TY - JOUR
T1 - Escape from ALL-CARTaz
T2 - Leukemia Immunoediting in the Age of Chimeric Antigen Receptors
AU - Zheng, Sisi
AU - Asnani, Mukta
AU - Thomas-Tikhonenko, Andrei
N1 - Funding Information:
Conflicts of Interest and Source of Funding: A.T.-T. has an interest in intellectual property “Discovery of CD19 Spliced Isoforms Resistant to CART-19.” This interest does not meet the definition of a reviewable interest under Children's Hospital of Philadelphia's (CHOP's) conflict of interest policy and is therefore not a financial conflict of interest. Furthermore, this intellectual property is held by CHOP and has not been licensed or otherwise commercialized to date. However, should this technology be commercialized in the future, A.T.-T. would be entitled to a share of royalties earned by CHOP per its patent policy. For the remaining authors, none were declared. Relevant research in our laboratory was supported by grants from the NIH (U01 CA232563), V Foundation for Cancer Research (T2018-014), and William Lawrence and Blanche Hughes Foundation. M.A. and A.T.-T. acknowledge support by St Baldrick's-Stand Up to Cancer Pediatric Dream Team Translational Research Grant (SU2C-AACR-DT-27-17).
Publisher Copyright:
© Wolters Kluwer Health, Inc. All rights reserved.
PY - 2019/5/1
Y1 - 2019/5/1
N2 - Chimeric antigen receptor (CAR) T-cell therapy has been transformative for the treatment of B-cell malignancies, with CD19- and CD22-directed CARs being prime examples. However, immunoediting and ensuing antigen loss remain the major obstacles to curative therapy in up to 25% of patients. For example, to achieve the CD19-negative phenotype, malignant cells can pick from a broad array of mechanisms, including focal loss-of-function mutations, dysregulated trafficking to the cell surface, alternative splicing, and lineage switching. In other cases, where resistance is mediated by insufficient antigen density, trogocytosis has been proposed as a possible underlying mechanism. To overcome these barriers, compensatory strategies will be needed, which could include using combinatorial CARs, harnessing epitope spreading, and targeting tumor neoantigens.
AB - Chimeric antigen receptor (CAR) T-cell therapy has been transformative for the treatment of B-cell malignancies, with CD19- and CD22-directed CARs being prime examples. However, immunoediting and ensuing antigen loss remain the major obstacles to curative therapy in up to 25% of patients. For example, to achieve the CD19-negative phenotype, malignant cells can pick from a broad array of mechanisms, including focal loss-of-function mutations, dysregulated trafficking to the cell surface, alternative splicing, and lineage switching. In other cases, where resistance is mediated by insufficient antigen density, trogocytosis has been proposed as a possible underlying mechanism. To overcome these barriers, compensatory strategies will be needed, which could include using combinatorial CARs, harnessing epitope spreading, and targeting tumor neoantigens.
KW - Adoptive T-cell therapy
KW - alternative splicing
KW - antigen escape
KW - chimeric antigen receptors
KW - epitope loss
KW - immunoediting
KW - immunotherapy
KW - leukemia
KW - lymphoma
KW - therapeutic resistance
UR - http://www.scopus.com/inward/record.url?scp=85066945173&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85066945173&partnerID=8YFLogxK
U2 - 10.1097/PPO.0000000000000381
DO - 10.1097/PPO.0000000000000381
M3 - Review article
C2 - 31135529
AN - SCOPUS:85066945173
SN - 1528-9117
VL - 25
SP - 217
EP - 222
JO - Cancer Journal
JF - Cancer Journal
IS - 3
ER -