文献研读作业

2021年1月30日发(作者：兰亭集序翻译)

西南交通大学

——

科学文献研读与评述期末作业

2016

年

10

月

27

日

1

目录

................................

错误！未定义书签。

一、题目的原文及翻译

.

< p>
.................................

1

二、

Abstract

< p>
的四部分

.................................

1

三、

introduction

部分

.

.. .............................

2

四、

materials and methods

.

...........................

4

五、

Result

部分

.....................................

4

六

. Conclusion

部分< /p>

...................................

5

七、

总结及收获

......................................

6

1

一、题目的原文及翻译

原文：

Tandem CAR T cells targeting HER2 and IL13R

α

2 mitigate tumor antigen

escape

翻译：串联

CAR T

细胞靶向

HER2 and IL13R

α

2

减轻肿瘤抗原的逃逸。

二、

Abstract

的四部分

原文：

In preclinical models of glioblastoma, antigen escape variants can lead to tumor

recurrence after treatment with CAR T cells that are redirected to single tumor antigens. Given the

heterogeneous

expression

of

antigens

on

glioblastomas,

we

hypothesized

that

a

bispecific

CAR

molecule would mitigate antigen escape and improve the antitumor activity of T cells. Here, we

created a CAR that joins a HER2-binding scF

v and an IL13Rα2

-binding IL-13 mutein to make a

tandem

CAR

exod

omain

(TanCAR)

and

a

CD28.ζ

endodomain.

We

determined

that

patient

TanCAR

T

cells

showed

distinct

binding

to

HER2

or

IL13Rα2

and

had

the

capability

to

lyse

autologous glioblastoma. TanCAR T cells exhibited activation dynamics that were comparable to

those of single CAR T cells upon encounter of HER2 or IL13Rα2. We observed that TanCARs

engaged

HER2

and

IL13Rα2

simultaneously

by

inducing

HER2

-

IL13Rα2

heterodimers,

which

promoted

superadditive

T

cell

activation

when

both

antigens

were

encountered

concurrently.

TanCAR

T

cell

activity

was

more

sustained

but

not

more

exhaustible

than

that

of

T

cells

that

coexpressed

a HER2 CAR and

an

IL13Rα2

CAR,

T

cells

with

a

unispecific

CAR,

or

a

pooled

product.

In

a

murine

glioblastoma

model,

TanCAR

T

cells

mitigated

antigen

escape,

displayed

enhanced

antitumor

efficacy,

and

improved

animal

survival.

Thus,

TanCAR

T

cells

show

therapeutic

potential

to

improve

glioblastoma

control

by

coengaging

HER2

and

IL13Rα2

in

an

augmented,

bivalent

immune

synapse

that

enhances

T

cell

functionality

and

reduces

antigen

escape.

翻译：

< p>
在胶质母细胞瘤的临床前模型中，抗原逃逸的变种可能会导致肿瘤复发后

治 疗与

CAR

T

细胞，被重定向到单肿 瘤抗原。考虑到不均匀的胶质母细胞抗原

的表达，

我们假设双特 异性分子会减轻

car

分子逃生和提高抗原的

< br>T

细胞的抗肿

瘤活性。这里，我们创造了一个

< p>
CAR

加入

HER2-binding

scFv

and

an

IL13R

α

2-binding < /p>

IL-13

突变蛋白来使串联

CAR

增值和

CD28.ζ

增值。我们决定病人< /p>

CAR

T

细胞表现出明显的结合

HER2

或

il13r

α

2

和有能力自体溶解胶质母细胞瘤。

TanCAR T

细胞

展现了及活动力与之我们之前对比过 得那些单独的

CART

细胞的在遇到

H ER2 or IL13R

α

2

。

我们观察到，

TANCARS

从事

HER2

和

il13r

α

2

同时诱导

her2-il13r< /p>

α

2

的异源二聚体，从而

促进

T

细胞活化抗原可加时遇到并发

< br>。

TANCAR

T

细胞活性更 持久的但不比

T

细胞

表达

HER2

的

CAR

和一个< /p>

il13r

α

2

更可耗竭，

与单种

CAR T

细胞，

或混合产物。

在小鼠胶质瘤模型，

TanCAR

减轻抗原

T

细胞逃逸，显示增强的抗肿瘤作用，提

高动物的生存。因此，

TanCAR T

细胞的治疗潜力的共同参与

HER2

和

il13r

α< /p>

2

在增强提高胶质瘤控制，双价免疫突触增强

T

细胞功能和降低抗原逃逸。

摘要四部分：

1

1.

背景：

In

preclinical

models

of

glioblastoma,

antigen

escape

variants

can

lead

to

tumor

recurrence after treatment with CAR T cells that are redirected to single tumor antigens. Given the

heterogeneous

expression

of

antigens

on

glioblastomas,

we

hypothesized

that

a

bispecific

CAR

molecule would mitigate antigen escape and improve the antitumor activity of T cells.

2.

方法：

Here, we created a CAR that joins a HER2-

binding scFv and an IL13Rα2

-binding IL-13

mutein to make a tandem CAR exod

omain (TanCAR) and a CD28.ζ endodomain. We determined

that patient TanCAR T cells showed distinct binding to HER2 or IL13Rα2 and had the capabi

lity

to lyse autologous glioblastoma.

3.

结果：

TanCAR T cells exhibited activation dynamics that were comparable to those of single

CAR T cells upon encounter of HER2 or IL13Rα2. We observed that TanCARs engaged HER2

and

IL13Rα2

simultaneously

by

inducing

HER2

-I

L13Rα2

heterodimers,

which

promoted

superadditive T cell activation when both antigens were encountered concurrently. TanCAR T cell

activity was more sustained but not more exhaustible than that of T cells that coexpressed a HER2

CAR

and

an

IL13Rα2 CAR,

T

cells

with

a

unispecific

CAR,

or

a pooled

product. In

a

murine

glioblastoma

model,

TanCAR

T

cells

mitigated

antigen

escape,

displayed

enhanced

antitumor

efficacy, and improved animal survival.

4.

结论：

Thus,

TanCAR

T

cells

show

therapeutic

potential

to

improve

glioblastoma

control

by

coengaging HER2 and IL13Rα2 in an augmented, bivalent immune synapse that enhances T cell

functionality and reduces antigen escape.

三、

introduction

部分

Adoptive transfer of chimeric antigen receptor

–

grafted (CARgrafted)

T cells has induced tumor

regression in several preclinical models of glioblastoma (GBM) , osteosarcoma ,and

neuroblastoma . However, only sporadic clinical responses have been observed in early-phase

clinical trials for these tumors . In contrast, the sustained remission seen in preclinical models of

CAR T cell transfer in B cell leukemia was successfully translated to favorable outcomes in early

clinical trials. These successes were achieved by targeting of CD19, a B-cell lineage marker that is

uniformly expressed in B cell precursor acute lymphoblastic leukemia and chronic lymphocytic

leukemia cells. Explanations for this discrepancy include but are not limited to transient T cell

persistence in vivo, modest T cell homing, and inadequate T cell activation and/or T cell inhibition

at the tumor site (8, 9). The limited spectrum of T cell specificity in the face of the heterogeneous

and potentially dynamic antigen landscape is perhaps the biggest challenge for CAR T cell therapy

for solid tumors .We previously reported on GB

M’s markedly heterogeneous antigenic landscape .

A mathematical model of the expression hierarchy of 3 validated glioma antigens ,HER2,IL13Rα2,

and EphA2, predicted enhanced odds of tumor elimination on targeting of any 2 of these 3

antigens . Specifically

, while targeting HER2 or IL13Rα2 alone predicted a60%–

70%probability

of near-

complete tumor elimination, simultaneously targeting HER2 and IL13Rα2 was predicted

to eliminate more than 90% in a cohort of 20 primary GBMs . We reasoned that a single CAR

molecule with docking capacity to 2 tumor-associated antigens (TAAs) will form a bivalent T

cell/GBM immunological synapse (IS), enhancing T cell activation and offsetting antigen escape,

and collectively, these attributes will translate into superior antitumor activity . We report on a

bispecific CAR molecule that incorporates 2 antigen recognition domains for HER2 and IL13Rα2,

joined in tandem, thus termed TanCAR . We describe the design, in silico modeling, and

2