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The Clinical Research of Chimeric Antigen Receptor T-cell Immunotherapy Presented by Haiping Yang 2015.8.16 Adaptive Cell Transfer Therapy Adoptive cell therapy (ACT) is a treatment that uses a cancer patient’s own T lymphocytes with anti-tumour activity, expanded in vitroand reinfused into the patient with cancer. Adaptive Cell Transfer Therapy TIL( Tumor infiltration T-lymphocytes therapy) TCR ( T-cell receptor therapy) CAR-T (Chimeric antigen receptor T-cell therapy) Cellular therapy has several pathways to the patient. Normal donor cells can be modified to inactivate their alloreactivity while being armed with antitumor CARs or TCRs, or a patient’s own cells can be modified with antitumor molecules. In the case of solid tumors,biopsy specimens can be used to isolate TILs for expansion. In most cases the patient will require some amount of conditioning before receiving antitumor lymphocyte infusions, and careful management of toxicities emerging from these therapies is also required. David M, Chimeric Antigen Receptor– and TCR-Modified T Cells Enter Main Street and Wall Street. The journal of immunology,2015 TIL The first paper to demonstrate the regression of cancer using TIL for the immunotherapy of patients with metastatic melanoma. Rosenberg, S. A.et al.Use of tumor infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. Preliminary report. N. Engl. J. Med. 319, 1676–1680 (1988). TCR The first paper demonstrating the adoptive cell transfer of lymphocytes transduced with a retrovirus encoding TCRs that recognize a cancer antigen can mediate anti-tumour responses in patients with metastatic melanoma. Morgan, R. A.et al.Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314, 126–129 (2006). CAR-T CAR-T cells recognize tumor cells independent of their expression of human leukocyte antigen (HLA) molecules, tumors that escape conventional T cells by downregulating HLA and/or mutating components of the antigen processing machinery can be eliminated. T-cell differentiation Classfication of T-cell Cytotoxic T-cell (CD8) Helper T-cell (CD4) Regulatory/suppressor T-cell Memory T-cell TCR TCR complex :TCR, CD3, ζ ITAM: immunoreceptor tyrosine-based activation motif CAR-T CARs consist of fusion molecules and are typically comprised of an extracellular single chain variable fragment (scFv) of a monoclonal antibody (mAb) specific for a surface molecule on the tumor cell, a spacer domain that provides flexibility and optimizes T cell and target cell engagement, a transmembrane domain, and signaling modules that trigger T cell effector functions. Michael ,Designing chimeric antigen receptors to effectively and safely target tumors. Current Opinion in Immunology 2015 Design of CAR T cells. First-generation CARs incorporated the CD3z-chain or similar signaling domains. Ab-based redirection of T cells was first described by Kuwana and refined by Eshhar. Roberts and Finney first described secondgeneration CARs incorporating CD28 or CD137 signaling domains. David M, Chimeric Antigen Receptor– and TCR-Modified T Cells Enter Main Street and Wall Street. The journal of immunology,2015 The clinical research of CAR-T Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. Aug 25 2011 Grupp SA, Kalos M, Barrett D, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. Apr 18 2013 Ahmed N, Brawley VS, Hegde M, et al. Human Epidermal Growth Factor Receptor 2 (HER2) -Specific Chimeric Antigen Receptor-Modified T Cells for the Immunotherapy of HER2-Positive Sarcoma. J Clin Oncol. May 20 2015 Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. Oct 16 2014 Kochenderfer JN, Dudley ME, Kassim SH, et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol. Feb 20 2015 Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. Aug 25 2011;365:725-33 Figure 1 Clinical Response in the Patient. Figure 1 Clinical Response in the Patient. Figure 2 Serum and Bone Marrow Cytokines before and after Chimeric Antigen Receptor T-Cell Infusion. Figure 2 Serum and Bone Marrow Cytokines before and after Chimeric Antigen Receptor T-Cell Infusion. Figure 3.Expansion and Persistence of Chimeric Antigen Receptor T Cells In Vivo. Failure Morgan RA, et al. Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J Immunother 2013;36:133–151. Morgan RA, Yang JC, Kitano M, Dudley ME,Laurencot CM, Rosenberg SA. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2.Mol Ther 2010;18:843–851. Parkhurst MR, et al. T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol Ther 2011;19:620–626. Brentjens R, Yeh R, Bernal Y, Riviere I, SadelainM. Treatment of chronic lymphocytic leukemia with genetically targeted autologous T cells: case report of an unforeseen adverse event in a phase I clinical trial. Mol Ther 2010;18:666–668. Challenges of CAR-T Target selection Optimize costimulatory signaling of T cell effector functions Toxicities (on-target but off-tumor toxicity) (The on-target toxicities result from the inability of engineered T cells to distinguish between normal cells and cancer cells that express the targeted Ag.) Cytokine release syndrome Toxicities Tumor lysis syndrome Neurologic toxicities Future perspectives of CAR-T 合作双方 事件日期 价值 简介 备注 杨森制药/Transposagen 2014年11月 24日 杨森制药支付Transposagen 每个疗法2.92亿美元, 其中包括头款和其它收 益 异体CAR-T细胞疗法 Janssen拥有双方合作的异体CAR-T 疗法独家代理权。 2014年10月 诺华支付Oxford BioMedica 9000万美 元其中包括1400万美 元头款 诺华获得Oxford慢病毒载体 LentiVector应用于CAR-T免疫 疗法CTL019的非独家全球开发 和商业化权利 Oxford已授予诺华此次合作所开发 的全部CAR-T产品的全球开发 和商业化权利。 诺华/ Oxford BioMedica Juno制药 2014年8月 B轮募资1.34亿美元 开发CAR-T细胞和TCR T细胞疗法 12个月共融资超过3亿美元。Juno 的技术来自3个过继T细胞疗法 最牛的研究机构:Fred Hutchinson Cancer Research Center、 Memorial Sloan Kettering Cancer Center、和Seattle Children’s Research Institute Kite制药 2014年7月 1.28亿美元IPO 开发CAR-T细胞和TCR工程自体T细胞 疗法 建于2009年 Juno制药 2014年4月 A轮募资1.76亿美元 开发CAR-T细胞和TCR工程自体T细胞 疗法 Servier/Cellectis 2014年2月 Servier支付后者1000万头款 和每个产品最高1.4亿 美元其它收益 开发靶向CD19和5个固体肿瘤的CART细胞疗法 Bluebird Bio 2013年6月 1.16亿美元IPO 开发CAR-T细胞和其它癌症基因疗法 赛尔基因/Bluebird Bio 2013年3月 赛尔基因支付未披露的头款和 每个产品最高2.25亿美 元其它收益 开发抗肿瘤CAR-T细胞疗法 诺华/宾夕法尼亚大学 2012年8月 未披露 开发抗肿瘤CAR-T细胞疗法 由Fred Hutchinson Cancer Research、Memorial Sloan-Kettering Cancer Center、和西雅图儿童医院 的科学家组建于2013年 初建于1992年(Genetix Pharmaceuticals)后改名 Bluebird Bio