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 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

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
杨森制药支付Transposagen
杨森制药/Transposagen 2014年11月 每个疗法2.92亿美元， Janssen拥有双方合作的异体CAR-T
异体CAR-T细胞疗法
24日 其中包括头款和其它收 疗法独家代理权。
益

诺华支付Oxford 诺华获得Oxford慢病毒载体
Oxford已授予诺华此次合作所开发
BioMedica 9000万美 LentiVector应用于CAR-T免疫
诺华/ Oxford BioMedica 2014年10月 的全部CAR-T产品的全球开发
元其中包括1400万美 疗法CTL019的非独家全球开发
和商业化权利。
元头款 和商业化权利

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
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 Research Center、
Memorial Sloan Kettering
Cancer Center、和Seattle
Children’s Research
Institute

开发CAR-T细胞和TCR工程自体T细胞
Kite制药 2014年7月 1.28亿美元IPO 建于2009年
疗法

由Fred Hutchinson Cancer

Research、Memorial
开发CAR-T细胞和TCR工程自体T细胞
Juno制药 2014年4月 A轮募资1.76亿美元 Sloan-Kettering Cancer
疗法
Center、和西雅图儿童医院
的科学家组建于2013年

Servier支付后者1000万头款
开发靶向CD19和5个固体肿瘤的CAR-
Servier/Cellectis 2014年2月 和每个产品最高1.4亿
T细胞疗法
美元其它收益

初建于1992年（Genetix
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 Pharmaceuticals）后改名
Bluebird Bio

赛尔基因支付未披露的头款和
赛尔基因/Bluebird Bio 2013年3月 每个产品最高2.25亿美 开发抗肿瘤CAR-T细胞疗法
元其它收益

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