UCART-22

CD19 CAR-T细胞疗法推动了血液瘤肿瘤治疗范式的转变，不过由于抗原逃逸和低持久性，仍有一部分患者在治疗后复发，同时，降低成本也是基于病毒载体CAR-T细胞疗法的一个重要挑战。一篇名为“Manufacturing CD20/CD19-targeted iCasp9 regulatable CAR-TSCM cells using a Quantum pBac-based CAR-T engineering system”的文章报道了利用基于piggyBac转座子的载体 Quantum pBac（qPB），开发了一种无病毒的细胞工程系统，用于开发和生产多重CAR-T疗法。 研究人员将携带iCasp9、CD20scFv和CD19scFv的转座子微环和qPBase质粒递送到激活的T细胞中，同时使用无血清CAR-T细胞培养补充物Quantum Booster（qBT），促进CAR-T细胞的增殖，同时保持干细胞，提升了CD4+和CD8+T细胞群体中CD45RA+CD62L+CD95+TSCM细胞的高百分比。基于此产生的，包含识别CD20和CD19的结合域以及由EFlu启动子驱动的iCasp9自杀基因的CARiC9-20/19 CAR-T细胞。在小鼠模型中，CARiC9-20/19 CAR-T细胞显示出增强的抗肿瘤效果，且可通过iCasp9自杀基因安全控制，小鼠的存活时间显著延长，特别是在高剂量组中，CAR-T细胞的治疗导致肿瘤完全清除，并且小鼠在整个试验期间均未复发。 研究者进一步在NCI-N87胃癌模型中评估了qPB系统生产的CAR-T细胞的抗肿瘤效果，与对照组相比，qPB系统生产的CAR-T细胞显著抑制了肿瘤的生长，并在试验的第17天实现了肿瘤的完全清除。而使用病毒载体（如慢病毒）生产的CAR-T细胞在相同条件下未能完全清除肿瘤。 整体而言，本研究展示了利用qPB系统制造CAR-TSCM细胞的可行性，这为生成高效、持久的CAR-T细胞疗法提供了一种新的策略。不过这一研究也存在一些局限性，仅在有限的小鼠模型中进行了体内实验，未来的研究需要在更大规模的动物模型以及人类临床试验中进一步验证CAR-T SCM细胞的疗效和安全性。 这一研究报告的亮点主要是在于利用了非病毒载体手段，并结合了双靶点能够有效避免肿瘤逃逸，同时加入了自杀基因，进一步增强了该候选产品的安全性。对CAR-T细胞疗法的多样化改造一直是业内努力的方向。近日，同样是利用非病毒手段改造CAR-T的企业Cellectis在Molecular Therapy上发表了一篇文章，展示了TALEN介导的基因编辑的能力，以设计双CAR靶向CAR-T细胞疗法。 TALEN（图片来源：官网） TALEN是基于一类衍生自转录激活子样效应物（TALE）的蛋白质，TALE是一种高度特异性的DNA结合蛋白，具有33或34个氨基酸重复序列。除了氨基酸位置12和13处的重复可变二残基（RVD）外，每个重复都是高度保守的。RVD决定了TALE将结合的DNA序列。TALE重复序列和相应的DNA序列之间简单的一一对应关系使得组装重复序列以识别新的DNA序列的过程变得简单。 这些TALE可以与DNA核酸酶FokI的催化结构域融合，产生转录激活剂样效应核酸酶（TALEN）。由此产生的TALEN构建体具有高特异性和高活性，有效地产生了工程序列特异性核酸酶，仅在预先选择的位点结合和切割DNA序列。与CRISPR/Cas9不同，TALEN可以靶向基因组内任何需要的序列，无PAM位点限制，且精确简单。 Cellectis提出了一种创新的CAR-T细胞工程策略——同种异体“Smart CAR-T”，能够表达组成型CAR，靶向实体瘤中的成纤维细胞激活蛋白（FAP），FAP在大多数成人组织中的表达量较低，主要表达于间质中的癌症相关成纤维细胞（CAF）细胞，也在一些肿瘤细胞如肉瘤、间皮瘤和食管等上皮性肿瘤中表达。同时，在TCR信号诱导基因座（如 PDCD1）处特异性表达肿瘤相关抗原（TAA） ，如间皮素。FAP CAR介导的CAF靶向诱导间皮素CAR的表达，建立对双抗原感应敏感的IF/THEN门控回路。该细胞可有效靶向免疫治疗顽固性实体瘤，同时降低潜在的安全风险。 同种异体“Smart CAR-T”（图片来源：参考资料2） 值得一提的是，Cellectis还开发了多款同种异体细胞疗法。UCART22是基于基因编辑技术TALEN和Cellectis开创性的电穿孔系统PulseAgile开发的同种异体基因编辑CAR-T疗法，靶向CD22（90%以上的B-ALL患者细胞能够表达CD22）。据公司官方称，UCART22是目前开发用于治疗R/R B-ALL的疗法中最先进的同种异体CAR-T疗法。目前，该候选产品已经完成首例患者给药，正在进行1期临床试验。 在研管线（图片来源：官网） UCART123是同种异体的基因编辑CAR-T疗法，靶向CD123，其利用TALEN敲除了TCRαβ，最大限度了地减少了GvHD发生的可能性，用于治疗AML。此前公布的数据显示，在15名患者中有4名患者观察到了UCART123抗肿瘤活性的证据，有25%的患者获得有意义的反应。目前，该候选产品正在处于临床1期研究阶段。 这家企业还获得了阿斯利康的青睐，将共同合作加速多达10项的下一代细胞与基因疗法开发，将主要专注于医疗需求显著未得到满足的领域，包括肿瘤、免疫学和罕见病等领域。根据协议，Cellectis将可能获得高达2.45亿美元款项。 总结  通过非病毒载体如Quantum pBac系统和TALEN基因编辑技术，加之双靶点、双CAR设计，科学家们正在不断推动CAR-T细胞疗法的前沿发展，不仅有望提高治疗效率与持久性，还增强了安全性与灵活性。 未来，随着更多体内外实验及临床研究的深入，我们有望看到这些新型CAR-T细胞疗法在更大规模的患者群体中验证其疗效与安全性。同时，随着技术的不断成熟与成本的进一步降低，CAR-T细胞疗法将更加普及，惠及更多患者。此外，与大型药企如阿斯利康的合作，将加速这些创新疗法的研发与商业化进程，推动整个细胞与基因治疗领域的快速发展，为解决当前医疗领域未满足的需求提供强有力的支持。 参考资料： 1.Chang PS, Chen YC, Hua WK, et al. Manufacturing CD20/CD19-targeted iCasp9 regulatable CAR-TSCM cells using a Quantum pBac-based CAR-T engineering system. PLoS One. 2024;19(8):e0309245. Published 2024 Aug 27. doi:10.1371/journal.pone.0309245 2.https://www.sciencedirect.com/science/article/pii/S1525001624005409?utm_campaign=STMJ_219742_AUTH_SERV_PA&utm_medium=email&utm_acid=300123771&SIS_ID=&dgcid=STMJ_219742_AUTH_SERV_PA&CMX_ID=&utm_in=DM500444&utm_source=AC_ 3.企业官网 封面图来源：123rf 版权声明/免责声明 本文为授权转载文章。 本文仅作信息交流之目的，不提供任何商用、医用、投资用建议。 文中图片、视频、字体、音乐等素材或为药时代购买的授权正版作品，或来自微信公共图片库，或取自公司官网/网络，部分素材根据CC0协议使用，版权归拥有者，药时代尽力注明来源。 如有任何问题，请与我们联系。 衷心感谢! 药时代官方网站:www.drugtimes.cn 联系方式: 电话:13651980212 微信:27674131 邮箱:contact@drugtimes.cn 尿路上皮癌治疗进入ADC时代！首个Nectin-4 ADC国内获批后，一线治疗也不远了 开卷！礼来推出替尔泊肽半价款 赛诺菲流感疫苗紧急召回，国内疫苗股涨停！ 点击这里，发现价值信息！

ODD and RPDD granted by the FDA and ODD granted by the European Commission to UCART22 for the treatment of ALLODD granted by the FDA to CLLS52 (alemtuzumab) for ALL treatmentCash position of $273 million as of June 30, 20241; cash runway projection into 2026 NEW YORK, Aug. 06, 2024 (GLOBE NEWSWIRE) -- Cellectis (the “Company”) (Euronext Growth: ALCLS - NASDAQ: CLLS), a clinical-stage biotechnology company using its pioneering gene editing platform to develop life-saving cell and gene therapies, today provided business updates and reported financial results for the six-month period ending June 30, 2024. "Over the past months, we have achieved a significant milestone with the granting of ODD designations by the Food and Drug Administration and the European Commission, complemented by the FDA’S Rare Pediatric Disease Designation. We have overcome major challenges, which reflects our ongoing commitment to innovation. Driven by an unwavering belief in our ability to revolutionize the healthcare field, we continue our pursuit of advancement with the confidence that our work will lead to the launch of a life-saving drug product. Our determination is the engine of our future success” said André Choulika, Ph.D., Chief Executive Officer at Cellectis. ________________________ 1 Cash position includes cash, cash equivalents, restricted cash and fixed-term deposits classified as current financial assets. Restricted cash was $5 million as of June 30, 2024. Fixed-term deposits classified as current financial assets were $119 million as of June 30, 2024. Pipeline Highlights UCART Clinical Programs On June 4, 2024, Cellectis received Orphan Drug Designation (ODD) from the European Commission (EC) for UCART22, for the treatment of acute lymphoblastic leukemia (ALL). The Orphan Drug Designation in the European Union is granted by the EC based on a positive opinion issued by the European Medicines Agency (EMA) Committee for Orphan Medicinal Products. This designation may allow certain regulatory, financial, and commercial incentives to develop medicines for rare diseases where there are no satisfactory treatment options.On July 25, 2024, the FDA designated UCART22 as a drug for a Rare Pediatric Disease (RPDD). This designation may allow to obtain a “Priority Review Voucher” at the time of Biologics License Application (BLA). The FDA also granted ODD to UCART22 product candidate for ALL treatment. Receiving ODD by the FDA may help to expedite and reduce the cost of development, approval, and commercialization of a therapeutic agent.Patients with relapsed/refractory ALL have limited, if any, treatment options, especially for those who have failed prior CD19 directed CAR T-cell therapy and allogeneic stem cell transplant. These designations for UCART22 mark an important step towards developing allogeneic CAR T products that would be readily available for all patients.On August 1, 2024, the FDA granted ODD to Cellectis’ CLLS52 (alemtuzumab), an Investigational Medicinal Product (IMP) used as part of the lymphodepletion regimen associated with UCART22, evaluated in the BALLI-01 clinical trial. The importance of adding alemtuzumab to the lymphodepletion regimen has been demonstrated in Cellectis’ BALLI-01 study, where the addition of this lymphodepletion agent to the fludarabine and cyclophosphamide regimen was associated with sustained lymphodepletion and significantly higher UCART22 cell expansion allowing for greater clinical activity.Cellectis continues to focus on the enrollment of patients in the BALLI-01 study, evaluating UCART22 in relapsed or refractory B-cell acute lymphoblastic leukemia, in the NatHaLi-01 study, evaluating UCART20x22 in relapsed or refractory B-cell non-Hodgkin lymphoma, and in the AMELI-01 study, evaluating UCART123 in relapsed or refractory acute myeloid leukemia. We expect to provide updates in the advancements of BALLI-01 until the end of the year 2024. Research Data & Preclinical Programs Non-viral Gene Therapy Approach for Sickle Cell Disease On June 12, 2024, Cellectis announces the publication of a scientific article in Nature Communications.Cellectis leverages TALEN® technology and a non-viral gene repair template delivery to develop a clinically relevant gene editing process in hematopoietic stem and progenitor cells (HSPCs). This process enables efficient HBB gene correction with high precision, specificity and minimal genomic adverse events. Applying this HBB gene correction process to SCD patient-HSPCs results in over 50% expression of normal adult hemoglobin in mature red blood cells and in the correction of sickle phenotype, without inducing β-thalassemic phenotype. Edited HSPCs engraft efficiently in an immunodeficient murine model and maintain clinically relevant levels of HBB gene correction events. This comprehensive preclinical data package sets the stage for the therapeutic application of autologous gene corrected HSPCs to address SCD. Partnerships Licensed Allogeneic CAR T-cell Development Programs Anti-CD19 Programs Allogene’s investigational oncology products utilize Cellectis technologies. We have initiated an arbitration proceeding through the Centre de Médiation et d'Arbitrage de Paris. We are requesting that the arbitral tribunal issue a decision (i) terminating the Servier License Agreement, and (ii) requiring Servier to pay us fair financial compensation for losses incurred due to the lack of development of the licensed products and for non-payment of milestone payments for milestones that have been achieved under the Servier License Agreement. In May 2024, Allogene announced the execution of an Amendment and Settlement Agreement (the "Servier Amendment"), which amended the license agreement between Servier and Allogene, under which Servier exclusively sublicensed to Allogene its rights under the License Agreement between Cellectis and Servier (the "Servier License"), for the development and commercialization of allogeneic anti-CD19 CAR T cell product candidates in the U.S. (the "Allogene Sublicense"). Allogene disclosed that, pursuant to the Servier Amendment to the Allogene Sublicense, the licensed territory was expanded to include the European Union and the United Kingdom, and Allogene was granted an option to further extend its licensed territory to include China and Japan subject to certain conditions. Corporate Updates Collaboration and Investment Agreements with AstraZeneca On May 6, 2024, Cellectis announced the completion of the subsequent investment of $140M in Cellectis by AstraZeneca (LSE/STO/Nasdaq: AZN) (the “Additional Investment”).AstraZeneca subscribed for 10,000,000 “class A” convertible preferred shares and 18,000,000 “class B” convertible preferred shares, in each case at a price of $5.00 per convertible preferred share, issued by the Board of Directors of Cellectis.On the completion date of the Additional Investment, AstraZeneca owned approximately 44% of the share capital and 30% of the voting rights of the Company (based on the number of voting rights outstanding at the time).Following the Additional Investment, Mr. Marc Dunoyer and Dr. Tyrell Rivers have been nominated members of the board of directors of Cellectis, designated by AstraZeneca. Annual Shareholders Meeting On June 28, 2024, Cellectis held a shareholders’ general meeting at the Biopark auditorium in Paris, France.At the meeting, during which approximately 40% of shares were exercised, resolutions 1 through 28 were adopted and resolution 29 was rejected, consistent with the recommendations of the management. The detailed results of the vote and the resolutions are available on Cellectis’ website: https://www.cellectis.com/en/investors/general-meetings/ Financial Results The interim condensed consolidated financial statements of Cellectis have been prepared in accordance with International Financial Reporting Standards, as issued by the International Accounting Standards Board (“IFRS”). As from June 1, 2023, and the deconsolidation of Calyxt, which corresponded to the Plants operating segment, we view our operations and manage our business in a single operating and reportable segment corresponding to the Therapeutics segment. For this reason, we are no longer presenting financial measures broken down between our two reportable segments – Therapeutics and Plants. In the appendices of this Q2 2024 financial results press release, Calyxt's results are isolated under "Income (loss) from discontinued operations" for the 6-month period ended June 30, 2023, and are no longer included for the 6-month period ended June 30, 2024, due to the deconsolidation. Cash: As of June 30, 2024, Cellectis had $273 million in consolidated cash, cash equivalents, restricted cash and fixed-term deposits classified as current-financial assets. This compares to $156 million in consolidated cash, cash equivalents, restricted cash and fixed-term deposits classified as current-financial assets as of December 31, 2023. This $117 million increase is mainly due to cash payments from Cellectis to suppliers of $26 million, including $18 million to R&D suppliers and $8 million to SG&A suppliers, Cellectis’ wages, bonuses and social expenses paid of $24 million, the payments of lease debts of $5 million and the repayment of the “PGE” loan of $3 million, partially offset by the $16 million cash received from EIB pursuant to the disbursement of the €15 million Tranche B, $5 million of cash-in from our financial investments, $14 million of cash-in from our revenue, $140 million cash received from AstraZeneca as part of its equity investment in Cellectis. With cash and cash equivalents of $149 million and $119 million term deposit classified as current financial assets as of June 30, 2024, the Company believes its cash and cash equivalents and deposits will be sufficient to fund its operations into 2026 and therefore for at least twelve months following the unaudited interim condensed consolidated financial statements' publication. Revenues and Other Income: Consolidated revenues and other income were $16.0 million for the six months ended June 30, 2024 compared to $5.6 million for the six months ended June 30, 2023. This $10.4 million increase between the six months ended June 30, 2023 and 2024 was mainly attributable to (i) recognition of a $12.3 million revenue in 2024 based (a) on the progress of our performance obligation rendered under the first research plan of the Joint Research and Collaboration Agreement (the “JRCA”) signed with AstraZeneca Ireland Limited (AZ Ireland) and (b) the reaching of a development milestone under the License Agreement signed with Servier, while revenues recognized for the six months ended June 30, 2023 were immaterial, (ii) a decrease of research tax credit of $1.1 million due to a decrease of eligible expenses, and (iii) the recognition in the six-month periods ended June 30, 2023 of $0.8 million representing the portion of an initial payments from BPI corresponding to a grant pursuant to our grant and repayable advance agreement with BPI signed in March 2023. R&D Expenses: Consolidated R&D expenses were $45.8 million for the six months ended June 30, 2024, compared to $43.6 million for the six months ended June 30, 2023. R&D personnel expenses decreased by $0.8 million from $20.0 million in 2023 to $19.2 million in 2024 primarily due to a decrease in the average unit fair value of stock options and free share awards vesting between the two periods. R&D purchases, external expenses and other increased by $3.1 million (from $23.6 million in 2023 to $26.7 million in 2024) mainly related to increase in manufacturing activities to support our R&D pipeline. SG&A Expenses: Consolidated SG&A expenses were $9.0 million for the six months ended June 30, 2024 compared to $8.9 million for the six months ended June 30, 2023. SG&A personnel expenses decreased by $0.2 million (from $4.0 million in 2023 to $3.8 million in 2024), with a $0.4 million increase in salaries being offset by a $0.6 million decrease in stock-based compensation expenses. SG&A purchases, external expenses and other increased by $0.3 million (from $4.9 million in 2023 to $5.2 million in 2024). Other operating income and expenses: Other operating income and expenses were a $0.7 million net income for the six months ended June 30, 2024 compared to a $0.1 million net expense for the six months ended June 30, 2023. Other operating income and expenses decreased by $0.8 million primarily due to the recognition of costs related to a litigation of $0.5 million in 2023. Net financial gain (loss): We had a consolidated net financial gain of $18.0 million for the six months ended June 30, 2024, compared to a $10.2 million loss for the six months ended June 30, 2023. This $28.3 million difference reflects mainly (i) a $14.3 million gain in change in fair value of SIA derivative instrument, (ii) a $3.2 million increase in gain from our financial investments, (iii) a $4.3 million gain in change in fair value of EIB tranche A and B, , (iv) a $5.5 million decrease of the loss in fair value of our investment in Cibus and (vi) the loss in fair value measurement on Cytovia convertible note recognized in the six months period ended June 30, 2023 of $6.8 million, partially offset by (i) a $1.3 million interest expense on EIB Tranche A and Tranche B loans and (ii) a $0.7 million increase in foreign exchange loss, and (iii) a decrease in net foreign exchange gain of $3.5 million. Net income (loss) from discontinued operations: Net income from discontinued operations of $8.4 million for the six months ended June 30, 2023 corresponded to Calyxt’s results. Since Calyxt has been deconsolidated since June 1, 2023, there is no longer any "Income (loss) from discontinued operations" for the six months ended June 30, 2024. Net Income (loss) Attributable to Shareholders of Cellectis: Consolidated net loss attributable to shareholders of Cellectis was $19.6 million (or a $0.24 loss per share) for the six months ended June 30, 2024, compared to a $41.8 million loss (or a $0.78 loss per share) for the six months ended June 30, 2023, of which $57.6 million was attributed to Cellectis continuing operations. The $29.5 million change in net loss was primarily driven by (i) an increase in revenues and other income of $10.4 million, (ii) a decrease of $1.5 million in non-cash stock based compensation expense due to a decrease in the average unit fair value of stock options and free share awards vesting between the two periods, (iii) a $28.3 million change from a net financial loss of $10.2 million to a net financial gain of $18.0 million and (iv) a decrease in net other operating expense of $0.8 million, and (v) a $8.4 million decrease in net income from discontinued operations attributable to shareholders of Cellectis, partially offset by (i) an increase of $3.3 million in purchases, external expenses and other, and a (ii) an increase of $0.4 million in wages. Adjusted Net Income (Loss) Attributable to Shareholders of Cellectis: Consolidated adjusted net loss attributable to shareholders of Cellectis was $17.9 million (or a $0.22 loss per share) for the six months ended June 30, 2024, compared to a net loss of $36.7 million (or a $0.68 loss per share) for the six months ended June 30, 2023. Please see "Note Regarding Use of Non-IFRS Financial Measures" for reconciliation of GAAP net income (loss) attributable to shareholders of Cellectis to adjusted net income (loss) attributable to shareholders of Cellectis. We currently foresee focusing our cash spending at Cellectis for 2024 in the following areas: Supporting the development of our pipeline of product candidates, including the manufacturing and clinical trial expenses of UCART22, UCART20x22, UCART123 and potential new product candidates, andOperating our state-of-the-art manufacturing capabilities in Paris (France), and Raleigh (North Carolina, USA); andContinuing strengthening our manufacturing and clinical departments. CELLECTIS S.A.STATEMENT OF CONSOLIDATED FINANCIAL POSITION (unaudited)($ in thousands) As of December 31, 2023 June 30, 2024ASSETS Non-current assets Intangible assets 671 653 Property, plant, and equipment 54,681 50,370 Right-of-use assets 38,060 33,671 Non-current financial assets 7,853 16,650 Total non-current assets 101,265 101,344 Current assets Trade receivables 569 9,741 Subsidies receivables 20,900 14,958 Other current assets 7,722 7,587 Current deferred tax assets 710 Cash and cash equivalent and Current financial assets 203,815 272,806 Total current assets 233,005 305,803 TOTAL ASSETS 334,270 407,147 LIABILITIES Shareholders’ equity Share capital 4,365 5,897 Premiums related to the share capital 522,785 606,146 Currency translation adjustment (36,690) (38,077)Retained earnings (304,707) (405,729)Net income (loss) (101,059) (19,627)Total shareholders’ equity - Group Share 84,695 148,610 Non-controlling interests 0 0 Total shareholders’ equity 84,695 148,610 Non-current liabilities Non-current financial liabilities 49,125 58,348 Non-current lease debts 42,948 38,362 Non-current provisions 2,200 2,194 Non-current deferred tax liabilities 158 0 Total non-current liabilities 94,431 98,904 Current liabilities Current financial liabilities 5,289 5,119 Current lease debts 8,502 8,357 Trade payables 19,069 18,213 Deferred revenues and deferred income 110,325 117,754 Current provisions 1,740 884 Current deferred tax liabilities 122 Other current liabilities 10,219 9,184 Total current liabilities 155,144 159,633 TOTAL LIABILITIES AND SHAREHOLDERS’ EQUITY 334,270 407,147 UNAUDITED STATEMENTS OF CONSOLIDATED OPERATIONSFor the three-month period ended June 30, 2024($ in thousands, except per share amounts) For the three-month period ended June 30, 2023* 2024 Revenues and other income Revenues 178 8,061 Other income 1,823 1,442 Total revenues and other income 2,001 9,504 Operating expenses Research and development expenses (22,200) (23,518)Selling, general and administrative expenses (3,950) (3,882)Other operating income (expenses) 528 686 Total operating expenses (25,622) (26,714) Operating income (loss) (23,621) (17,211) Financial gain (loss) (5,844) (8,251) Income tax (258) 193 Income (loss) from continuing operations (29,724) (25,270)Income (loss) from discontinued operations 13,083 0 Net income (loss) (16,641) (25,270)Attributable to shareholders of Cellectis (11,707) (25,270)Attributable to non-controlling interests (4,934) 0 Basic and diluted net income (loss) attributable to shareholders of Cellectis, per share ($/share) (0.20) (0.28)Diluted net income (loss) attributable to shareholders of Cellectis, per share ($/share) (0.20) (0.28)Basic and diluted net income (loss) attributable to shareholders of Cellectis from discontinued operations, per share ($ /share) 0.32 0.00 Diluted net income (loss) attributable to shareholders of Cellectis from discontinued operations, per share ($ /share) 0.32 0.00 Number of shares used for computing Basic 55,583,768 89,852,142 Diluted 55,583,768 89,852,142 *These amounts reflect Calyxt's adjustments as presented in Cellectis 2023 20F (Note 3) Cellectis S.A.UNAUDITED STATEMENTS OF CONSOLIDATED OPERATIONSFor the six-month period ended June 30, 2024($ in thousands, except per share amounts) For the six-month period ended June 30, 2023* 2024 Revenues and other income Revenues 317 12,589 Other income 5,242 3,412 Total revenues and other income 5,560 16,002 Operating expenses Research and development expenses (43,614) (45,841)Selling, general and administrative expenses (8,914) (8,986)Other operating income (expenses) (83) 721 Total operating expenses (52,612) (54,107) Operating income (loss) (47,053) (38,105) Financial gain (loss) (10,246) 18,023 Income tax (258) 455 Income (loss) from continuing operations (57,557) (19,627)Income (loss) from discontinued operations 8,392 0 Net income (loss) (49,165) (19,627)Attributable to shareholders of Cellectis (41,781) (19,627)Attributable to non-controlling interests (7,384) 0 Basic net income (loss) attributable to shareholders of Cellectis, per share ($/share) (0.78) (0.24)Diluted net income (loss) attributable to shareholders of Cellectis, per share ($/share) (0.78) (0.24)Basic net income (loss) attributable to shareholders of Cellectis from discontinued operations, per share ($ /share) 0.29 0.00 Diluted net income (loss) attributable to shareholders of Cellectis from discontinued operations, per share ($ /share) 0.29 0.00 Number of shares used for computing Basic 53,541,010 80,881,026 Diluted 53,541,010 80,881,026 *These amounts reflect Calyxt's adjustments as presented in Cellectis 2023 20F (Note 3) Note Regarding Use of Non-IFRS Financial Measures Cellectis S.A. presents adjusted net income (loss) attributable to shareholders of Cellectis in this press release. Adjusted net income (loss) attributable to shareholders of Cellectis is not a measure calculated in accordance with IFRS. We have included in this press release a reconciliation of this figure to net income (loss) attributable to shareholders of Cellectis, which is the most directly comparable financial measure calculated in accordance with IFRS. Because adjusted net income (loss) attributable to shareholders of Cellectis excludes non-cash stock-based compensation expense—a non-cash expense, we believe that this financial measure, when considered together with our IFRS financial statements, can enhance an overall understanding of Cellectis’ financial performance. Moreover, our management views the Company’s operations, and manages its business, based, in part, on this financial measure. In particular, we believe that the elimination of non-cash stock-based expenses from Net income (loss) attributable to shareholders of Cellectis can provide a useful measure for period-to-period comparisons of our core businesses. Our use of adjusted net income (loss) attributable to shareholders of Cellectis has limitations as an analytical tool, and you should not consider it in isolation or as a substitute for analysis of our financial results as reported under IFRS. Some of these limitations are: (a) other companies, including companies in our industry which use similar stock-based compensation, may address the impact of non-cash stock- based compensation expense differently; and (b) other companies may report adjusted net income (loss) attributable to shareholders or similarly titled measures but calculate them differently, which reduces their usefulness as a comparative measure. Because of these and other limitations, you should consider adjusted net income (loss) attributable to shareholders of Cellectis alongside our IFRS financial results, including Net income (loss) attributable to shareholders of Cellectis. RECONCILIATION OF IFRS TO NON-IFRS NET INCOME (unaudited)For the three-month period ended June 30, 2024($ in thousands, except per share data) For the three-month period ended June 30, 2023* 2024 Net income (loss) attributable to shareholders of Cellectis (11,707) (25,270)Adjustment: Non-cash stock-based compensation expense attributable to shareholders of Cellectis 3,140 830 Adjusted net income (loss) attributable to shareholders of Cellectis (8,567) (24,440)Basic adjusted net income (loss) attributable to shareholders of Cellectis ($/share) (0.15) (0.27)Basic adjusted net income (loss) attributable to shareholders of Cellectis from discontinued operations ($ /share) (0.04) 0.00 Weighted average number of outstanding shares, basic (units) (1) 55,583,768 89,852,142 Diluted adjusted net income (loss) attributable to shareholders of Cellectis ($/share) (1) (0.15) (0.27)Diluted adjusted net income (loss) attributable to shareholders of Cellectis from discontinued operations ($/share) (0.04) 0.00 Weighted average number of outstanding shares, diluted (units) (1) 55,583,768 89,852,142 *These amounts reflect Calyxt's adjustments as presented in Cellectis 2023 20F (Note 3) RECONCILIATION OF IFRS TO NON-IFRS NET INCOME (unaudited)For the six-month period ended June 30, 2024($ in thousands, except per share data) For the six-month period ended June 30, 2023* 2024 Net income (loss) attributable to shareholders of Cellectis (41,781) (19,627)Adjustment: Non-cash stock-based compensation expense attributable to shareholders of Cellectis 5,119 1,717 Adjusted net income (loss) attributable to shareholders of Cellectis (36,662) (17,910)Basic adjusted net income (loss) attributable to shareholders of Cellectis ($/share) (0.68) (0.22)Basic adjusted net income (loss) attributable to shareholders of Cellectis from discontinued operations ($ /share) (0.09) 0.00 Weighted average number of outstanding shares, basic (units) (1) 53,541,010 80,881,026 Diluted adjusted net income (loss) attributable to shareholders of Cellectis ($/share) (1) (0.68) (0.22)Diluted adjusted net income (loss) attributable to shareholders of Cellectis from discontinued operations ($/share) (0.09) 0.00 Weighted average number of outstanding shares, diluted (units) (1) 53,541,010 80,881,026 *These amounts reflect Calyxt's adjustments as presented in Cellectis 2023 20F (Note 3) About Cellectis  Cellectis is a clinical-stage biotechnology company using its pioneering gene-editing platform to develop life-saving cell and gene therapies. Cellectis utilizes an allogeneic approach for CAR-T immunotherapies in oncology, pioneering the concept of off-the-shelf and ready-to-use gene-edited CAR T-cells to treat cancer patients, and a platform to make therapeutic gene editing in hemopoietic stem cells for various diseases. As a clinical-stage biopharmaceutical company with 25 years of experience and expertise in gene editing, Cellectis is developing life-changing product candidates utilizing TALEN®, its gene editing technology, and PulseAgile, its pioneering electroporation system to harness the power of the immune system in order to treat diseases with unmet medical needs. Cellectis’ headquarters are in Paris, France, with locations in New York, New York and Raleigh, North Carolina. Cellectis is listed on the Nasdaq Global Market (ticker: CLLS) and on Euronext Growth (ticker: ALCLS). Forward-looking Statements     This press release contains “forward-looking” statements within the meaning of applicable securities laws, including the Private Securities Litigation Reform Act of 1995. Forward-looking statements may be identified by words such as ”future,” “projection,” “will,” “ may,” “would,” “expect,” and “believe” or the negative of these and similar expressions. These forward-looking statements are based on our management’s current expectations and assumptions and on information currently available to management. Forward-looking statements include statements about the advancement, timing and progress of clinical trials, the timing of our presentation of clinical data, the potential of our candidate products programs and CLLS52, the outcome of the arbitration proceedings against Servier, and the sufficiency of cash to fund operations. These forward-looking statements are made in light of information currently available to us and are subject to numerous risks and uncertainties, including with respect to the numerous risks associated with biopharmaceutical product candidate development, including the risk of losing the orphan drug designation if it is established that the product no longer meets the orphan drug criteria before market authorization is granted (if any). With respect to our cash runway, our operating plans, including product candidates development plans, may change as a result of various factors, including factors currently unknown to us. Furthermore, many other important factors, including those described in our Annual Report on Form 20-F and the financial report (including the management report) for the year ended December 31, 2023 and subsequent filings Cellectis makes with the Securities Exchange Commission from time to time, as well as other known and unknown risks and uncertainties may adversely affect such forward-looking statements and cause our actual results, performance or achievements to be materially different from those expressed or implied by the forward-looking statements. Except as required by law, we assume no obligation to update these forward-looking statements publicly, or to update the reasons why actual results could differ materially from those anticipated in the forward-looking statements, even if new information becomes available in the future.      For further information on Cellectis, please contact: Media contacts: Pascalyne Wilson, Director, Communications, +33 (0)7 76 99 14 33, media@cellectis.com Patricia Sosa Navarro, Chief of Staff to the CEO, +33 (0)7 76 77 46 93 Investor Relations contact: Arthur Stril, Interim Chief Financial Officer, +1 (347) 809 5980, investors@cellectis.com Attachment 20240805_Cellectis Reports Financial Results for Second Quarter 2024 - V0508[7]