Regulating innovation in the early development of cell therapies

IF 4.1 Q2 IMMUNOLOGY
A. Exley, J. McBlane
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引用次数: 2

Abstract

Clinical need for paradigm shifts in efficacy and safety is driving the rapid and wide-ranging innovation in cell therapies for cancer beyond existing regulatory frameworks. Critical issues emerging during clinical trials frequently reflect unresolved elements of the regulation of innovation conundrum from earlier stages of development. We address this challenge using a global regulators’ perspective on the preclinical development of cell therapies, as a navigational aid to intended commercial use which maximises the clinical relevance of developmental data. We examine the implications of tumour targeting based on B cell, natural killer cell, conventional and unconventional T cell receptor domains; multiplex approaches; genetic manipulation strategies; and autologous versus allogeneic cell sources. We propose that detailed characterisation of both the cell source and final product is critical to optimising manufacture of individualised autologous or off the shelf allogeneic cell therapies, enabling product consistency to underpin extrapolation of clinical trial data to the expected commercial use. We highlight preclinical approaches to characterising target antigens including the Human Cell Atlas initiative, multi-dimensional cell culture, and safety testing against activated, proliferating or stressed control cells. Practical solutions are provided for preclinical toxicity studies when cell therapies target uniquely human tumour antigens, including illustrative mitigation measures for potential toxicity likely to support timely approval of first-in-human clinical trials. We recommend addressing the regulation of innovation conundrum through serial engagement between innovators and regulators early in the development of cell therapies for cancer, accelerating patient access while safeguarding against unacceptable toxicities.
调控细胞疗法早期发展的创新
对有效性和安全性范式转变的临床需求正在推动癌症细胞疗法的快速和广泛创新,超越现有的监管框架。临床试验中出现的关键问题往往反映了早期开发阶段创新监管难题的未解决因素。我们利用全球监管机构对细胞疗法临床前开发的观点来应对这一挑战,作为预期商业用途的导航辅助,最大限度地提高开发数据的临床相关性。我们研究了基于B细胞、自然杀伤细胞、传统和非常规T细胞受体结构域的肿瘤靶向的意义;多路复用的方法;基因操作策略;自体和异体细胞来源。我们建议,细胞来源和最终产品的详细特征对于优化个体化自体或现成同种异体细胞疗法的制造至关重要,从而使产品一致性能够支撑临床试验数据推断到预期的商业用途。我们重点介绍了临床前表征靶抗原的方法,包括人类细胞图谱计划、多维细胞培养和针对活化、增殖或应激对照细胞的安全性测试。当细胞疗法针对独特的人类肿瘤抗原时,为临床前毒性研究提供了实用的解决方案,包括可能支持及时批准首次人体临床试验的说明性减轻毒性措施。我们建议在癌症细胞疗法开发的早期,通过创新者和监管机构之间的连续接触来解决创新监管难题,加速患者获得,同时防止不可接受的毒性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
5.00
自引率
0.00%
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审稿时长
7 weeks
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