Obsidian Therapeutics, Inc.

2024年，细胞免疫疗法在实体瘤治疗方面迎来新契机：本年度全球已成功上市两款针对实体瘤的细胞疗法，包括全球首款肿瘤浸润淋巴细胞（TIL）疗法Amtagvi以及一款T细胞受体（TCR-T）疗法Tecelra，这无疑是细胞免疫治疗在实体瘤领域的重大突破。 01 2款创新疗法上市 （一）TIL疗法 2024年2月，美国Iovance Biotherapeutics的Lifileucel（商品名：Amtagvi）获FDA加速批准上市，用于治疗PD-1/PD-L1抗体治疗后进展的黑色素瘤，成为全球首款上市的TIL疗法。 根据Iovance发布的第三季度财务业绩报告，其全球首款获批的TIL疗法Amtagvi在今年第二季度销售额达到1280万美元，而到了第三季度，销售额迅速增长至5860万美元，收入呈现出快速增长的强劲态势。 Iovance预计本年度全年营收将在1.60亿至1.65亿美元之间，并且预计到2025年全年营收将进一步增长至4.5亿至4.75亿美元，销售峰值有望超过10亿美元。 （二）TCR-T疗法 Immunocore Holdings plc公司开发的Kimmtrak，作为全球首个获得批准的TCR-T疗法，最早于2022年1月26日获得了FDA的批准。 Kimmtrak是一款靶向gp100的TCR与靶向CD3的scFv的融合蛋白，用于治疗HLA-A*02:01基因型、转移性或不可切除的葡萄膜黑色素瘤。目前，Kimmtrak已在包括美国、欧盟、加拿大、澳大利亚和英国等在内的30多个国家获批，随着其市场推广的持续深入，销售额呈现出持续上扬的良好态势，其中2022年全年销售额约为1.44亿美元，而到了2023年，全年净销售额达到了2.38亿美元。 在2024年8月1日，FDA又批准了Adaptimune Therapeutics公司的工程化T细胞疗法Afami-cel（商品名：Tecelra），该疗法用于二线治疗既往接受过化疗治疗的不可切除或转移性滑膜肉瘤成人患者。 值得一提的是，Tecelra是过去十多年来针对滑膜肉瘤治疗的首个被证实有效的疗法，据市场分析预测，其年销售额峰值有可能达到4亿美元。 表1 全球已获批TCR-T疗法产品 数据来源：公开数据 02 研发热度高涨 （一）TIL疗法 国外布局TIL疗法的代表公司有Achilles Therapeutics、Instil Bio、Obsidian和Turnstone等。国内布局TIL疗法的公司接近20家，其TIL疗法适应症涵盖肝癌、宫颈癌、乳腺癌、非小细胞肺癌等实体瘤。 国内首个获批临床的TIL细胞药物为苏州沙砾生物的GT101注射液，I期临床试验结果显示14例复发或转移性实体瘤患者的客观缓解率（ORR）为35.7%。值得关注的是，在11名宫颈癌患者中，ORR达到45.5%，疾病控制率（DCR）高达90.9%，在宫颈癌治疗中表现出色。 表2 国内重点在研TIL疗法 数据来源：药智数据，公司官网 （二）TCR-T疗法 国外布局TCR-T疗法的代表公司有Immatics、TScan Therapeutics、Alaunos Therapeutics和Adaptive Biotechnologies等。国内布局TCR-T细胞疗法的企业约有17家，大部分都已经进入临床研究阶段，如香雪生命科学、来恩生物、星汉德、天科雅、百吉生物、可瑞生物、恒瑞医药、东北制药、鼎成肽源、镔铁生物等。 国内TCR-T细胞疗法进展最快的是香雪制药，其TAEST16001已进入II期，Ⅱ期临床试验数据显示TAEST16001治疗软组织肉瘤的最佳缓解率达到50%，展现出良好的治疗效果，2024年7月30日TAEST16001被CDE纳入突破性治疗品种名单。 表3 国内重点在研TCR-T疗法 数据来源：药智数据，公司官网 03 挑战与趋势 TIL疗法 （一）面临挑战 1.制备工艺复杂，需要技术支持与严格质控，提高效率与降低成本是关键。 2.个体差异大，预测和筛选合适患者群体困难。 3.肿瘤微环境抑制TIL细胞疗效和持久性。 4.依赖新鲜肿瘤组织，限制了适用患者范围。 （二）发展趋势 1.基因编辑技术应用：通过敲除抑制性基因或导入增强基因，提高TIL细胞特异性识别和杀伤能力，非病毒载体基因修饰技术有望成为主流。 2.联合治疗策略：与免疫检查点抑制剂、化疗、放疗等联合，发挥协同作用。 3.个性化治疗深化：精准筛选患者，制定个性化方案，如DC细胞与TIL细胞共培养扩增新生抗原TIL细胞。 TCR-T疗法 （一）面临挑战 1.TCR-T的生产过程复杂，成本高昂。 2.靶向正常组织引起的免疫毒性。 3.T细胞耗竭和功能障碍。 4.肿瘤免疫逃逸。 5.疗法的有效性受限于患者的MHC类型，大多数癌症患者缺乏有效的肿瘤特异性抗原作为靶点。 （二）发展趋势 1.优化靶点选择与设计：深入研究肿瘤相关抗原，筛选出更为特异性的靶点，同时优化TCR的设计，提高其对肿瘤细胞的亲和力和特异性，减少对正常组织的毒性。 2.克服耐药机制研究：开发能够增强T细胞功能、克服肿瘤细胞内在抗性的方法，以及寻找抑制免疫检查点配体上调和维持MHC I类分子稳定表达的手段。 3.技术改进与创新：探索前沿技术来突破个体化治疗的复杂性和MHC限制性，如采用基因编辑技术开发通用型TCR降低成本并拓宽适用患者群体。 04 展望 攻克实体瘤是肿瘤治疗领域的重大飞跃，TIL和TCR-T疗法有望成为未来肿瘤治疗的核心手段之一。但TIL和TCR-T疗法在攻克实体瘤的道路上依然面临诸多挑战，科研人员、企业和监管机构应携手合作，加大研发投入，优化治疗方案，克服现有挑战，在各方的共同努力下，TIL和TCR-T疗法将在实体瘤治疗领域取得更大的突破，为患者带来更多福祉。 声明：本内容为作者独立观点，不代表药智网立场。如需转载，请务必注明文章作者和来源。对本文有异议或投诉，请联系maxuelian@yaozh.com。 责任编辑 | 八角 转载开白 | 马老师 18996384680（同微信） 如需定制医药咨询服务，请扫描下方二维码咨询！  阅读原文，是受欢迎的文章哦

CAMBRIDGE, Mass.--( BUSINESS WIRE )-- Obsidian Therapeutics, Inc. , a clinical-stage biotechnology company pioneering engineered cell and gene therapies, today announced the publication of 3 abstracts for poster presentations at the SITC Annual Meeting 2024, including sharing preclinical data supporting the potential of its cytoDRiVE platform to enable a more patient-centric, core needle biopsy tumor tissue procurement procedure for OBX-115 manufacturing in non-small cell lung cancer (NSCLC) and to potentially expand the therapeutic window and application of potent, immune-modulating cytokines for armored cell therapies. Obsidian will present preclinical data supporting a more patient-centric tumor tissue procurement procedure using core needle biopsy for OBX-115 manufacturing in patients with NSCLC, which is enabled by Obsidian’s proprietary and optimized manufacturing process, including IL15-driven tumor-infiltrating lymphocyte (TIL) expansion. This poster for abstract 444 provides evidence that, as observed with melanoma, 1 core needle biopsy can be used in NSCLC to successfully generate OBX-115 product that is phenotypically and functionally similar to product manufactured using surgical excision, maintaining similar TCR clonotype repertoire and predominantly effector-memory, stem-like phenotype with low PD-1 expression. Obsidian has previously presented clinical data demonstrating clinical efficacy in patients with advanced melanoma receiving OBX-115 where tumor tissue was obtained with a core needle biopsy. 2 Core needle biopsy is minimally invasive and typically completed as a routine outpatient procedure, reducing time, logistical complexity and total cost of care compared to surgical excision, and has the potential to increase access to care. Obsidian is presenting two additional posters showcasing the ability of its novel cytoDRiVE regulation platform to unlock the therapeutic window of potent cytokines and broaden the reach of armored cell therapies. The poster for abstract 463 demonstrates the application of Obsidian’s drug-inducible cytoDRiVE platform to enhance antigen-responsive promoter-induced (“spatial”) activation by adding a critical pharmacologically regulatable second (“temporal”) signal to exert tight “spatiotemporal” control over IL12 expression, resulting in a positive impact on safety and tumor control in physiologically relevant animal models relative to methods from previous clinical experience. 3 This abstract has been selected by the SITC Communications Committee to be presented at the SITC 2024 Annual Meeting Press Conference, scheduled for Wednesday Nov. 6, 2024, from 12:00-1:30pm CT. To attend this press briefing, you must register as a member of the press for SITC 2024. To register, please visit https://www.sitcancer.org/2024/press/press-registration . After registration is confirmed, press will receive instructions for the briefing. The poster for abstract 457 demonstrates that cytoDRiVE can bring two potent cytokines, membrane-bound IL15 (mbIL15) and LIGHT (TNFSF14), a potent immune mediator that is part of the tumor necrosis factor family, under pharmacologic regulation using a single drug-responsive domain (DRD)-ligand pairing (the same pairing used in OBX-115). The engineered mbIL15-LIGHT cell therapy demonstrated in vivo antitumor activity and evidence of tumor microenvironment (TME) remodeling in fibroblast-rich models, supporting the potential for cytoDRiVE to address solid tumors marked with an immunosuppressive TME. Obsidian is also presenting at the Tumor Infiltrating Lymphocytes (TIL) Symposium on Wednesday November 6. Dr. Parameswaran Hari will deliver a talk titled, “ OBX-115: An engineered, pharmacologically regulatable membrane-bound IL15 TIL cell therapy for advanced solid tumors” at 9:40 am CT. Obsidian Posters at SITC 2024: Potential feasibility of core needle biopsy tumor tissue procurement method for TIL cell therapy with OBX-115 in non-small cell lung cancer (NSCLC) (Abstract 444) Presenting Authors: Matthew Bott, Memorial Sloan Kettering Cancer Center; Zheng Ao, Obsidian Therapeutics Poster: Thursday, Nov 7, 3:10-5:00 pm CT (Immune Engineering Workshop Poster Session) and Saturday, Nov 9 (Annual Meeting Poster Session) Antigen-responsive promoters coupled with cytoDRiVE® technology provide tight spatiotemporal regulation for tumor-infiltrating lymphocytes (TIL) expressing membrane-bound IL12 (Abstract 463) Presenting Author: Sean Smith, Obsidian Therapeutics Poster: Thursday, Nov 7, 3:10-5:00 pm CT (Immune Engineering Workshop Poster Session) and Friday, Nov 8 (Annual Meeting Poster Session) Engineered tumor-infiltrating lymphocytes (TIL) with co-regulated membrane-bound IL15 (mbIL15) and LIGHT (TNFSF14) generate significant antitumor efficacy in fibrotic tumor models (Abstract 457) Presenting Author: Benjamin Primack, Obsidian Therapeutics Poster: Friday, Nov 8 (Annual Meeting Poster Session) 1 Bernatchez et al., ISCT 2024 (Abstract 909). 2 Amaria et al., ASCO 2024 (Abstract 9515). 3 Zhang et al., Clin Cancer Res (2015) 21 (10): 2278–2288. About OBX-115 Obsidian’s lead investigational cytoTIL15™ program, OBX-115, is a novel engineered tumor-derived autologous T cell immunotherapy (tumor-infiltrating lymphocyte [TIL] cell therapy) armored with pharmacologically regulatable membrane-bound IL15 (mbIL15). OBX-115 has the potential to become a meaningful therapeutic option for patients with advanced or metastatic melanoma and other solid tumors by leveraging the expected benefits of mbIL15 and Obsidian’s proprietary, differentiated manufacturing process to enhance persistence, antitumor activity, and clinical safety of TIL cell therapy. Obsidian is investigating OBX-115 in the phase 1/2 Agni-01 multicenter trial in patients with advanced solid tumors ( NCT06060613 ). About Obsidian Therapeutics Obsidian Therapeutics, Inc. is a clinical-stage biotechnology company pioneering engineered cell and gene therapies to deliver transformative outcomes for patients with intractable diseases. Obsidian’s proprietary cytoDRiVE® technology is designed to precisely regulate the timing and level of protein function by using FDA-approved small-molecule drugs. Obsidian is headquartered in Cambridge, MA. The Company has collaborations with Bristol Myers Squibb and Vertex Pharmaceuticals. For more information, please visit www.obsidiantx.com and follow us on LinkedIn.

CAMBRIDGE, Mass.--( BUSINESS WIRE )-- Obsidian Therapeutics, Inc. , a clinical-stage biotechnology company pioneering engineered cell and gene therapies, today announced that the U.S. Food and Drug Administration (FDA) has granted Regenerative Medicine Advanced Therapy (RMAT) designation to OBX-115 for the treatment of patients with unresectable or metastatic melanoma that is resistant to immune checkpoint inhibitor (ICI) therapy. OBX-115 is a novel engineered tumor-derived autologous T cell immunotherapy (tumor-infiltrating lymphocyte [TIL] cell therapy) armored with membrane-bound IL15 (mbIL15) that is pharmacologically regulated using FDA-approved small molecule drug acetazolamide. This second FDA designation follows a July 2024 announcement of Fast Track designation for OBX-115. “RMAT designation for OBX-115 highlights the unmet need in ICI-resistant melanoma and OBX-115’s potential to provide patient-centric, transformative care in this setting,” said Parameswaran Hari, M.D., Chief Development Officer of Obsidian. “In an oral presentation at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, initial Phase 1 data showed that OBX-115 exhibited a favorable safety profile relative to what has been observed historically from IL2-dependent non-engineered TIL cell therapy, encouraging efficacy in patients with heavily pre-treated disease, and compatibility with non-surgical core needle biopsy tumor tissue procurement . We look forward to continued collaborative interaction with the FDA as we advance OBX-115 clinical development in both melanoma and non-small cell lung cancer (NSCLC).” Established under the 21st Century Cures Act, RMAT designation is a dedicated program that includes the benefits of Fast Track and Breakthrough Therapy designations and is designed to expedite the development and review processes for certain promising drug candidates, including cell therapies. An investigational cell therapy is eligible for RMAT designation if it meets the definition of regenerative medicine therapy, is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition, and preliminary clinical evidence indicates that the therapy has the potential to address unmet medical needs for that disease. RMAT designation provides early and frequent interactions with the FDA, including intensive guidance on efficient drug development. Candidates receiving RMAT designation may also be eligible for Accelerated Approval and Priority Review. About OBX-115 Obsidian’s lead investigational cytoTIL15™ program, OBX-115, is a novel engineered tumor-derived autologous T cell immunotherapy (tumor-infiltrating lymphocyte [TIL] cell therapy) armored with pharmacologically regulatable membrane-bound IL15 (mbIL15). OBX-115 has the potential to become a meaningful therapeutic option for patients with advanced or metastatic melanoma and other solid tumors by leveraging the expected benefits of mbIL15 and Obsidian’s proprietary, differentiated manufacturing process to enhance persistence, antitumor activity, and clinical safety of TIL cell therapy. Obsidian is investigating OBX-115 in a multicenter trial in patients with advanced melanoma or relapsed / refractory NSCLC ( NCT06060613 ). About Obsidian Therapeutics Obsidian Therapeutics, Inc. is a clinical-stage biotechnology company pioneering engineered cell and gene therapies to deliver transformative outcomes for patients with intractable diseases. Obsidian’s proprietary cytoDRiVE® technology is designed to precisely regulate the timing and level of protein function by using FDA-approved small-molecule drugs. Obsidian is headquartered in Cambridge, MA. The Company has collaborations with Bristol Myers Squibb and Vertex Pharmaceuticals. For more information, please visit www.obsidiantx.com and follow us on LinkedIn.