Clinical Pharmacology, Genentech, South San Francisco, California, USA.
Clin Pharmacol Ther. 2024 Jun;115(6):1233-1250. doi: 10.1002/cpt.3241. Epub 2024 Mar 19.
Autologous chimeric antigen receptor T-cell (CAR-T) therapies have garnered unprecedented clinical success with multiple regulatory approvals for the treatment of various hematological malignancies. However, there are still several clinical challenges that limit their broad utilization for aggressive disease conditions. To address some of these challenges, allogeneic cell therapies are evaluated as an alternative approach. As compared with autologous products, they offer several advantages, such as a more standardized "off the shelf" product, reduced manufacturing complexity, and no requirement of bridging therapy. As with autologous CAR-T therapies, allogeneic cell therapies also present clinical pharmacology challenges due to their in vivo living nature, unique pharmacokinetics or cellular kinetics (CKs), and complex dose-exposure-response relationships that are impacted by various patient- and product-related factors. On top of that, allogeneic cell therapies present additional unique challenges, including attenuated in vivo persistence and graft-vs.-host disease risk as compared with autologous counterparts. This review draws comparison between autologous and allogeneic cell therapies, summarizing key engineering aspects unique to allogeneic cell therapy. Clinical pharmacology learnings from emerging clinical data of allogeneic cell therapy programs are also highlighted, with particular emphasis on CK, dose-exposure-response relationship, lymphodepletion regimen, repeat dosing, and patient- and product-related factors that can impact CK and patient outcomes. There are specific unique challenges and opportunities arising from the development of allogeneic cell therapies, especially in optimizing lymphodepletion and establishing a regimen for repeat dosing. This review highlights how clinical pharmacologists are well positioned to help address these challenges by leveraging novel clinical pharmacology and modeling and simulation approaches.
自体嵌合抗原受体 T 细胞（CAR-T）疗法在治疗各种血液恶性肿瘤方面取得了前所未有的临床成功，并获得了多项监管批准。然而，仍有一些临床挑战限制了它们在侵袭性疾病情况下的广泛应用。为了应对其中的一些挑战，异体细胞疗法被评估为一种替代方法。与自体产品相比，它们具有一些优势，如更标准化的“现货”产品、简化的生产过程，以及无需桥接治疗。与自体 CAR-T 疗法一样，异体细胞疗法也因其体内的活体特性、独特的药代动力学或细胞动力学（CKs）以及复杂的剂量-暴露-反应关系而带来临床药理学挑战，这些关系受到各种患者和产品相关因素的影响。除此之外，异体细胞疗法还存在其他独特的挑战，包括与自体产品相比，体内持久性降低和移植物抗宿主病风险增加。本综述比较了自体和异体细胞疗法，总结了异体细胞疗法特有的关键工程方面。还重点介绍了新兴异体细胞治疗方案的临床数据所获得的临床药理学知识，特别强调了 CK、剂量-暴露-反应关系、淋巴耗竭方案、重复给药以及可能影响 CK 和患者结局的患者和产品相关因素。异体细胞疗法的开发带来了特定的独特挑战和机遇，特别是在优化淋巴耗竭和建立重复给药方案方面。本综述强调了临床药理学家如何通过利用新型临床药理学和建模与模拟方法来帮助应对这些挑战。
