MHC2TA

前言过继性免疫治疗是血液学的一种变革性治疗方法，它通过基因工程在T细胞表达合成嵌合抗原受体（CAR）。针对 B 细胞白血病和淋巴瘤中的 CD19 抗原的 CAR-T 细胞已得到临床认可，目前成为全球范围癌症中心实施的“常规” 治疗手段。CAR结构由三部分组成：细胞外抗原识别结构域、跨膜结构域和含有CD3ζ或共刺激分子的细胞内信号转导结构域。CAR-T细胞具有诱导体液和细胞免疫抗CAR应答的潜力，这些免疫应答是针对CAR的非自身成分或源自基因转移载体的残余蛋白，这些蛋白具有固有的免疫原性。这种免疫反应可能会限制CAR-T细胞得疗效。目前临床开发中的许多CAR的单链抗体来自小鼠或其他非人类抗体。虽然到目前为止，还没有确凿的证据表明这种抗CAR免疫反应会导致其他不良反应，如细胞因子释放综合征（CRS）和免疫效应细胞相关神经毒性综合征（ICANS），但是已有证据表明，CAR或载体残留蛋白特异性的T细胞会清除和灭活注入的CAR-T细胞。同样，体液免疫产生的CAR中和抗体也会促进CAR-T细胞的凋亡。因此，随着CAR-T技术的进展，在提高疗效和持久性的同时，了解CAR-T细胞免疫原性的起源和机制仍非常关键，尤其是在实体瘤患者。抗CAR免疫的临床证据在已获批上市的CAR-T产品中，Kymirah和Yescarta都观察到了已存在的体液免疫。在临床试验中，接受Kymirah的绝大多数B-ALL患者（84.6%，n=88）有预先存在的抗CAR抗体，在难治性弥漫性大B细胞淋巴瘤的患者中比例高达91.4%。相比而言，在接受Yescarta治疗的患者中，预先存在的抗CAR抗体就少的多（3%，n=94）。但是总体而言，这些存在的抗CAR抗体的患者并没有表现出更差的临床结果，CD19靶向CAR的抗抗体似乎不会损害初始的临床反应。然而与预先存在的抗体相比，输注后出现的CAR特异性细胞毒性T细胞可能与一些临床试验的治疗失败有关。在第一代自体CD19 CAR-T细胞的剂量递增试验中，首次报道了这种细胞免疫情况。两名患者在第一次输注（108个细胞/m2）24小时后虽然都检测到了CAR-T细胞，但它们无法持续存在，甚至不到1周。尽管以更高剂量再输注并使用IL-2支持，CAR-T细胞在体内仍不能存活。这种失败可能在一定程度上是制造方法的原因，但在第一次输注前存在的T细胞介导的抗CAR反应可能会加剧这种结果。尽管一些血液系统恶性肿瘤患者在首次输注CD19 CAR-T细胞的完全缓解率很高，但疾病复发仍然是一个问题，大约30-50%的患者在12个月内复发。对于这些复发的患者，重复输注是一种很有吸引力的选择。然而，第二次或随后输注的临床反应一般都不理想，通常只有<25%的患者出现完全缓解。随后的患者的亚组分析中，观察到了CAR特异性的细胞毒性T细胞的扩增，这种细胞与重复输注后CAR-T细胞的扩增减少有关。此外，针对除CD19外的其它靶点的CAR-T细胞和新一代的CAR-T细胞，都发现了存在针对CAR-T细胞的体液和细胞免疫，可能与不良的临床结果相关。降低固有的CAR免疫原性CAR结构的几个组成部分有可能触发患者的抗CAR免疫反应。可以使用各种方法降低这些成分的免疫原性。人源化肿瘤反应性单链抗体一些研究人员正在开发和测试人源化单链抗体，以规避与小鼠源性单链抗体相关的抗CAR反应。人源化后的免疫原性可能较低，并且对于初次输注小鼠来源的CAR-T细胞后疾病复发的患者或未经CAR-T细胞治疗的患者是一种不错的选择。另一种策略是用缺乏轻链和潜在免疫原性连接序列的重链抗体。2019年11月报告了BCMA特异性全人重链抗体CAR-T的首个临床结果。然而从理论上讲，全人源抗体仍然可以在患者中引发涉及抗独特型抗体的免疫反应，因此，直接比较小鼠源性和人源化单链抗体免疫原性的头对头临床试验是有必要的。肿瘤特异性结构域除了基于单链抗体的CARs，肿瘤细胞也可以通过内源性肿瘤特异性受体-配体相互作用作为靶点。CAR的scFv部分可以被受体的胞外区或与受体结合的配体所取代。目前正在进行临床前和早期临床评估的这种CAR结构包括嵌合NKG2D受体，IL-13、整合素αvβ6结合肽和heregulin-ζ chimaeras。然而，到目前为止，还没有关于使用这种通用受体策略的免疫原性数据。CAR间隔区突变scFv与靶抗原表位的最佳结合对于有效的CAR-T细胞治疗至关重要，尤其是靠近肿瘤细胞膜的近端表位可能需要具有更长和更灵活铰链结构域的CAR-T细胞。许多研究小组使用了各种IgG重链的恒定区作为间隔，然而重链恒定区的CH2和CH3结构域可被固有免疫细胞（如巨噬细胞、粒细胞和NK细胞）上的Fc受体靶向，并可能造成免疫原性风险。这种情况可以通过突变间隔区内的Fc受体结合表位来避免，从而阻止先天免疫细胞活化。新型CAR技术的免疫原性细胞因子CAR添加细胞因子旨在提高CAR-T细胞的抗肿瘤效果，特别是为了克服免疫抑制微环境，如IL-15。然而，细胞因子的应用，可能增加患者免疫原反应的风险，并可引起诸如发热、寒战、低血压、血小板减少和淋巴细胞减少等毒性反应。旁观者T细胞活化是这种旁分泌细胞因子支持策略固有的理论风险，尽管旁分泌细胞因子是否能放大任何抗CAR反应仍有待进一步研究。相应地，通过改造CAR-T细胞的细胞因子受体或受体胞内信号结构域可仅向CAR-T细胞提供免疫调节细胞因子信号，而不影响旁观者淋巴细胞，这种策略目前正在临床试验中进行研究（NCT035332和NCT0499997）。自杀基因与清除标记尽管对某些血液恶性肿瘤患者有效，但由于靶向非肿瘤毒性以及附加技术带来的不可预测的不良影响，使CAR-T细胞治疗面临着很多安全风险。在CAR-T细胞中加入自杀基因和清除标记是一种减少严重不良事件的有效手段，可以控制CAR-T细胞的定向清除。然而，这种方法也存在着免疫原性反应的风险。例如，在表达HSV-TK作为自杀基因的T细胞中鉴定出多个免疫原表位，从而导致CD4+T细胞和CD8+T细胞介导的抗CAR-T细胞反应。由人类来源的蛋白（如截短的EGFR或iCaspase 9自杀系统）改造的清除标记同样也可能增加免疫原性的风险。为在CAR-T细胞产品中实现安全基因，许多研究人员选择将2A序列与CAR共表达，最近，包括基因编辑也被用来创建无转基因的自杀开关，这些方法相关免疫原性的风险都需要进一步的研究。基因编辑基因编辑增强CAR-T细胞的功能是目前热门的研究领域，如通过基因敲除破坏内源性免疫检查点蛋白的表达，从而提高CAR-T细胞的性能。此外，基因编辑也可用于通过消除细胞表面MHC的表达来逃避T细胞介导的抗CAR免疫，用于同种异体CAR-T细胞。基因编辑除了要避免脱靶效应意外，由CRISPR–Cas9系统引起的免疫原性相关风险，也可能导致T细胞介导的Cas9表达细胞的清除。然而，临床研究显示，瞬时CRISPR–Cas9递送系统并未影响异源TCR重定向T细胞的持久存在。因此，与组成性过度表达相反，瞬时表达可能是CAR-T细胞基因编辑的首选方法，值得进一步研究。异基因CAR-T细胞的免疫原性使用健康捐赠者的细胞制作现成的同种异体CAR-T细胞是一种非常有吸引力的方法，可能扩大这些细胞的临床适用性，确保及时可用性。然而，在这些CAR-T细胞上表达的非自身MHCs可能引起宿主源性的免疫反应，导致免疫介导的细胞清除。异基因CAR-T细胞可被患者的对外来主要MHC抗原具有特异反应性的T细胞靶向。即使是部分HLA匹配的供体，也可能由于多态性引起的微小抗原差异产生额外的免疫原性。有几种方法被用来产生MHC抗原表达减少的CAR-T细胞，从而使患者的治疗不受HLA差异的影响。通过直接编辑HLA位点或破坏B2M基因编码，有可能阻止CD8+T细胞的同种异体排斥反应。然而，由于T细胞活化引起MHCⅡ的上调，同种特异性CD4+T细胞介导的CAR-T细胞排斥反应也可能发生。通过敲除MHCⅡ基因的主要转录因子CIITA来消除MHCⅡ的表达，可以减轻这种排斥。这些方法对T细胞介导的排斥反应有一定的抑制作用，然而，矛盾的是，HLA分子的丢失使得异基因CAR-T细胞也容易被NK细胞杀伤。因此，人们开发出NK细胞抑制转基因来促进转基因细胞在免疫活性宿主中的持久性。例如，Gornalusse等人通过在人类多能干细胞中表达融合到B2M和诱饵抗原的非多态性HLA-E分子，开发出对CD8+T细胞和NK细胞的排斥具有抵抗力的细胞。其他策略还包括多重基因编辑、CD47过表达以及一种“同种免疫防御受体”的方法。此外，广泛的淋巴耗竭也可以降低立即发生同种异体排斥的风险。但是，这种方法可能由于持续的同种异体CAR-T细胞增殖而导致移植物抗宿主病（GvHD）的可能性。为了降低GvHD的风险，研究人员选择将CAR转移到病毒特异性T细胞中，从而产生更安全的产品，因为此类细胞的TCR不太可能具有同种异体反应。小结CAR-T细胞是目前治疗某些复发和/或难治性恶性血液病的重要手段。然而，CAR-T细胞具有免疫原性，可能影响CAR-T细胞治疗的效果。虽然在血液瘤中，通过清除内源性B细胞可以降低对CAR-T细胞免疫应答的风险，然而，针对非B细胞恶性肿瘤（如实体瘤）的CAR-T细胞可诱导T细胞和B细胞反应，从而增加免疫原性的风险。此外，开发提高CAR-T细胞安全性和/或功能性的技术，如自杀基因或细胞因子，也可能带来新的免疫原性风险，异基因供体来源的CAR-T细胞的出现和发展同样引起了人们对免疫原性问题的关注。现有的策略，通过替换人源化单链抗体或其他免疫原性较弱成分的CAR可能降低抗CAR免疫的风险，在临床上，加强淋巴耗竭对于减轻抗CAR免疫反应和促进CAR-T细胞的持久性仍然至关重要。因此，有必要在临床前和临床研究中纳入CAR相关免疫原性分析，以便对免疫原性反应及其影响进行详细研究，以确保CAR-T细胞在癌症患者治疗中的安全性和有效性。这些信息也会增加我们对免疫原性临床相关性的理解，并为未来CAR-T细胞策略的发展提供帮助。参考文献：1.  Immunogenicity of CAR T cells in cancer therapy.Nat Rev Clin Oncol. 2021 Jun;18(6):379-393.封面图来源：123rf点击阅读原文，查看更多精彩内容

Preclinical data with SC262, a HIP-modified CD22-directed allogeneic CAR T cell, further support completed IND submission Validation of novel and fully-human GPRC5D-specific CARs for the development of a HIP-modified allogeneic GPRC5D-directed CAR T cell therapy SEATTLE, Dec. 11, 2023 (GLOBE NEWSWIRE) -- Sana Biotechnology, Inc. (NASDAQ: SANA), a company focused on changing the possible for patients through engineered cells, today announced preclinical data supporting the anti-tumor and immune evasion capabilities of allogeneic CAR T cells engineered with Sana’s proprietary hypoimmune (HIP) technology were presented at the 65th American Society of Hematology (ASH) Annual Meeting in San Diego, CA. “These data, indicating that HIP-modified CAR T cells are consistently able to avoid detection by the immune system while retaining their functionality and eliciting an anti-tumor effect, add to our learnings about and the opportunities for our allogeneic CAR T cell platform,” said Terry Fry, MD, Sana’s Senior Vice President and Head of T Cell Therapeutics. “HIP-modified allogeneic CAR T cells remain well-tolerated in preclinical models. We look forward to initiating several additional clinical studies with our promising therapeutic candidates, with proof-of-concept data from multiple trials expected next year, including from SC291, our CD19-targeted HIP-modified CAR T cell therapy, and SC262. We also continue to develop our allogeneic CAR T cell pipeline, including our fully-human GPRC5D-targeted CAR T cell therapy.” On Sunday, December 10, abstract #3437 titled “Hypoimmune, Allogeneic CD22-Directed CAR T Cells That Evade Innate and Adaptive Immune Rejection for the Treatment of Large B Cell Lymphoma Patients That Are Relapsed/Refractory to CD19-Directed CAR T Cell Therapy” detailed preclinical data supporting the advancement of SC262, a CD22-directed HIP CAR T cell therapy, into human clinical studies. The results demonstrated that CD22 HIP CAR T cells evaded adaptive immune cell recognition and cytolysis through B2M and CIITA gene disruption and innate immune cell recognition through the overexpression of CD47. Furthermore, CD22 HIP CAR T cells elicited robust tumor control that produced cytokine/effector analytes and expanded in a dose- and antigen-dependent manner in vitro, with consistent effect across lots manufactured from different donors. CD22 HIP CAR T cells were well tolerated with no signs of graft-versus-host disease (GvHD). Sana submitted the investigational new drug (IND) application and intends to begin human testing of SC262 in early 2024. On Sunday, December 10, abstract #3290 titled “Development of a Novel, Allogeneic GPRC5D-Directed CAR for Treatment of Multiple Myeloma Patients” outlined preclinical data demonstrating the characterization and candidate selection of fully-human GPRC5D-specific CARs for use in combination with HIP technology to develop an allogeneic GPRC5D CAR T cell therapy. The data showed that candidate GPRC5D CARs elicited in vitro cytotoxicity and effector cytokine production that is comparable to clinically validated benchmark control CARs. Additionally, these GPRC5D CAR T cells controlled multiple myeloma tumor cells both in vitro and in vivo, demonstrating efficacy that is on par with clinical benchmark GPRC5D CAR T cells. About Hypoimmune PlatformSana’s hypoimmune platform is designed to create cells ex vivo that can evade the patient’s immune system to enable the transplant of allogeneic cells without the need for immunosuppression. We are applying the hypoimmune technology to both donor-derived allogeneic T cells, with the goal of making potent and persistent CAR T cells at scale, and pluripotent stem cells, which can then be differentiated into multiple cell types at scale. Preclinical data published in peer-reviewed journals demonstrate across a variety of cell types that these transplanted allogeneic cells are able to evade both the innate and adaptive arms of the immune system while retaining their activity. Our most advanced programs utilizing this platform include an allogeneic CAR T program targeting CD19+ cancers, an allogeneic CAR T program for B-cell mediated autoimmune diseases, an allogeneic CAR T program targeting CD22+ cancers, and stem-cell derived pancreatic islet cells for patients with type 1 diabetes. About Sana BiotechnologySana Biotechnology, Inc. is focused on creating and delivering engineered cells as medicines for patients. We share a vision of repairing and controlling genes, replacing missing or damaged cells, and making our therapies broadly available to patients. We are a passionate group of people working together to create an enduring company that changes how the world treats disease. Sana has operations in Seattle, Cambridge, South San Francisco, and Rochester. For more information about Sana Biotechnology, please visit https://sana.com/. Cautionary Note Regarding Forward-Looking StatementsThis press release contains forward-looking statements about Sana Biotechnology, Inc. (the “Company,” “we,” “us,” or “our”) within the meaning of the federal securities laws, including those related to the Company’s vision, progress, and business plans; expectations for its development programs, product candidates and technology platforms, including its pre-clinical, clinical and regulatory development plans and timing expectations, including with respect to the submission of IND for the SC262 program; the potential significance and impact of preclinical data regarding the HIP platform; expectations regarding the substance, timing, and scale of data from the company’s clinical trials; the ability of HIP-modified CAR T cells to consistently avoid detection by the immune system while retaining their functionality and eliciting an anti-tumor effect; the ability to use the HIP platform to create cells ex vivo that can evade a patient’s immune system and enable the transplant of allogeneic cells without the need for immunosuppression and the potential benefits associated therewith; and the ability to apply the HIP technology to donor-derived allogeneic T cells to make potent and persistent CAR T cells at scale and pluripotent stem cells, which can then be differentiated into multiple cell types at scale. All statements other than statements of historical facts contained in this press release, including, among others, statements regarding the Company’s strategy, expectations, cash runway and future financial condition, future operations, and prospects, are forward-looking statements. In some cases, you can identify forward-looking statements by terminology such as “aim,” “anticipate,” “assume,” “believe,” “contemplate,” “continue,” “could,” “design,” “due,” “estimate,” “expect,” “goal,” “intend,” “may,” “objective,” “plan,” “positioned,” “potential,” “predict,” “seek,” “should,” “target,” “will,” “would” and other similar expressions that are predictions of or indicate future events and future trends, or the negative of these terms or other comparable terminology. The Company has based these forward-looking statements largely on its current expectations, estimates, forecasts and projections about future events and financial trends that it believes may affect its financial condition, results of operations, business strategy and financial needs. In light of the significant uncertainties in these forward-looking statements, you should not rely upon forward-looking statements as predictions of future events. These statements are subject to risks and uncertainties that could cause the actual results to vary materially, including, among others, the risks inherent in drug development such as those associated with the initiation, cost, timing, progress and results of the Company’s current and future research and development programs, preclinical and clinical trials. For a detailed discussion of the risk factors that could affect the Company’s actual results, please refer to the risk factors identified in the Company’s SEC reports, including but not limited to its Quarterly Report on Form 10-Q dated November 8, 2023. Except as required by law, the Company undertakes no obligation to update publicly any forward-looking statements for any reason. Investor Relations & Media:Nicole Keithinvestor.relations@sana.commedia@sana.com

– Data presented at 65th ASH Annual Meeting show CNTY-101 was generally well tolerated at Dose Level 1 (100 million cells) in a high-risk, heavily pretreated R/R B-cell lymphoma patient – – Preliminary clinical data demonstrate six-month durable complete response in Dose Level 1 in a single patient following multiple cycles of CNTY-101 without lymphodepletion – – Pharmacokinetic data suggests CNTY-101 exposure may be maintained upon administration of additional cycles without lymphodepletion due to lack of observed allo-rejection – – Company to host conference call on Monday, December 11 at 7:30 AM PT/10:30 AM ET to review ASH data including additional clinical results from Dose Level 1 (100 million cells) and Dose Level 2 (300 million cells), as well as clinical plans for CNTY-101 in systemic lupus erythematosus – PHILADELPHIA, Dec. 09, 2023 (GLOBE NEWSWIRE) -- Century Therapeutics (NASDAQ: IPSC), an innovative biotechnology company developing induced pluripotent stem cell (iPSC)-derived cell therapies in immuno-oncology and autoimmune and inflammatory disease, today announced the presentation of initial clinical data from a single-patient case study which Century believes support the potential for a multi-dosing strategy for CAR iNK enabled by Allo-Evasion™ edits at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition, being held December 9-12 in San Diego. The poster, titled, “Multiple Doses of CNTY-101, an iPSC-Derived Allogeneic CD19 Targeting CAR-NK Product, are Safe and Result in Tumor Microenvironment Changes Associated with Response: A Case Study”, is available on the Scientific Resources page of the Company’s website. “We are thrilled that the initial clinical evidence for CNTY-101 provides support for the potential for Allo-Evasion™ to enable a multi-dosing regimen without the need for continued lymphodepletion. This is highly encouraging in advancing our goal to increase persistence of the cells during the treatment period and potentially lead to deeper and more durable responses,” said Brent Pfeiffenberger, Pharm.D., Chief Executive Officer of Century Therapeutics. “We look forward to advancing the study at both higher and more frequent doses of CNTY-101, and plan to present additional clinical data in mid-2024.” “As the first cell therapy product candidate engineered with six precision gene edits aimed at providing selectivity and persistence, CNTY-101 is positioned to potentially fill a high unmet need among heavily pretreated non-Hodgkin lymphoma patients,” said Krish Patel, M.D., Director of Lymphoma Program, Director of Hematologic Malignancies and Cellular Therapy, Swedish Cancer Institute, Seattle. “The encouraging initial data presented today from this patient who received low doses of CNTY-101 exhibits signals of persistence of CNTY-101 cells out of circulation and supports testing at higher doses. I look forward to the continuation of the study and to further investigating the full therapeutic potential of CNTY-101.” Data featured in a single-patient case study presented at ASH involves a 63-year-old patient with relapsed/refractory (R/R) progressive follicular lymphoma previously treated with four prior lines of therapy who was enrolled at Dose Level 1 (100 million cells). As of a data cutoff date of November 13, 2023, the patient has received seven 28-day cycles of a single infusion of CNTY-101 at Dose Level 1. Cycles one and two included three days of lymphodepletion (LD), whereas cycles three through seven were given with no LD. Interleukin-2 (IL-2) was administered for all cycles except for the first. The patient maintained a complete response with a duration of six months before subsequently progressing. Data from the single-patient case study indicated that CNTY-101 was generally well tolerated in this patient at Dose level 1 (100 million cells). No dose-limiting toxicities, cytokine release syndrome or immune effector cell–associated neurotoxicity syndrome were observed, and no adverse events related to treatment with CNTY-101 were detected in this patient, to date. Additionally, no concerted changes in inflammatory cytokines and mediators associated with cytokine release syndrome or neurotoxicity have been detected in this patient. Following administration of two cycles with and three cycles without LD, serum assessments from available data of the first five cycles of CNTY-101 treatment in this patient showed no evidence of functional pre-existing or induced humoral immunogenicity against CNTY-101. Importantly, tumor microenvironment initial analyses demonstrated a vigorous increase in T cells within 8 days of the 1st CNTY-101 cell infusion. Increases in proliferating cytotoxic T cells and TNFα and IFNγ-secreting cells were observed, suggestive of induction of adaptive immune responses within the tumor. Additionally, ddPCR analysis of CNTY-101 genomic DNA and cell-free DNA from Dose Level 1 patient (n=4) samples suggest that CNTY-101 cells were able to traffic out of circulation shortly after infusion and showed persistence in tissues for at least 3 days. In addition to the preliminary clinical data presented today, the Company will also present additional results from patients treated at Dose Level 1 (100 million cell dose), as well as preliminary data from three patients treated at Dose Level 2 (300 million cell dose) during a conference call and webcast on Monday, December 11 at 7:30 AM PT/10:30 AM ET. In addition, the Company will discuss its planned Phase 1 trial, including supporting preclinical data, for CNTY-101 in systemic lupus erythematosus, the Company’s first autoimmune and inflammatory disease indication. Conference Call and Webcast The live audio webcast and accompanying slides may be accessed through the Events & Presentations page in the Investors section of the Company's website. Alternatively, the conference call may be accessed through the following: Conference ID: century2023Domestic Dial-in Number: (800) 590-8290International Dial-in Number: (240) 690-8800 Live webcast: https://century-therapeutics-initial-clinical-data-call.open-exchange.net/ For those unable to participate in the conference call or webcast, a replay will be available on the Investors section of the Company's website at www.centurytx.com approximately 24 hours after the conference call and will be available for 90 days following the call. About Allo-Evasion™ Century’s proprietary Allo-Evasion™ technology is used to engineer cell therapy product candidates with the potential to evade identification by the host immune system so they can be dosed multiple times without rejection, enabling increased persistence of the cells during the treatment period and potentially leading to deeper and more durable responses. More specifically, Allo-Evasion™ 1.0 technology incorporates three gene edits designed to avoid recognition by patient/host CD8+ T cells, CD4+ T cells and NK cells. Knockout of beta-2-microglobulin or β2m, designed to prevent CD8+ T cell recognition, knock-out of the Class II Major Histocompatibility Complex Transactivator, or CIITA, designed to prevent CD4+ T cell recognition, and knock-in of the HLA-E gene, designed to enable higher expression of the HLA-E protein to prevent killing of CNTY-101 cells by host NK cells. Allo-Evasion™ technology may allow the implementation of more flexible and effective repeat dosing protocols for off-the-shelf product candidates. About ELiPSE-1 The Phase 1 ELiPSE-1 trial (NCT05336409) is intended to assess the safety, tolerability, pharmacokinetics, and preliminary efficacy of CNTY-101 in adult patients with relapsed or refractory CD19-positive B-cell lymphomas. All patients will receive an initial standard dose of conditioning chemotherapy consisting of cyclophosphamide (300 mg/m2) and fludarabine (30mg/m2) for 3 days. Schedule A of the trial includes a single-dose escalation of CNTY-101 and subcutaneous IL-2. Schedule B will evaluate a three-dose schedule per cycle of CNTY-101. Patients who demonstrate a clinical benefit are eligible for additional cycles of treatment with or without additional lymphodepletion. About CNTY-101 CNTY-101 is an investigational off-the-shelf immunotherapy product candidate that utilizes iPSC-derived natural killer (NK) cells with a CD19-directed chimeric antigen receptor (CAR) and includes Century’s core Allo-Evasion™ edits designed to overcome the three major pathways of host versus graft rejection - CD8+ T cells, CD4+ T cells and NK cells. In addition, the product candidate is engineered to express IL-15 to provide homeostatic cytokine support, which has been shown pre-clinically to improve functionality and persistence. Further, to potentially improve safety, the iNK cells were engineered with an EGFR safety switch, and proof-of-concept studies have demonstrated that the cells can be quickly eliminated by the administration of cetuximab, an antibody against EGFR approved by the U.S. Food and Drug Administration for certain cancers. Century is currently assessing CNTY-101 in patients with relapsed or refractory CD19-positive B-cell lymphomas in its Phase 1 ELiPSE-1 clinical trial and intends to initiate its second Phase 1 clinical trial assessing CNTY-101 in patients with moderate to severe systemic lupus erythematosus. About Century Therapeutics Century Therapeutics (NASDAQ: IPSC) is harnessing the power of adult stem cells to develop curative cell therapy products for cancer and autoimmune and inflammatory diseases that we believe will allow us to overcome the limitations of first-generation cell therapies. Our genetically engineered, iPSC-derived cell product candidates are designed to specifically target hematologic and solid tumor cancers, with a broadening application to autoimmune and inflammatory diseases. We are leveraging our expertise in cellular reprogramming, genetic engineering, and manufacturing to develop therapies with the potential to overcome many of the challenges inherent to cell therapy and provide a significant advantage over existing cell therapy technologies. We believe our commitment to developing off-the-shelf cell therapies will expand patient access and provide an unparalleled opportunity to advance the course of cancer and autoimmune and inflammatory disease care. For more information on Century Therapeutics please visit www.centurytx.com. Century Therapeutics Forward-Looking Statement This press release contains forward-looking statements within the meaning of, and made pursuant to the safe harbor provisions of, The Private Securities Litigation Reform Act of 1995. All statements contained in this press release, other than statements of historical facts or statements that relate to present facts or current conditions, including but not limited to, statements regarding our clinical development plans and timelines, are forward-looking statements. These statements involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance, or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements. In some cases, you can identify forward-looking statements by terms such as “may,” “might,” “will,” “should,” “expect,” “plan,” “aim,” “seek,” “anticipate,” “could,” “intend,” “target,” “project,” “contemplate,” “believe,” “estimate,” “predict,” “forecast,” “potential” or “continue” or the negative of these terms or other similar expressions. The forward-looking statements in this press release are only predictions. We have based these forward-looking statements largely on our current expectations and projections about future events and financial trends that we believe may affect our business, financial condition, and results of operations. These forward-looking statements speak only as of the date of this press release and are subject to a number of risks, uncertainties and assumptions, some of which cannot be predicted or quantified and some of which are beyond our control, including, among others: our ability to successfully advance our current and future product candidates through development activities, preclinical studies, and clinical trials; our dependence on the success of our lead product candidate, CNTY-101; the ability of CNTY-101 to be administered as part of a multi-dose strategy and to enable responses without lymphodepletion; uncertainties inherent in the results of preliminary data, pre-clinical studies and earlier-stage clinical trials, which may not be predictive of final results or the results of later-stage clinical trials; the timing of and our ability to initiate and successfully enroll the Phase 1 SLE trial; our ability to obtain FDA clearance of our future IND submissions and commence and complete clinical trials on expected timelines, or at all; our reliance on the maintenance of certain key collaborative relationships for the manufacturing and development of our product candidates; the timing, scope and likelihood of regulatory filings and approvals, including final regulatory approval of our product candidates; the impact of geopolitical issues, banking instability and inflation on our business and operations, supply chain and labor force; the performance of third parties in connection with the development of our product candidates, including third parties conducting our clinical trials as well as third-party suppliers and manufacturers; our ability to successfully commercialize our product candidates and develop sales and marketing capabilities, if our product candidates are approved; our ability to recruit and maintain key members of management and our ability to maintain and successfully enforce adequate intellectual property protection. These and other risks and uncertainties are described more fully in the “Risk Factors” section of our most recent filings with the Securities and Exchange Commission and available at www.sec.gov. You should not rely on these forward-looking statements as predictions of future events. The events and circumstances reflected in our forward-looking statements may not be achieved or occur, and actual results could differ materially from those projected in the forward-looking statements. Moreover, we operate in a dynamic industry and economy. New risk factors and uncertainties may emerge from time to time, and it is not possible for management to predict all risk factors and uncertainties that we may face. Except as required by applicable law, we do not plan to publicly update or revise any forward-looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise. For More Information: Investors/Media: Melissa Forst/Maghan Meyers – century@argotpartners.com