NKG2D CAR-NK cells(The Third Affiliated Hospital of Guangzhou Medical University)

在过去的十年中，CAR-T(嵌合抗原受体细胞疗法)已经成为一种有前途的免疫治疗方法来对抗癌症。这种方法由基因工程修饰的免疫细胞组成，表达一种表面受体，称为CAR，专门针对肿瘤细胞表面表达的抗原。在血液系统恶性肿瘤，如白血病、骨髓瘤和非霍奇金B细胞淋巴瘤中，CAR-T细胞疗法已显示出治疗化疗难治性患者的疗效。然而，这种疗法在实体瘤中的价值仍然不确定，并且受到几个障碍的限制，包括有限的肿瘤浸润能力，免疫抑制肿瘤微环境的存在，会产生一定的不良反应。随着研究的深入，越来越多的CAR细胞疗法如 CAR-NK(自然杀伤细胞)、CAR-M(巨噬细胞)，展现出应对实体肿瘤的疗效。本文综合讨论CAR-T、CAR-NK和CAR-M细胞在实体肿瘤中的新作用。并且比较了CAR-NK和CAR-M细胞相对于CAR-T细胞的优缺点。             前言癌症发病率和死亡率不断上升，包括手术、放疗和化疗在内的传统治疗方法存在重大缺陷，许多转移性或复发性疾病患者仍然面临比较差的治疗效果。在过去的十年中，基于分子医学和免疫肿瘤学的发展，各种靶向治疗有了很大的发展，使得精准医学的发展成为一种更特异性并且毒性更小的癌症治疗方法。抗肿瘤免疫疗法主要是通过调节免疫系统增强其识别和破坏恶性肿瘤细胞的能力，为癌症治疗提供了重大进展。一种广泛成功的抗肿瘤细胞免疫治疗方法包括工程免疫细胞表达能够识别肿瘤细胞表面表达的抗原并摧毁它们的细胞表面受体。随后，基因修饰的免疫细胞通过嵌合抗原受体(Chimeric Antigen Receptor, CAR)被重定向到肿瘤细胞。目前，已批准的CAR-T细胞治疗靶点主要是针对多发性骨髓瘤B细胞成熟抗原(BCMA)，以及针对各种淋巴细胞恶性肿瘤的B细胞抗原CD19。根据已发表的抗BCMA CAR-T细胞临床试验，61例复发/难治性多发性骨髓瘤患者的完全缓解率达到29%至60%。靶向CD19的CAR-T细胞可使高达85%的急性淋巴细胞白血病患者获得初始完全缓解，高达100%的难治性或复发性B细胞急性淋巴细胞白血病患者获得完全缓解。从实体瘤的角度来看，利用CAR-T细胞治疗实体肿瘤的临床试验正在进行中，包括胶质母细胞瘤、肺癌、肝癌、胃癌、肾癌、前列腺癌等。这种免疫治疗方法产生了有希望的临床结果。然而，它也显示出一些根本性的局限性，如细胞毒性T细胞难以浸润肿瘤，实体瘤细胞分泌的趋化因子异常导致T细胞募集不足到肿瘤部位，以及免疫抑制肿瘤微环境。此外，CAR-T细胞有一定副作用，包括，靶外肿瘤毒性和细胞因子释放综合征。此外，CAR-T细胞诱导的其他毒性，如肿瘤裂解综合征、神经毒性、细胞减少等也是该疗法的常见局限性。为了克服这些障碍，目前正在研究各种创新战略。此外，科学家们正在寻找替代的免疫效应细胞，这些细胞可以与CAR一起进行工程设计，用于抗肿瘤细胞免疫治疗。随着研究的深入，研发人员将研究重点从CAR-T扩展到CAR-NK和CAR-M细胞免疫治疗。本文就CART、CAR-NK和CAR-M细胞在实体瘤患者治疗中的临床应用现状、面临的挑战和前景进行了讨论。我们还强调了CAR-NK和CAR-M细胞相对于CAR-T细胞的潜在优势。          图1 CAT-CELL作用机制示意图CAR-T细胞在实体瘤中的应用以及挑战近年来，CAR修饰的T细胞在治疗B细胞白血病和淋巴瘤方面表现出良好的效果，证明了其抗癌治疗潜力。两种CAR-T细胞疗法Tisagenlecleucel和Axicabtagen-ciloleucel已被EMA和FDA批准用于治疗复发或难治性弥漫性大B细胞淋巴瘤患者。另外两种产品也被批准用于这些适应症:套膜淋巴瘤和，滤泡性淋巴瘤。这一成功在很大程度上是由于选择了靶标B细胞标记CD19，以不依赖MHC的方式产生针对恶性B细胞的T细胞免疫应答。这些在血液学恶性肿瘤治疗方面的重大突破，使得越来越多的研究人员尝试CAR-T细胞应用于实体肿瘤的治疗。如图一所示，目前有多种针对实体瘤的CAR-T疗法处于临床实验或者获批上市。图2 CAR-T针对实体瘤的常用靶点靶向HER2的CAR-T疗法：在一项I/ II期临床研究中，使用HER2-CAR-T细胞治疗19例HER2阳性肉瘤(16例骨肉瘤、1例原始神经外胚层肉瘤、1例尤因肉瘤和1例原纤维母细胞小圆细胞瘤)获得较好的临床实验结果。在本研究中，19例患者的中位总生存期为10.3个月 (从5.1个月到29.1个月)。大剂量CAR-T细胞治疗后，除1例患者出现高烧外，未观察到任何不良事件。此外，一项针对17例胶质母细胞瘤患者的HER2特异性CAR-T细胞治疗的I期研究报告了对CAR-T细胞给予剂量的巨大耐受性，治疗后8例患者和诊断后24.5个月的中位总生存期(OS)为11.1个月。靶向GD2的CAR-T疗法：在神经母细胞瘤细胞中，GD2是高表达的，可能被认为是CAR-T细胞的潜在靶点。一项评估GD-2 CAR-T细胞对11例神经母细胞瘤患者疗效的I期临床试验(NCT00085930)显示，3例患者完全缓解。靶向ROR1的CAR-T疗法：ROR1也是CAR-T细胞治疗的候选靶点，它在许多淋巴和上皮恶性肿瘤表面表达。一项I临床实验结果表明，靶向ROR1的CAR-T疗法具有较好的安全性。靶向EGFR的CAR-T疗法：表皮生长因子受体（EGFR）在实体瘤的发展和进展中起着重要作用，并已成为不同类型癌症的重要治疗靶点，如非小细胞肺癌、乳腺癌、胃食管癌和结直肠癌。此外，已经对靶向EGFR的CAR-T细胞进行了许多临床试验，用于治疗EGFR阳性的实体瘤。对11例EGFR+难治/复发非小细胞肺癌（NSCLC）患者进行EGFR-CAR-T细胞治疗的一期临床试验表明，2例患者获得部分缓解，5例患者病情稳定2至8个月，无严重毒性。靶向CEA的CAR-T疗法：已知高水平的癌胚抗原（CEA）与癌症预后不良有关。因此，CEA已成为治疗肺癌、乳腺癌、胰腺癌和胃癌的靶向药物，被认为是最有希望治疗结直肠癌（CRC）的靶点之一。一项针对转移性CRC中表达的CEA的CAR-T细胞治疗的I期递增剂量试验报告称，10名患者中有7名病情稳定，持续时间长达30周，2名患者肿瘤缩小，无不良事件。靶向CD133的CAR-T疗法：CD133被广泛用作鉴定CRC干细胞和内皮祖细胞的标志物。它还可用于预测CRC的肿瘤进展、患者生存率和放化疗抵抗，是各种肿瘤类型中癌症干细胞（CSC）最具特征性的标记物之一，包括肝细胞癌（HCC）。在一项I/II期临床试验中，对21名晚期肝细胞癌患者给予CD133 CAR-T细胞。这项研究证明了抗肿瘤的疗效和较低的治疗相关毒性。在21名可评估的患者中，1例出现部分反应，14例病情稳定2至16.3个月，6例在给予CAR-T细胞后病情进展。只有4名患者出现3级高胆红素血症，2名患者出现三级贫血，无其他严重不良事件。靶向的CAR-T疗法：Claudin18.2是Claudin-18的一种胃特异性亚型，在70%的原发性胃癌及其转移中表达。它被认为是治疗这些恶性肿瘤的潜在靶点。CT041是一种抗CLDN18.2 CAR-T细胞产品，已获得美国食品药品监督管理局的研究新药（IND）批准，用于CLDN18.2分泌型胃、胰腺和胃食管交界腺癌患者。IND清除率得到了一项I期试验（NCT03874897）的支持，该试验发现Claudin18.2 CAR-T细胞在癌症患者中的总有效率和疾病控制率分别为57.1%和75.0%，6个月的总生存率为81.2%。未报告严重不良事件。CAR-T疗法面临的挑战：CAR-T细胞治疗实体瘤的主要挑战包括识别真正特异性的肿瘤抗原作为靶点，克服肿瘤抗原逃逸，提高CAR-T细胞对肿瘤的浸润和扩增，以及它们在敌对肿瘤微环境中的持久性和功能。CAR-NK细胞在实体瘤中的应用考虑到CAR-T细胞的缺点，有必要研究用于CAR治疗的其他免疫细胞，由于NK细胞具有非MHC限制性识别、较强浸润肿瘤组织的能力、细胞溶解能力、和较小的毒副作。因此，CAR-NK细胞可以被认为是治疗实体瘤的潜在有效手段。包括到目前为止，只有少数临床研究评估了基于NK92、PB-NK和UCB-NK的CAR-NK细胞产物，对一些常见的肿瘤靶点如ROBO1、NKG2D、MSLN、HER2和MUC1的作用。MUC-1特异性CAR-NK细胞被设想用于多发复发或难治性实体瘤治疗。在这项研究中，在8名可评估的患者中，有7名患者病情稳定，无严重不良事件。此外，一项I期临床试验研究了NKG2D CAR-NK92细胞治疗复发/难治性实体瘤的效果。目前，一项I期临床试验正在招募转移性实体瘤患者，以评估NKG2DL靶向CAR-NK细胞的安全性。CAR-M细胞在实体瘤中的应用目前，持续的研究正试图确定靶向实体瘤的理想CAR细胞类型。巨噬细胞由于其吞噬功能、抗原呈递和对肿瘤微环境的自然渗透，最近已成为治疗实体瘤的竞争候选物。与CAR-NK类似，CAR-M可以从不同的来源产生，包括外周血、iPSC和人类白血病单核细胞系THP-1。PBMC衍生的M1巨噬细胞的特征是其重要的促炎因子产生，如IL-8、IL-6和TNF-α，以及炎性表面标志物的显著表达，如钠尿肽受体（NPR）、CD14和CD68。iPSCs可被诱导为表达CAR的巨噬细胞（CAR-IMAC），发挥先天免疫功能，如M2表型以抗原依赖的方式重新极化为促炎M1，分泌免疫相关细胞因子，以及吞噬作用和抗肿瘤能力。此外，THP-1细胞在受到脂多糖（LPS）和IFN-γ刺激后可以产生M1巨噬细胞，并且易于培养和分化为巨噬细胞。总之，与CAR-T细胞不同，CAR-M可以使用几种可靠的来源产生。作为一个额外的优势，CAR-M的GvHD风险较低。因此，CAR-M方法可能是一种有吸引力的实体瘤异基因细胞免疫疗法。增强CAR细胞功能的潜在联用疗法如图三所示，CAR-T细胞可以与化疗、放疗、溶瘤病毒以及免疫检查点抑制剂联用来增加疗效。图3 CAR-T治疗与其他疗法潜在联用治疗方案联合化疗当以低剂量给药时，化疗发挥免疫调节作用；它促进树突细胞活化和肿瘤抗原向CAR-T细胞呈递，抑制性免疫细胞，导致CAR-T细胞的持久性增加，并通过促进颗粒酶B渗透到肿瘤细胞中使肿瘤细胞对CAR-T细胞活性敏感。最近有研究表明化疗与CAR-T细胞治疗相结合具有积极作用。这种联合治疗可以解决CAR-T细胞肿瘤转移到TME的问题，从而产生更明显的抑瘤反应，并增加肿瘤排斥反应率，从而提高生存率。联合放疗使用：放射治疗可以通过凋亡和坏死直接杀死癌症细胞，从而诱导树突状细胞成熟和活化，并促进肿瘤抗原的提呈。辐射后，损伤相关分子模式（DAMPS）和INF-γ被释放，导致CAR-T细胞向肿瘤的迁移和浸润增加，因此，CAR-T细胞治疗与放射治疗相结合发挥协同抗肿瘤作用。联合溶瘤病毒使用：另一种组合策略是CAR-T细胞与溶瘤病毒的组合。这种组合克服了限制CAR-T细胞单独治疗疗效的挑战。首先，病毒可以突破肿瘤细胞，这对CAR-T细胞治疗来说是一项艰巨的任务。其次，溶瘤病毒可以通过破坏一些实体瘤用来逃避免疫系统攻击的分子屏障来诱导肿瘤消退。这种作用可以增强CAR-T细胞向肿瘤部位的浸润。第三，溶瘤病毒使免疫抑制TME恢复到促炎环境，导致CAR-T细胞的增殖和存活增加。联合PD-1使用策略：研究广泛表明，被称为免疫检查点抑制剂(ICIs)的PD-1阻断抗体可以重新激活CTL的抗肿瘤功能。CAR与ICIs的结合显示出令人鼓舞的结果。有趣的是，PD-1阻断CAR-T细胞自身分泌的抗体可竞争性地与PD-1结合，增强CAR-T细胞的增殖和细胞毒性。总结与展望近年来，CAR-T细胞治疗实体瘤的临床发展取得了巨大的进展。然而，CAR-T细胞治疗实体瘤面临的一些挑战与肿瘤微环境有关，如缺乏肿瘤特异性抗原、CAR-T细胞运输效率低、迁移到肿瘤部位以及存在免疫抑制肿瘤微环境。其他主要挑战与CAR-T细胞直接相关，包括“非肿瘤”毒性等。这些缺陷可以使用CAR-NK以及CAR-M细胞疗法来尝试替代。CAR-NK细胞疗法也已经在临床前得到了很好的研究并转化为临床应用。事实上，NK细胞释放的细胞因子降低了CRS和神经毒性的风险。此外，CAR-NK细胞可以从不同的来源产生，其异体反应性风险较低，并且可以通过CAR依赖和CAR独立的方式攻击肿瘤，这被认为是NK细胞的独特优势。然而，CAR-NK细胞也观察到与CAR-T细胞相关的一些其他挑战，包括浸润肿瘤组织并抵抗其免疫抑制微环境。CAR-M细胞介导疗法为当前CAR -T细胞疗法面临的挑战提供了解决策略，通过结合先天免疫系统和适应性免疫系统，从而对肿瘤发起多管齐下的攻击。最近的研究结果强调了修饰或未修饰巨噬细胞与T细胞或NK细胞相互作用在肿瘤消退中的重要性。考虑到这些优势，我们建议CAR-M与CAR-NK细胞或CAR-T细胞联合使用(图四)，以增强其抗肿瘤效果。研究人员目前正在寻求通过使用包括人工智能(AI)在内的各种策略来提高car细胞治疗的疗效，这可能有助于克服与CAR细胞治疗相关的许多障碍。图4 CAR-T、CAR-NK、CAR-M联用策略参考文献[1] Maalej et al. CAR-cell therapy in the era of solid tumor treatment: current challenges and emerging therapeutic advances [J] Molecular Cancer, (2023) 22:20.https://doi.org/1 0.1186/s 12943-023-01723-z[2] World Health Organization (WHO) Cancer [https:// www. who. int/ news- room/ fact- sheets/ detail/ cancer[3] Orzetti S, Tommasi F , Bertola A, Bortolin G, Caccin E, Cecco S, et al. Genetic Therapy and Molecular Targeted Therapy in Oncology: Safety, Pharmacovigilance, and Perspectives for Research and Clinical Practice. Int J Mol Sci. 2022;23:3012.[4] Fang F , Xie S, Chen M, Li Y, Yue J, Ma J, et al. Advances in NK cell production. Cell Mol Immunol. 2022;19:460–81识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

– Preclinical data supports SENTI-202 as a potential first-in-class logic gated CAR-NK cell therapy; remains on track for IND submission in 2H 2023 – – Additional data presented on SENTI-301A and crIL-15 support Senti’s development of gene circuit enhanced CAR-NK programs for multiple cancer indications – SOUTH SAN FRANCISCO, Calif., April 17, 2023 (GLOBE NEWSWIRE) -- Senti Biosciences Inc. (Nasdaq: SNTI) (“Senti Bio”), a biotechnology company innovating next-generation cell and gene therapies using its proprietary gene circuit platform, today announced the presentation of preclinical data from multiple wholly-owned pipeline programs at the American Association for Cancer Research (AACR) Annual Meeting being held April 14-19, 2023, in Orlando, Florida. Senti Bio is advancing a pipeline of gene circuit-enabled chimeric antigen receptor natural killer (CAR-NK) cell therapies for the treatment of liquid and solid tumors. “We are excited to share strong preclinical data on SENTI-202 as the program advances towards the clinic,” said Tim Lu, MD, PhD, Chief Executive Officer and Co-Founder of Senti Bio. “The data presented at AACR from multiple programs continue to support the pro our gene circuit programs as next generation cell therapies that aim to circumvent resistance mechanisms and safely drive enhanced and durable responses across blood cancers and solid tumors.” The Company’s three posters will be part of AACR’s “Clinical Research Excluding Trials” and “Immunology” sessions today, April 17, from 1:30 p.m. to 5:00 p.m. ET. The posters are also available on the Scientific Presentations & Publications page on the Senti Bio website. Presentation Title: Preclinical development of SENTI-202, an off-the-shelf logic gated CAR-NK cell therapy, for the treatment of CD33/FLT3+ hematologic malignancies including AML Location: Section 37 SENTI-202 CAR-NK cells, which include a CD33 and/or FLT3 targeting activating CAR, showed increased cytotoxic activity, serial killing, and cytokine production compared to unengineered NK cells within in vitro and in vivo AML models, as well as killing of primary tumor-derived samples from AML and MDS patients. SENTI-202, which has the endomucin (EMCN) inhibitory CAR as part of its gene circuit, preferentially protected healthy hematopoietic cells (HSCs) compared to CAR-NK cells without the iCAR. The colony-forming potential of hematopoietic stem and progenitor cells (HSPCs) was preserved after exposure to SENTI-202. SENTI-202, which expressescrIL-15, showed increased persistence compared to unengineered NK cells. Senti Bio remains on track to Investigational New Drug (IND) application for SENTI-202 in patients with CD33 and/or FLT3 expressing hematologic malignancies in the second half of 2023 with the planned Phase 1 trial focusing on relapsed/refractory patients including AML. Presentation Title: Off-the-Shelf CAR-NK cells engineered to express crIL-15 exhibit enhanced persistence and anti-tumor activity Location: Section 22 Inclusion of crIL15 to gene circuits resulted in enhanced NK cell persistence and tumor killing activity in CAR-NK cells as well as activation of neighboring T cells and NK cells. Additionally, wide biodistribution and prolonged persistence of NK cells engineered with crIL-15 were observed. Importantly, in AML xenograft models, data showed CAR-NK cells engineered with crIL-15 technology significantly reduced tumor burden and prolonged mouse survival compared to unengineered NK cells. These data demonstrate that NK cells engineered to co-express CAR and crIL-15 can improve persistence and anti-tumor activity of CAR-NK cells. Presentation Title: SENTI-301A, an off-the-shelf multi-armed preclinical CAR-NK cell therapy for the treatment of GPC3 expressing tumors Location: Section 22 SENTI-301A demonstrated CAR-driven killing and antigen specificity against target cell lines, and showed significantly higher in vitro cytotoxic activity against both HCC and non-HCC GPC3-expressing cell lines. SENTI-301A exhibited increased crIL-15-driven persistence and cytotoxicity compared to unengineered NK cells. SENTI-301A demonstrated tumor infiltration and enhanced persistence, antitumor function, and increased median survival compared to unengineered NK cells in HCC xenograft models. About Senti Bio Our mission is to create a new generation of smarter medicines that outmaneuver complex diseases using novel and unprecedented approaches. To accomplish this, we are building a synthetic biology platform that may enable us to program next-generation cell and gene therapies with what we refer to as Gene Circuits. These novel and proprietary Gene Circuits are designed to reprogram cells with biological logic to sense inputs, compute decisions and respond to their cellular environments. We aim to design Gene Circuits to improve the intelligence of cell and gene therapies in order to enhance their therapeutic effectiveness, precision, and durability against a broad range of diseases that conventional medicines do not readily address. Our synthetic biology platform utilizes off-the-shelf chimeric antigen receptor natural killer (CAR-NK) cells, outfitted with Gene Circuit technologies, to target particularly challenging liquid and solid tumor oncology indications. Our lead product candidate is SENTI-202 for the treatment of CD33 and/or FLT3 expressing hematologic malignancies, such as AML and MDS. Additionally, our SENTI-401 program is being designed for the treatment of colorectal cancer (CRC) and other CEA-positive cancers. We have also demonstrated in preclinical studies the potential breadth of our Gene Circuits in other modalities, including T cells, AAVs and iPSCs, and diseases outside of oncology; and we have executed partnerships with Spark Therapeutics and BlueRock Therapeutics to advance these capabilities. Forward-Looking Statements This press release and document contain certain statements that are not historical facts and are considered forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. These forward-looking statements generally are identified by the words “believe,” “could,” “predict,” “continue,” “ongoing,” “project,” “expect,” “anticipate,” “estimate,” “intend,” “strategy,” “future,” “opportunity,” “plan,” “may,” “should,” “will,” “would,” “will be,” “will continue,” “will likely result,” “forecast,” “seek,” “target” and similar expressions that predict or indicate future events or trends or that are not statements of historical matters. Forward-looking statements are predictions, projections, and other statements about future events that are based on current expectations of Senti Bio’s management and assumptions, whether or not identified in this document, and, as a result, are subject to risks and uncertainties. Forward-looking statements include, but are not limited to, statements regarding Senti Bio’s development platform and potential therapies, its presentations, and its plans to submit an IND application for SENTI-202 and the timing of such submission. , These forward-looking statements are provided for illustrative purposes only and are not intended to serve as and must not be relied on by any investor as, a guarantee, an assurance, a prediction, or a definitive statement of fact or probability. Actual events and circumstances are difficult or impossible to predict and will differ from assumptions. Many actual events and circumstances are beyond the control of Senti Bio. Many factors could cause actual future results to differ materially from the forward-looking statements in this document, including but not limited to: the risk that results observed in studies of the Company’s product candidates, including preclinical studies and future clinical trials of any of its product candidates, will not be observed in ongoing or future studies involving these product candidates, the risk that Senti Bio may cease or delay development of any of its product candidates for a variety of reasons (including requirements that may be imposed by regulatory authorities on the initiation or conduct of clinical trials, the amount and type of data to be generated, or otherwise to support regulatory approval, difficulties or delays in subject enrollment and continuation of clinical trials, difficulties in manufacturing or supplying Senti Bio’s product candidates for preclinical and clinical testing, and any adverse events or other negative results that may be observed during preclinical or clinical development), Senti Bio’s ability to obtain, maintain, and protect its intellectual property, Senti Bio’s dependence on third parties for development and manufacture of product candidates, Senti Bio’s ability to manage expenses and to obtain additional funding when needed to support its business activities and establish and maintain strategic business alliances and new business initiatives, the impacts of macroeconomic and geopolitical events, including changing conditions from the COVID-19 pandemic, the hostilities in Ukraine, increasing rates of inflation and rising interest rates on business operations and expectation, and the risk that Senti Bio’s product candidates may not have beneficial attributes or may cause other unanticipated adverse effects. The foregoing list of factors is not exhaustive. You should carefully consider the foregoing factors and the other risks and uncertainties described in the “Risk Factors” section of Senti Bio’s Annual Report on Form 10-K, filed with the SEC on March 22, 2023, and other documents filed by Senti Bio from time to time with the SEC. These filings identify and address other important risks and uncertainties that could cause actual events and results to differ materially from those contained in the forward-looking statements in this document. There may be additional risks that Senti Bio does not presently know, or that Senti Bio currently believes are immaterial that could also cause actual results to differ from those contained in the forward-looking statements in this document. Forward-looking statements speak only as of the date they are made. Senti Bio anticipates that subsequent events and developments may cause Senti Bio’s assessments to change. Except as required by law, Senti Bio assumes no obligation to update publicly any forward-looking statements, whether as a result of new information, future events, or otherwise. Availability of Other Information About Senti Biosciences, Inc. For more information, please visit the Senti Bio website at or follow Senti Bio on Linkedin (Senti Biosciences). Investors and others should note that we communicate with our investors and the public using our company website ( ), including, but not limited to, company disclosures, investor presentations and FAQs, Securities and Exchange Commission filings, press releases, public conference call transcripts and webcast transcripts, as well as on social media. The information that we post on our website or on social media could be deemed to be material information. As a result, we encourage investors, the media and others interested to review the information that we post there on a regular basis. The contents of our website or social media shall not be deemed incorporated by reference in any filing under the Securities Act of 1933, as amended. Find more information at sentibio.com Follow us on LinkedIn and Twitter Investor Contact: investors@sentibio.com Media Contact: Kelli Perkins, kelli@redhousecomms.com