CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity

Elad Jacoby; Sang M. Nguyen; Thomas J. Fountaine; Kathryn Welp; Berkley Gryder; Haiying Qin; Yinmeng Yang; Christopher D. Chien; Alix E. Seif; Haiyan Lei; Young K. Song; Javed Khan; Daniel W. Lee; Crystal L. Mackall; Rebecca A. Gardner; Michael C. Jensen; Jack F. Shern; Terry J. Fry

doi:10.1038/ncomms12320

CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity

Elad Jacoby, Sang M. Nguyen, Thomas J. Fountaine, Kathryn Welp, Berkley Gryder, Haiying Qin, Yinmeng Yang, Christopher D. Chien, Alix E. Seif, Haiyan Lei, Young K. Song, Javed Khan, Daniel W. Lee, Crystal L. Mackall, Rebecca A. Gardner, Michael C. Jensen, Jack F. Shern, Terry J. Fry

School of Medicine

Research output: Contribution to journal › Article › peer-review

176 Scopus citations

Abstract

Adoptive immunotherapy using chimeric antigen receptor (CAR) expressing T cells targeting the CD19 B lineage receptor has demonstrated marked success in relapsed pre-B-cell acute lymphoblastic leukaemia (ALL). Persisting CAR-T cells generate sustained pressure against CD19 that may drive unique mechanisms of resistance. Pre-B ALL originates from a committed pre-B cell or an earlier progenitor, with potential to reprogram into other hematopoietic lineages. Here we report changes in lineage markers including myeloid conversion in patients following CD19 CAR therapy. Using murine ALL models we study the long-term effects of CD19 CAR-T cells and demonstrate partial or complete lineage switch as a consistent mechanism of CAR resistance depending on the underlying genetic oncogenic driver. Deletion of Pax5 or Ebf1 recapitulates lineage reprogramming occurring during CD19 CAR pressure. Our findings establish lineage switch as a mechanism of CAR resistance exposing inherent plasticity in genetic subtypes of pre-B-cell ALL.

Original language	English (US)
Article number	12320
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms12320
State	Published - Jul 27 2016

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

Access to Document

10.1038/ncomms12320

Cite this

Jacoby, E., Nguyen, S. M., Fountaine, T. J., Welp, K., Gryder, B., Qin, H., Yang, Y., Chien, C. D., Seif, A. E., Lei, H., Song, Y. K., Khan, J., Lee, D. W., Mackall, C. L., Gardner, R. A., Jensen, M. C., Shern, J. F., & Fry, T. J. (2016). CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity. Nature communications, 7, [12320]. https://doi.org/10.1038/ncomms12320

Jacoby, E, Nguyen, SM, Fountaine, TJ, Welp, K, Gryder, B, Qin, H, Yang, Y, Chien, CD, Seif, AE, Lei, H, Song, YK, Khan, J, Lee, DW, Mackall, CL, Gardner, RA, Jensen, MC, Shern, JF & Fry, TJ 2016, 'CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity', Nature communications, vol. 7, 12320. https://doi.org/10.1038/ncomms12320

@article{68955ea7cd924ac3b10ac2b40f9006cf,

title = "CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity",

abstract = "Adoptive immunotherapy using chimeric antigen receptor (CAR) expressing T cells targeting the CD19 B lineage receptor has demonstrated marked success in relapsed pre-B-cell acute lymphoblastic leukaemia (ALL). Persisting CAR-T cells generate sustained pressure against CD19 that may drive unique mechanisms of resistance. Pre-B ALL originates from a committed pre-B cell or an earlier progenitor, with potential to reprogram into other hematopoietic lineages. Here we report changes in lineage markers including myeloid conversion in patients following CD19 CAR therapy. Using murine ALL models we study the long-term effects of CD19 CAR-T cells and demonstrate partial or complete lineage switch as a consistent mechanism of CAR resistance depending on the underlying genetic oncogenic driver. Deletion of Pax5 or Ebf1 recapitulates lineage reprogramming occurring during CD19 CAR pressure. Our findings establish lineage switch as a mechanism of CAR resistance exposing inherent plasticity in genetic subtypes of pre-B-cell ALL.",

author = "Elad Jacoby and Nguyen, {Sang M.} and Fountaine, {Thomas J.} and Kathryn Welp and Berkley Gryder and Haiying Qin and Yinmeng Yang and Chien, {Christopher D.} and Seif, {Alix E.} and Haiyan Lei and Song, {Young K.} and Javed Khan and Lee, {Daniel W.} and Mackall, {Crystal L.} and Gardner, {Rebecca A.} and Jensen, {Michael C.} and Shern, {Jack F.} and Fry, {Terry J.}",

year = "2016",

month = jul,

day = "27",

doi = "10.1038/ncomms12320",

language = "English (US)",

volume = "7",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity

AU - Jacoby, Elad

AU - Nguyen, Sang M.

AU - Fountaine, Thomas J.

AU - Welp, Kathryn

AU - Gryder, Berkley

AU - Qin, Haiying

AU - Yang, Yinmeng

AU - Chien, Christopher D.

AU - Seif, Alix E.

AU - Lei, Haiyan

AU - Song, Young K.

AU - Khan, Javed

AU - Lee, Daniel W.

AU - Mackall, Crystal L.

AU - Gardner, Rebecca A.

AU - Jensen, Michael C.

AU - Shern, Jack F.

AU - Fry, Terry J.

PY - 2016/7/27

Y1 - 2016/7/27

N2 - Adoptive immunotherapy using chimeric antigen receptor (CAR) expressing T cells targeting the CD19 B lineage receptor has demonstrated marked success in relapsed pre-B-cell acute lymphoblastic leukaemia (ALL). Persisting CAR-T cells generate sustained pressure against CD19 that may drive unique mechanisms of resistance. Pre-B ALL originates from a committed pre-B cell or an earlier progenitor, with potential to reprogram into other hematopoietic lineages. Here we report changes in lineage markers including myeloid conversion in patients following CD19 CAR therapy. Using murine ALL models we study the long-term effects of CD19 CAR-T cells and demonstrate partial or complete lineage switch as a consistent mechanism of CAR resistance depending on the underlying genetic oncogenic driver. Deletion of Pax5 or Ebf1 recapitulates lineage reprogramming occurring during CD19 CAR pressure. Our findings establish lineage switch as a mechanism of CAR resistance exposing inherent plasticity in genetic subtypes of pre-B-cell ALL.

AB - Adoptive immunotherapy using chimeric antigen receptor (CAR) expressing T cells targeting the CD19 B lineage receptor has demonstrated marked success in relapsed pre-B-cell acute lymphoblastic leukaemia (ALL). Persisting CAR-T cells generate sustained pressure against CD19 that may drive unique mechanisms of resistance. Pre-B ALL originates from a committed pre-B cell or an earlier progenitor, with potential to reprogram into other hematopoietic lineages. Here we report changes in lineage markers including myeloid conversion in patients following CD19 CAR therapy. Using murine ALL models we study the long-term effects of CD19 CAR-T cells and demonstrate partial or complete lineage switch as a consistent mechanism of CAR resistance depending on the underlying genetic oncogenic driver. Deletion of Pax5 or Ebf1 recapitulates lineage reprogramming occurring during CD19 CAR pressure. Our findings establish lineage switch as a mechanism of CAR resistance exposing inherent plasticity in genetic subtypes of pre-B-cell ALL.

UR - http://www.scopus.com/inward/record.url?scp=84979901487&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84979901487&partnerID=8YFLogxK

U2 - 10.1038/ncomms12320

DO - 10.1038/ncomms12320

M3 - Article

C2 - 27460500

AN - SCOPUS:84979901487

SN - 2041-1723

VL - 7

JO - Nature Communications

JF - Nature Communications

M1 - 12320

ER -

CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this