demonstrating significant preliminary efficacy of Ori-CAR-001 in patients with advanced HCC.

Good Safety Profile

Ori-CAR-001 CAR-T infusion demonstrated good safety and tolerability in 11 patients. Cytokine release syndrome (CRS) was observed in 9 patients (7 cases grade 1-2 and 2 cases grade 4), which were resolved after treatment with steroids and tocilizumab. No neurotoxicity was observed.

Regarding the results from this exploratory study, Professor Ji Jiansong, principal investigator of Lishui Central hospital, who is also Chief scientist of the National Key R&D Program, director of Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research of Zhejiang China, said, “There is currently no effective treatment for relapsed/refractory hepatocellular carcinoma. Many challenges such as the tumor micro environment is difficult to overcome and have limited the therapeutic effects of cell therapy in solid tumors. However, Ori-CAR-001, developed by OriginCell Therapeutics, has managed to achieve an objective response rate of 44% and a disease control rate of 77% in patients with relapsed/refractory HCC, demonstrating a level of safety and anti-tumor activity that cannot be achieved by currently available drugs. Given its preliminary promising efficacy and safety data, we are confident in the future development prospects of Ori-CAR-001 and will continue our research studies. We take great pride and hope Ori-CAR-001 will one day become a new treatment option for patients with advanced HCC.

Dr. He Xiaowen, co-founder and chief scientific officer of OriginCell Therapeutics, said, " Although Immuno-cell therapies have produced remarkable clinical responses in hematological tumors, they have limited efficacy against solid tumors. OrginCell will continue to explore the broader unmet needs in this space, with the hope to bring more effective immuno-cell therapies to clinicians and patients with advanced stage cancer.”

About Ori-CAR-001

Ori-CAR-001 is a next generation autologous chimeric antigen receptor T cell therapy targeting GPC3 for the treatment of refractory/ relapsed hepatocellular carcinoma (HCC). The construct of Ori-CAR-001 is comprised of humanized anti-GPC3 scFv, a CD8-derived hinge region, a transmembrane domain linked to 4-1BB co-stimulatory domain, a CD3z intracellular signaling domain, and Ori2 components simultaneously expressed through T2A. Compared with conventional CAR-T cells, Ori-CAR-001 has significantly higher proportion of memory stem T cells, which may translate to improved expansion and persistence in the body, thereby increasing their anti-tumor activity.

It is worth noting that, in addition to the preliminary safety and efficacy data of Ori-CAR-001 presented at 2021 ASCO annual meeting, OriginCell and study investigators also carried out translational medicine studies, in which the mode of administration, dosing, PK/PD, and biomarkers were explored. This will futher promote the application and development of cell therapy for solid tumors.

OriginCell will plan more clinical development programs to further explore Ori-CAR-001’s potential based on existing data, and the Investigational New Drug (IND) application with the National Medical Products Administration (NPMA) is currently in progress.

About ASCO

With more than 40,000 members from more than 100 countries, the American Society of Clinical Oncology (ASCO) is the world’s leading academic organization for physicians and oncology professionals caring for people with cancer. Its mission is to prevent cancer and improve cancer care, and promote the translation of research findings into clinical practice. By providing access to a global network of oncology expertise, the ASCO annual meeting is recognized as the world’s most influential academic congress in the field of oncology.

About OriginCell Therapeutics

Founded in 2015, OriginCell Therapeutics Co., Ltd. ( Chinese name changed from “原能医学”to “原启生物” on May 25) received pre-Series A funding of nearly 100 million yuan exclusively from Qiming Venture Capital at the end of 2019, and the company completed Series A funding of more than 200 million yuan at the end of 2020. With the support of Qiming Venture Capital, OriginCell has been spun off from the OriginCell Group as an innovative drug research and development asset, and will focus on developing new immunotherapies for cancer treatment in the future.

Dedicated to independent innovation, OriginCell has built four innovative and synergistic proprietary technology platforms, i.e. Ori™Ab, an antibody development and optimization technology platform; Ori™CAR, a high-memory CAR T technology platform; Ori ™TIL, an efficient cell expansion and culture technology platform; and Ori™UCAR, a universal CAR-T technology platform.

About Ori™Ab—Antibody Discovery Technology Platform

Ori™Ab is a technology platform that enables the expression of 1011 fully human antibody phage display libraries, 1012 nano antibody libraries, and adds antibody engineering capabilities. A series of superior antibody drug candidates and CAR-T cell target antibodies have been produced from this platform.

About Ori™CAR Technology Platform

Ori™CAR enables the insertion of unique signaling domains into novel and proprietary CAR construct, which greatly enhances the expansion efficiency of memory immune cells, effectively resists the stressful immune environment of solid tumors, enhances the efficacy and persistence of CAR-T, and effectively inhibits tumor growth and prevents recurrence.

About Ori™TIL—A Cell Expansion and Culture Technology Platform

Ori™TIL can substantially increase the number of expanded TIL cells, improve quality attributes, and process parameters to break the therapeutic limitations. The clinical efficacy and safety can be ensured via younger TIL cells that can bring enhanced anti-tumor activity.

About Ori™ UCAR Technology Platform

Ori™ UCAR can efficiently synergize with antibody technology, Ori technology, gene editing, and cell differentiation technology to make future CAR-T therapies more universal and convenient, while effectively reducing its cost of use.