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从药物开发的角度看工程化T细胞疗法
Engineered T Cell Therapies from a Drug Development Viewpoint
Cancer is one of the leading causes of death worldwide. Recent advances in cellular therapy have demonstrated that this platform has the potential to give patients with certain cancers a second chance at life. Unlike chemical compounds and proteins, cells are living, self-replicating drugs that can be engineered to possess exquisite specificity. For example, T cells can be genetically modified to express chimeric antigen receptors (CARs), endowing them with the capacity to recognize and kill tumor cells and form a memory pool that is ready to strike back against persisting malignant cells. Anti-CD19 chimeric antigen receptor T cells (CART19s) have demonstrated a remarkable degree of clinical efficacy for certain malignancies. The process of developing CART19 essentially follows the conventional “one gene, one drug, one disease” paradigm derived from Paul Ehrlich’s “magic bullet” concept. With major players within the pharmaceutical industry joining forces to commercialize this new category of “living drugs,” it is useful to use CART19 as an example to examine the similarities and differences in its development, compared with that of a conventional drug. In this way, we can assimilate existing knowledge and identify the most effective approach for advancing similar strategies. This article reviews the use of biomarker-based assays to guide the optimization of CAR constructs, preclinical studies, and the evaluation of clinical efficacy; adverse effects (AEs); and CART19 cellular kinetics. Advanced technologies and computational tools that enable the discovery of optimal targets, novel CAR binding domains, and biomarkers predicting clinical response and AEs are also discussed. We believe that the success of CART19 will lead to the development of other engineered T cell therapies in the same manner that the discovery of arsphenamine initiated the era of synthetic pharmaceuticals.
Engineered T cell therapies / Chimeric antigen receptor / Drug development process / Biomarkers / CD19-specific chimeric antigen receptor / Anti-CD19 chimeric antigen receptor T cells
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The authors are grateful for support from the Center for Cellular Immunotherapies and the Abramson Cancer Center at the Perelman School of Medicine, University of Pennsylvania; the Parker Institute for Cancer Immunotherapy; and Peking University. The authors thank Regina Young for coordinating the effort in the clearance of this paper.
Carl H. June: Celldex Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceutical Corporation: Patents & Royalties, Research Funding; Immune Design: Membership on an entity's Board of Directors or advisory committees; Tmunity Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Joseph A. Fraietta and Simon F. Lacey: Novartis Pharmaceutical Corporation: Patents & Royalties, Research Funding; Tmunity Therapeutics: Research Funding. J. Joseph Melenhorst: Novartis Pharmaceutical Corporation: Patents & Royalties, Research Funding; Incyte: Research Funding; Simcere: Consultancy; Shanghai Unicar: Consultancy. Fang Chen: Novartis Pharmaceutical Corporation: Patents & Royalties. Zhongwei Xu: BIOCELTECH: Equity Ownership, Research Funding.
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