Presented by Haiping Yang

2015.8.16

The Clinical Research of Chimeric Antigen Receptor T-cell

Immunotherapy

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.

TIL( Tumor infiltration T-lymphocytes therapy)

TCR ( T-cell receptor therapy)

CAR-T (Chimeric antigen receptor T-cell therapy)

Adaptive Cell Transfer 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

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).

TIL

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).

TCR

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.

CAR-T

T-cell differentiation

Cytotoxic T-cell (CD8)

Helper T-cell (CD4)

Regulatory/suppressor T-cell

Memory T-cell

Classfication of T-cell

 ITAM: immunoreceptor tyrosine-based activation motif

TCR complex :TCR, CD3, ζ

TCR

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 thatprovides flexibility and optimizes T cell and target cell engagement, a transmembrane domain, and signalingmodules that trigger T cell effector functions.

Michael ,Designing chimeric antigen receptors to effectively andsafely target tumors. Current Opinion in Immunology 2015

CAR-T

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 second-generation 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

Tumor lysis syndrome

Neurologic toxicities

Toxicities

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。

诺华 / Oxford BioMedica2014 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。

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

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

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CAR-T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初建于 1992年（ Genetix

Pharmaceuticals）后改名Bluebird Bio

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  

Future perspectives of CAR-T