wloe2gf 发表于 2024-6-23 01:58:25

治疗多种癌症类型，“通用”CAR-T细胞要来了？


    <p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">2024年5月14日</span></p>
    <p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">医麦客<span style="color: black;">资讯</span> eMedClub News</span></p>
    <p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">自从首款嵌合抗原受体（CAR）-T细胞疗法在2017年<span style="color: black;">得到</span>FDA<span style="color: black;">准许</span><span style="color: black;">败兴</span>，已有多款CAR-T疗法<span style="color: black;">得到</span><span style="color: black;">全世界</span>监管单位的<span style="color: black;">准许</span>，展现其治愈癌症的<span style="color: black;">潜能</span>。然而，<strong style="color: blue;">这些<span style="color: black;">获准</span>CAR-T疗法的适应症多集中于B细胞类血液癌症</strong>，<span style="color: black;">重点</span><span style="color: black;">原由</span>之一是<span style="color: black;">因为</span>靶向T细胞抗原可能会<span style="color: black;">诱发</span>CAR-T细胞自相残杀（fratricide），<span style="color: black;">从而</span>影响整体治疗效果。</span><span style="color: black;">然而<strong style="color: blue;"><span style="color: black;">经过</span>单碱基编辑（base editing）技术，<span style="color: black;">专家</span><span style="color: black;">已然</span><span style="color: black;">研发</span>出靶向T细胞的CAR-T细胞疗法，并在临床上<span style="color: black;">得到</span>验证</strong>。</span><span style="color: black;">除<span style="color: black;">另外</span></span><span style="color: black;">，</span><span style="color: black;">潜在靶向所有血液肿瘤<span style="color: black;">类型</span>的CAR-T疗法<span style="color: black;">亦</span>已在临床前实验中展现积极抗癌效力</span><strong style="color: blue;"><span style="color: black;">。</span></strong><span style="color: black;">CAR-T疗法正在逐步且深入地扩展其在癌症治疗的应用。</span></p>
    <p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><strong style="color: blue;">多重碱基编辑CAR-T细胞治疗T细胞癌症获临床验证</strong></p>
    <p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">eMedClub</span></p>
    <p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">为了<span style="color: black;">研发</span>出用以治疗T细胞血液癌症且不会相互残杀的CAR-T细胞，来自大奥蒙德街医院（Great Ormond Street Hospital）的<span style="color: black;">专家</span>团队<span style="color: black;">运用</span>胞嘧啶碱基编辑器（coBE）对T细胞进行多重编辑。这种胞嘧啶碱基编辑器将一种改变碱基的脱氨酶（deaminase）与<span style="color: black;">没</span>酶切活性的Cas9变体融合在<span style="color: black;">一块</span>，可在细胞内不产生DNA双链断裂的情形下制造C-G至T-A点突变，以产生过早终止<span style="color: black;">暗码</span>子或破坏剪接位点来达到沉默特定基因表达的效果。</span></p>
    <p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><img src="//q8.itc.cn/q_70/images03/20240523/db4a30263d1248d0ae770f744d0f5036.jpeg" style="width: 50%; margin-bottom: 20px;"></p>
    <p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;"><span style="color: black;">▲</span></span><span style="color: black;"><span style="color: black;">经过</span>碱基编辑制造靶向T细胞的CAR-T疗法（<span style="color: black;">照片</span><span style="color: black;">源自</span>：参考资料）</span></p>
    <p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">该<span style="color: black;">科研</span>团队将靶向TRBC1和TRBC2（编码T细胞受体β链）、CD7和CD52 mRNA的3个单向导RNA（sgRNA）与编码coBE的mRNA，<span style="color: black;">经过</span>电穿孔的方式送入健康捐赠者的T细胞中，并接着<span style="color: black;">运用</span>编码CAR的慢病毒载体转染这些细胞，从而生成碱基编辑的靶向CD7的CAR（BE-CAR7）-T细胞库，用以治疗复发性或难治性T细胞急性淋巴细胞白血病（T-ALL）儿童<span style="color: black;">病人</span>。<strong style="color: blue;"><span style="color: black;">经过</span>单碱基编辑破坏T细胞受体可防止CAR-T细胞攻击<span style="color: black;">病人</span>的常驻T细胞，<span style="color: black;">从而</span>避免移植物抗宿主病（GvHD）的<span style="color: black;">出现</span>。而<span style="color: black;">经过</span>敲除CD7的表达则可避免CAR-T细胞自相残杀。</strong><span style="color: black;">另外</span>，CD52的失活则可<span style="color: black;">保证</span><span style="color: black;">病人</span>在接受预处理<span style="color: black;">方法</span>中像是Campath（alemtuzumab）这类CD52靶向疗法治疗时，所接受的同种异体CAR-T细胞能够存活。</span></p>
    <p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">这项1期<span style="color: black;">实验</span>中接受该疗法的前三位T-ALL儿童<span style="color: black;">病人</span>的治疗结果<span style="color: black;">颁布</span>于去年的《新英格兰医学杂志》<span style="color: black;">其中</span>，<strong style="color: blue;">其中两位<span style="color: black;">病人</span>在接受BE-CAR7治疗后<span style="color: black;">一月</span>内达成完全缓解！</strong>首例<span style="color: black;">病人</span>是一名13岁<span style="color: black;">女子</span>，她在接受同种异体干细胞移植后T-ALL产生复发，<strong style="color: blue;">在输注单剂量BE-CAR7细胞后28天内实现了分子缓解。她后来接受来自原始捐赠者的低强度同种异体干细胞移植后，成功实现免疫重建和持久的白血病缓解。</strong>来自同一细胞库的BE-CAR7在<span style="color: black;">另一</span>两例<span style="color: black;">病人</span>中<span style="color: black;">也</span><span style="color: black;">表示</span>出有效活性，其中一例<span style="color: black;">病人</span><span style="color: black;">出现</span>致命的真菌并发症，另一例<span style="color: black;">病人</span>则在缓解<span style="color: black;">时期</span>接受了同种异体干细胞移植。</span></p>
    <p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><img src="//q1.itc.cn/q_70/images03/20240523/7a53f1216fab4bf8a22700461d03595f.jpeg" style="width: 50%; margin-bottom: 20px;"></p>
    <p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;"><span style="color: black;">▲</span></span><span style="color: black;">接受BE-CAR7治疗首位<span style="color: black;">病人</span>的疗效结果（<span style="color: black;">照片</span><span style="color: black;">源自</span>：参考资料）</span></p>
    <p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">虽然在<span style="color: black;">实验</span><span style="color: black;">其中</span><span style="color: black;">病人</span><span style="color: black;">出现</span><span style="color: black;">包含</span>细胞因子释放<span style="color: black;">综合症</span>和机会性感染等严重不良事件，这项<span style="color: black;">实验</span><span style="color: black;">没</span>疑证实多重单碱基编辑在临床应用上的可行性，并进一步扩展CAR-T疗法的应用范围。<strong style="color: blue;"><span style="color: black;">研发</span>中的</strong><strong style="color: blue;">类似疗法还有Beam Therapeutics的BEAM-201。</strong>与BE-CAR7不同的是，除了对以上所提基因进行编辑外，BEAM-201还对T细胞的PD-L1进行编辑，目的是潜在避免T细胞耗竭与延长细胞存活时间，该疗法已在去年完成首次<span style="color: black;">病人</span>给药。<span style="color: black;">另外</span>，Wugen<span style="color: black;">机构</span><span style="color: black;">亦</span>在去年美国血液学会（ASH）年会上<span style="color: black;">颁布</span>其经双重编辑的同种异体CD7靶向CAR-T疗法WU-CART-007用于治疗T-ALL或淋巴细胞淋巴瘤（LBL）的<span style="color: black;">全世界</span>1/2期临床<span style="color: black;">实验</span>数据。分析<span style="color: black;">表示</span>，WU-CART-007表现出可控的安全性，未观察到GvHD。<strong style="color: blue;">在剂量水平≥2的18例疗效可<span style="color: black;">评定</span><span style="color: black;">病人</span>中，复合完全缓解（CRc）率为67%，接受<span style="color: black;">举荐</span>的2期剂量（RP2D）治疗<span style="color: black;">病人</span>的CRc为73%。</strong></span></p>
    <p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><img src="//q1.itc.cn/q_70/images03/20240523/13b5ca08e58444eab09e79851b7c13f7.jpeg" style="width: 50%; margin-bottom: 20px;"></p>
    <p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;"><span style="color: black;"><span style="color: black;"><span style="color: black;"><span style="color: black;"><span style="color: black;"><span style="color: black;"><span style="color: black;">▲</span></span><span style="color: black;">WU-CART-007<span style="color: black;">实验</span>疗效结果（<span style="color: black;">照片</span><span style="color: black;">源自</span>：参考资料）</span></span></span></span></span></span></span></p>
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    <p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><strong style="color: blue;">潜在治疗所有类型血液肿瘤的CAR-T疗法</strong></p>
    <p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">eMedClub</span></p>
    <p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;"><span style="color: black;">研发</span>出能够潜在治疗T细胞癌症的CAR-T疗法是一项令人鼓舞的医学<span style="color: black;">发展</span>，然而单碱基编辑在创新CAR-T疗法<span style="color: black;">研发</span>上的应用不仅限于此。<strong style="color: blue;">碱基编辑使得<span style="color: black;">专家</span>能够在维持基因功能的<span style="color: black;">同期</span>引入单核苷酸改变，<span style="color: black;">从而</span>创造出新型的治疗靶标。</strong><strong style="color: blue;">这种<span style="color: black;">办法</span>被<span style="color: black;">叫作</span>为</strong></span><span style="color: black;"><strong style="color: blue;">表位编辑（epitope editing）</strong></span><span style="color: black;"><strong style="color: blue;">，可进一步扩大CAR-T细胞疗法的范围，涵盖所有血液癌症，<span style="color: black;">包含</span><span style="color: black;">哪些</span>缺乏可靶向癌症特异性抗原的癌症。</strong></span></p>
    <p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">表位编辑的应用在去年8月两篇临床前<span style="color: black;">科研</span><span style="color: black;">其中</span><span style="color: black;">得到</span>初步证实。由宾夕法尼亚大学Saar Gill博士所带领的<span style="color: black;">科研</span>团队利用腺嘌呤碱基编辑器，将CD45蛋白转化为所有血液系统恶性肿瘤的可行CAR靶标。<span style="color: black;">C</span><span style="color: black;">D4</span><span style="color: black;">5是一种表达于</span><span style="color: black;">几乎所有血液细胞表面的<span style="color: black;">蛋白</span>。</span><strong style="color: blue;"><span style="color: black;">科研</span>人员将一种功能<span style="color: black;">保存</span>、可逃避CAR攻击的CD45安装到造血干细胞和CD45靶向的CAR-T细胞中。</strong><span style="color: black;">而后</span>，<span style="color: black;">她们</span>将这两种经修饰的细胞输注入<span style="color: black;">身患</span>急性髓系白血病的小鼠<span style="color: black;">身体</span>。实验结果<span style="color: black;">表示</span>，CAR-T细胞<span style="color: black;">可发动针对癌细胞专一性的攻击，且</span>本身并不相互残杀，而经表位编辑的干细胞则在小鼠<span style="color: black;">身体</span>成功重建了一个健康的免疫系统。这项技术有<span style="color: black;">潜能</span>治疗任何血液或骨髓癌。Gill博士打算授权该技术或创建一家<span style="color: black;">机构</span>以将之进一步应用于临床。</span></p>
    <p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><img src="//q6.itc.cn/q_70/images03/20240523/6f552859345d42ea8c57f7ef0422f21b.jpeg" style="width: 50%; margin-bottom: 20px;"></p>
    <p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;"><span style="color: black;">▲</span></span><span style="color: black;">经表位编辑的造血系统不受CD45靶向CAR-T细胞攻击（<span style="color: black;">照片</span><span style="color: black;">源自</span>：参考资料）</span></p>
    <p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">另一项<span style="color: black;">科研</span>则<span style="color: black;">是由于</span>来自丹娜-法伯癌症<span style="color: black;">科研</span>所（Dana-Farber Cancer Institute）的Pietro Genovese博士所领导。<strong style="color: blue;">他的团队<span style="color: black;">一样</span>采用了腺嘌呤碱基编辑器来创建造血干细胞，使得经编辑后的造血干细胞表面蛋白与白血病细胞所表达的蛋白仅存在一个氨基酸的差异。</strong>这一微小的变化使得小鼠<span style="color: black;">身体</span>的癌症得以根除，<span style="color: black;">同期</span>不影响正常的造血系统。Genovese博士打算<span style="color: black;">起步</span>一项临床<span style="color: black;">实验</span>，让急性髓系白血病<span style="color: black;">病人</span>接受经表位编辑的同种异体干细胞的移植。若日后<span style="color: black;">病人</span>的癌症复发，<span style="color: black;">大夫</span>将能够在避免靶向与非靶向毒性的<span style="color: black;">同期</span>，用CAR-T细胞或其他疗法有效对抗癌细胞。</span></p>
    <p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">以上这些<span style="color: black;">科研</span><span style="color: black;">表示</span>，若能</span><span style="color: black;">有效、策</span><span style="color: black;">略性地将新兴技术</span><span style="color: black;">相结合，则有望扩大治疗范畴，造福<span style="color: black;">更加多</span><span style="color: black;">病人</span>。</span><span style="color: black;">随着学术界与产业界<span style="color: black;">连续</span><span style="color: black;">持续</span>在单碱基编辑技术与CAR-T疗法上的改进，相信在<span style="color: black;">将来</span>会有<span style="color: black;">更加多</span>癌症<span style="color: black;">病人</span>受惠，让<span style="color: black;">咱们</span><span style="color: black;">一起</span>期待。</span></p>
    <p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">参考资料：</span></p>
    <p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;"> Dolgin, Elie. “Super-resistant CAR Ts take on cancers.” Nature biotechnology vol. 42,1 (2024): 5-7. doi:10.1038/s41587-023-02092-0</span></p>
    <p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;"> Chiesa, Robert et al. “Base-Edited CAR7 T Cells for Relapsed T-Cell Acute Lymphoblastic Leukemia.” The New England journal of medicine vol. 389,10 (2023): 899-910. doi:10.1056/NEJMoa2300709</span></p>
    <p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;"> WUCART7 1001 Phase 1/2 Dose-Escalation/Dose-Expansion Study of Anti-CD7 Allogeneic CAR-T Cells (WU-CART-007) in Relapsed or Refractory (R/R) T-Cell Acute Lymphoblastic Leukemia/ Lymphoblastic Lymphoma (T-ALL/LBL). Retrieved January 24, 2024 from https://wugen.com/wp-content/uploads/2023/12/2023-ASH-WUCART7_FINAL.pdf</span></p>
    <p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;"> Wellhausen N, OConnell RP, Lesch S, Engel NW, Rennels AK, Gonzales D, Herbst F, Young RM, Garcia KC, Weiner D, June CH, Gill SI. Epitope base editing CD45 in hematopoietic cells enables universal blood cancer immune therapy. Sci Transl Med. 2023 Sep 20;15(714):eadi1145. doi: 10.1126/scitranslmed.adi1145. Epub 2023 Sep 20. PMID: 37651540; PMCID: PMC10682510.</span></p>
    <p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;"> Casirati G, Cosentino A, Mucci A, Salah Mahmoud M, Ugarte Zabala I, Zeng J, Ficarro SB, Klatt D, Brendel C, Rambaldi A, Ritz J, Marto JA, Pellin D, Bauer DE, Armstrong SA, Genovese P. Epitope editing enables targeted immunotherapy of acute myeloid leukaemia. Nature. 2023 Sep;621(7978):404-414. doi: 10.1038/s41586-023-06496-5. Epub 2023 Aug 30. PMID: 37648862; PMCID: PMC10499609.</span></p>
    <p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">声明：</span><span style="color: black;">本文旨在于传递行业发展信息、探究生物医药前沿<span style="color: black;">发展</span>。</span><span style="color: black;"><span style="color: black;">文案</span>内容仅<span style="color: black;">表率</span>作者观点，并不<span style="color: black;">表率</span>医麦客立场，<span style="color: black;">也</span>不<span style="color: black;">形成</span>任何价值判断、投资<span style="color: black;">意见</span>或医疗<span style="color: black;">指点</span>，如有需求请咨询专业人士投资或前往正规医院就诊。</span></p>
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4zhvml8 发表于 2024-9-30 23:36:44

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qzmjef 发表于 2024-11-13 12:33:00

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