Performance of anti-CD19 chimeric antigen receptor T cells in
genetically defined classes of chronic lymphocytic leukemia

J 2020

Performance of anti-CD19 chimeric antigen receptor T cells in genetically defined classes of chronic lymphocytic leukemia

MANČÍKOVÁ, Veronika, Helena PESCHELOVÁ, Veronika KOZLOVÁ, Aneta LEDEREROVÁ, Adriana LADUNGOVÁ et. al.

Basic information

Original name

Performance of anti-CD19 chimeric antigen receptor T cells in genetically defined classes of chronic lymphocytic leukemia

Authors

MANČÍKOVÁ, Veronika (703 Slovakia, belonging to the institution), Helena PESCHELOVÁ (203 Czech Republic, belonging to the institution), Veronika KOZLOVÁ (203 Czech Republic, belonging to the institution), Aneta LEDEREROVÁ (203 Czech Republic, belonging to the institution), Adriana LADUNGOVÁ (703 Slovakia, belonging to the institution), Jan VERNER (203 Czech Republic, belonging to the institution), Tomáš LOJA (703 Slovakia, belonging to the institution), František FOLBER (203 Czech Republic, belonging to the institution), Jiří MAYER (203 Czech Republic, belonging to the institution), Šárka POSPÍŠILOVÁ (203 Czech Republic, belonging to the institution) and Michal ŠMÍDA (203 Czech Republic, guarantor, belonging to the institution)

Edition

Journal for ImmunoTherapy of Cancer, Switzerland, Springer International Publishing AG, 2020, 2051-1426

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30204 Oncology

Country of publisher

United Kingdom of Great Britain and Northern Ireland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 13.751

RIV identification code

RIV/00216224:14740/20:00115788

Organization unit

Central European Institute of Technology

DOI

http://dx.doi.org/10.1136/jitc-2019-000471

UT WoS

000534747200004

Keywords in English

genetics; haematology; immunology

Abstract

V originále

Background While achieving prolonged remissions in other B cell-derived malignancies, chimeric antigen receptor (CAR) T cells still underperform when injected into patients with chronic lymphocytic leukemia (CLL). We studied the influence of genetics on CLL response to anti-CD19 CAR T-cell therapy. Methods First, we studied 32 primary CLL samples composed of 26 immunoglobulin heavy-chain gene variable (IGHV)-unmutated (9 ATM-mutated, 8 TP53-mutated, and 9 without mutations in ATM, TP53, NOTCH1 or SF3B1) and 6 IGHV-mutated samples without mutations in the above-mentioned genes. Then, we mimicked the leukemic microenvironment in the primary cells by '2S stimulation' through interleukin-2 and nuclear factor kappa B. Finally, CRISPR/Cas9-generated ATM-knockout and TP53-knockout clones (four and seven, respectively) from CLL-derived cell lines MEC1 and HG3 were used. All these samples were exposed to CAR T cells. In vivo survival study in NSG mice using HG3 wild-type (WT), ATM-knockout or TP53-knockout cells was also performed. Results Primary unstimulated CLL cells were specifically eliminated after >24 hours of coculture with CAR T cells. '2S' stimulated cells showed increased survival when exposed to CAR T cells compared with unstimulated ones, confirming the positive effect of this stimulation on CLL cells' in vitro fitness. After 96 hours of coculture, there was no difference in survival among the genetic classes. Finally, CAR T cells were specifically activated in vitro in the presence of target knockout cell lines as shown by the production of interferon-gamma when compared with control (CTRL) T cells (p=0.0020), but there was no difference in knockout cells' survival. In vivo, CAR T cells prolonged the survival of mice injected with WT, TP53-knockout and ATM-knockout HG3 tumor cells as compared with CTRL T cells (p=0.0485, 0.0204 and <0.0001, respectively). When compared with ATM-knockout, TP53-knockout disease was associated with an earlier time of onset (p<0.0001), higher tumor burden (p=0.0002) and inefficient T-cell engraftment (p=0.0012). Conclusions While in vitro no differences in survival of CLL cells of various genetic backgrounds were observed, CAR T cells showed a different effectiveness at eradicating tumor cells in vivo depending on the driver mutation. Early disease onset, high-tumor burden and inefficient T-cell engraftment, associated with TP53-knockout tumors in our experimental setting, ultimately led to inferior performance of CAR T cells.

Citovat

MANČÍKOVÁ, Veronika, Helena PESCHELOVÁ, Veronika KOZLOVÁ, Aneta LEDEREROVÁ, Adriana LADUNGOVÁ, Jan VERNER, Tomáš LOJA, František FOLBER, Jiří MAYER, Šárka POSPÍŠILOVÁ and Michal ŠMÍDA. Performance of anti-CD19 chimeric antigen receptor T cells in genetically defined classes of chronic lymphocytic leukemia. Journal for ImmunoTherapy of Cancer. Switzerland: Springer International Publishing AG, 2020, vol. 8, No 1, p. 000471-481. ISSN 2051-1426. Available from: https://dx.doi.org/10.1136/jitc-2019-000471.

@article{1662457,
   author = {Mančíková, Veronika and Peschelová, Helena and Kozlová, Veronika and Ledererová, Aneta and Ladungová, Adriana and Verner, Jan and Loja, Tomáš and Folber, František and Mayer, Jiří and Pospíšilová, Šárka and Šmída, Michal},
   article_location = {Switzerland},
   article_number = {1},
   doi = {http://dx.doi.org/10.1136/jitc-2019-000471},
   keywords = {genetics; haematology; immunology},
   language = {eng},
   issn = {2051-1426},
   journal = {Journal for ImmunoTherapy of Cancer},
   title = {Performance of anti-CD19 chimeric antigen receptor T cells in genetically defined classes of chronic lymphocytic leukemia},
   url = {https://jitc.bmj.com/content/8/1/e000471},
   volume = {8},
   year = {2020}
}

TY  - JOUR
ID  - 1662457
AU  - Mančíková, Veronika - Peschelová, Helena - Kozlová, Veronika - Ledererová, Aneta - Ladungová, Adriana - Verner, Jan - Loja, Tomáš - Folber, František - Mayer, Jiří - Pospíšilová, Šárka - Šmída, Michal
PY  - 2020
TI  - Performance of anti-CD19 chimeric antigen receptor T cells in genetically defined classes of chronic lymphocytic leukemia
JF  - Journal for ImmunoTherapy of Cancer
VL  - 8
IS  - 1
SP  - 000471
EP  - 000471
PB  - Springer International Publishing AG
SN  - 20511426
KW  - genetics
KW  - haematology
KW  - immunology
UR  - https://jitc.bmj.com/content/8/1/e000471
L2  - https://jitc.bmj.com/content/8/1/e000471
N2  - Background While achieving prolonged remissions in other B cell-derived malignancies, chimeric antigen receptor (CAR) T cells still underperform when injected into patients with chronic lymphocytic leukemia (CLL). We studied the influence of genetics on CLL response to anti-CD19 CAR T-cell therapy. Methods First, we studied 32 primary CLL samples composed of 26 immunoglobulin heavy-chain gene variable (IGHV)-unmutated (9 ATM-mutated, 8 TP53-mutated, and 9 without mutations in ATM, TP53, NOTCH1 or SF3B1) and 6 IGHV-mutated samples without mutations in the above-mentioned genes. Then, we mimicked the leukemic microenvironment in the primary cells by '2S stimulation' through interleukin-2 and nuclear factor kappa B. Finally, CRISPR/Cas9-generated ATM-knockout and TP53-knockout clones (four and seven, respectively) from CLL-derived cell lines MEC1 and HG3 were used. All these samples were exposed to CAR T cells. In vivo survival study in NSG mice using HG3 wild-type (WT), ATM-knockout or TP53-knockout cells was also performed. Results Primary unstimulated CLL cells were specifically eliminated after >24 hours of coculture with CAR T cells. '2S' stimulated cells showed increased survival when exposed to CAR T cells compared with unstimulated ones, confirming the positive effect of this stimulation on CLL cells' in vitro fitness. After 96 hours of coculture, there was no difference in survival among the genetic classes. Finally, CAR T cells were specifically activated in vitro in the presence of target knockout cell lines as shown by the production of interferon-gamma when compared with control (CTRL) T cells (p=0.0020), but there was no difference in knockout cells' survival. In vivo, CAR T cells prolonged the survival of mice injected with WT, TP53-knockout and ATM-knockout HG3 tumor cells as compared with CTRL T cells (p=0.0485, 0.0204 and <0.0001, respectively). When compared with ATM-knockout, TP53-knockout disease was associated with an earlier time of onset (p<0.0001), higher tumor burden (p=0.0002) and inefficient T-cell engraftment (p=0.0012). Conclusions While in vitro no differences in survival of CLL cells of various genetic backgrounds were observed, CAR T cells showed a different effectiveness at eradicating tumor cells in vivo depending on the driver mutation. Early disease onset, high-tumor burden and inefficient T-cell engraftment, associated with TP53-knockout tumors in our experimental setting, ultimately led to inferior performance of CAR T cells.
ER  -

MANČÍKOVÁ, Veronika, Helena PESCHELOVÁ, Veronika KOZLOVÁ, Aneta LEDEREROVÁ, Adriana LADUNGOVÁ, Jan VERNER, Tomáš LOJA, František FOLBER, Jiří MAYER, Šárka POSPÍŠILOVÁ and Michal ŠMÍDA. Performance of anti-CD19 chimeric antigen receptor T cells in genetically defined classes of chronic lymphocytic leukemia. \textit{Journal for ImmunoTherapy of Cancer}. Switzerland: Springer International Publishing AG, 2020, vol.~8, No~1, p.~000471-481. ISSN~2051-1426. Available from: https://dx.doi.org/10.1136/jitc-2019-000471.

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