Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts

Renier J. Brentjens, Elmer Santos, Yan Nikhamin, Raymond Yeh, Maiko Matsushita, Krista La Perle, Alfonso Quintás-Cardama, Steven M. Larson, Michel Sadelain

Research output: Contribution to journalArticle

236 Citations (Scopus)

Abstract

Purpose: Human T cells targeted to the B cell-specific CD19 antigen through retroviral-mediated transfer of a chimeric antigen receptor (CAR), termed 19z1, have shown significant but partial in vivo antitumor efficacy in a severe combined immunodeficient (SCID)-Beige systemic human acute lymphoblastic leukemia (NALM-6) tumor model. Here, we investigate the etiologies of treatment failure in this model and design approaches to enhance the efficacy of this adoptive strategy. Experimental Design: A panel of modified CD19-targeted CARs designed to deliver combined activating and costimulatory signals to the T cell was generated and tested in vitro to identify an optimal second-generation CAR. Antitumor efficacy of T cells expressing this optimal costimulatory CAR, 19-28z, was analyzed in mice bearing systemic costimulatory ligand-deficient NALM-6 tumors. Results: Expression of the 19-28z CAR, containing the signaling domain of the CD28 receptor, enhanced systemic T-cell antitumor activity when compared with 19z1 in treated mice. A treatment schedule of 4 weekly T-cell injections, designed to prolong in vivo T-cell function, further improved long-term survival. Bioluminescent imaging of tumor in treated mice failed to identify a conserved site of tumor relapse, consistent with successful homing by tumor-specific T cells to systemic sites of tumor involvement. Conclusions: Both in vivo costimulation and repeated administration enhance eradication of systemic tumor by genetically targeted T cells. The finding that modifications in CAR design as well as T-cell dosing allowed for the complete eradication of systemic disease affects the design of clinical trials using this treatment strategy.

Original languageEnglish
Pages (from-to)5426-5435
Number of pages10
JournalClinical Cancer Research
Volume13
Issue number18
DOIs
Publication statusPublished - 2007 Sep 15
Externally publishedYes

Fingerprint

Precursor Cell Lymphoblastic Leukemia-Lymphoma
Heterografts
Antigen Receptors
T-Lymphocytes
Neoplasms
CD19 Antigens
Disease Eradication
Treatment Failure
Appointments and Schedules
Research Design
Clinical Trials
Ligands
Recurrence
Injections
Survival
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Brentjens, R. J., Santos, E., Nikhamin, Y., Yeh, R., Matsushita, M., La Perle, K., ... Sadelain, M. (2007). Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts. Clinical Cancer Research, 13(18), 5426-5435. https://doi.org/10.1158/1078-0432.CCR-07-0674

Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts. / Brentjens, Renier J.; Santos, Elmer; Nikhamin, Yan; Yeh, Raymond; Matsushita, Maiko; La Perle, Krista; Quintás-Cardama, Alfonso; Larson, Steven M.; Sadelain, Michel.

In: Clinical Cancer Research, Vol. 13, No. 18, 15.09.2007, p. 5426-5435.

Research output: Contribution to journalArticle

Brentjens, RJ, Santos, E, Nikhamin, Y, Yeh, R, Matsushita, M, La Perle, K, Quintás-Cardama, A, Larson, SM & Sadelain, M 2007, 'Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts', Clinical Cancer Research, vol. 13, no. 18, pp. 5426-5435. https://doi.org/10.1158/1078-0432.CCR-07-0674
Brentjens, Renier J. ; Santos, Elmer ; Nikhamin, Yan ; Yeh, Raymond ; Matsushita, Maiko ; La Perle, Krista ; Quintás-Cardama, Alfonso ; Larson, Steven M. ; Sadelain, Michel. / Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts. In: Clinical Cancer Research. 2007 ; Vol. 13, No. 18. pp. 5426-5435.
@article{b828a46f256b4a6e825c317fbf86fe04,
title = "Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts",
abstract = "Purpose: Human T cells targeted to the B cell-specific CD19 antigen through retroviral-mediated transfer of a chimeric antigen receptor (CAR), termed 19z1, have shown significant but partial in vivo antitumor efficacy in a severe combined immunodeficient (SCID)-Beige systemic human acute lymphoblastic leukemia (NALM-6) tumor model. Here, we investigate the etiologies of treatment failure in this model and design approaches to enhance the efficacy of this adoptive strategy. Experimental Design: A panel of modified CD19-targeted CARs designed to deliver combined activating and costimulatory signals to the T cell was generated and tested in vitro to identify an optimal second-generation CAR. Antitumor efficacy of T cells expressing this optimal costimulatory CAR, 19-28z, was analyzed in mice bearing systemic costimulatory ligand-deficient NALM-6 tumors. Results: Expression of the 19-28z CAR, containing the signaling domain of the CD28 receptor, enhanced systemic T-cell antitumor activity when compared with 19z1 in treated mice. A treatment schedule of 4 weekly T-cell injections, designed to prolong in vivo T-cell function, further improved long-term survival. Bioluminescent imaging of tumor in treated mice failed to identify a conserved site of tumor relapse, consistent with successful homing by tumor-specific T cells to systemic sites of tumor involvement. Conclusions: Both in vivo costimulation and repeated administration enhance eradication of systemic tumor by genetically targeted T cells. The finding that modifications in CAR design as well as T-cell dosing allowed for the complete eradication of systemic disease affects the design of clinical trials using this treatment strategy.",
author = "Brentjens, {Renier J.} and Elmer Santos and Yan Nikhamin and Raymond Yeh and Maiko Matsushita and {La Perle}, Krista and Alfonso Quint{\'a}s-Cardama and Larson, {Steven M.} and Michel Sadelain",
year = "2007",
month = "9",
day = "15",
doi = "10.1158/1078-0432.CCR-07-0674",
language = "English",
volume = "13",
pages = "5426--5435",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "18",

}

TY - JOUR

T1 - Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts

AU - Brentjens, Renier J.

AU - Santos, Elmer

AU - Nikhamin, Yan

AU - Yeh, Raymond

AU - Matsushita, Maiko

AU - La Perle, Krista

AU - Quintás-Cardama, Alfonso

AU - Larson, Steven M.

AU - Sadelain, Michel

PY - 2007/9/15

Y1 - 2007/9/15

N2 - Purpose: Human T cells targeted to the B cell-specific CD19 antigen through retroviral-mediated transfer of a chimeric antigen receptor (CAR), termed 19z1, have shown significant but partial in vivo antitumor efficacy in a severe combined immunodeficient (SCID)-Beige systemic human acute lymphoblastic leukemia (NALM-6) tumor model. Here, we investigate the etiologies of treatment failure in this model and design approaches to enhance the efficacy of this adoptive strategy. Experimental Design: A panel of modified CD19-targeted CARs designed to deliver combined activating and costimulatory signals to the T cell was generated and tested in vitro to identify an optimal second-generation CAR. Antitumor efficacy of T cells expressing this optimal costimulatory CAR, 19-28z, was analyzed in mice bearing systemic costimulatory ligand-deficient NALM-6 tumors. Results: Expression of the 19-28z CAR, containing the signaling domain of the CD28 receptor, enhanced systemic T-cell antitumor activity when compared with 19z1 in treated mice. A treatment schedule of 4 weekly T-cell injections, designed to prolong in vivo T-cell function, further improved long-term survival. Bioluminescent imaging of tumor in treated mice failed to identify a conserved site of tumor relapse, consistent with successful homing by tumor-specific T cells to systemic sites of tumor involvement. Conclusions: Both in vivo costimulation and repeated administration enhance eradication of systemic tumor by genetically targeted T cells. The finding that modifications in CAR design as well as T-cell dosing allowed for the complete eradication of systemic disease affects the design of clinical trials using this treatment strategy.

AB - Purpose: Human T cells targeted to the B cell-specific CD19 antigen through retroviral-mediated transfer of a chimeric antigen receptor (CAR), termed 19z1, have shown significant but partial in vivo antitumor efficacy in a severe combined immunodeficient (SCID)-Beige systemic human acute lymphoblastic leukemia (NALM-6) tumor model. Here, we investigate the etiologies of treatment failure in this model and design approaches to enhance the efficacy of this adoptive strategy. Experimental Design: A panel of modified CD19-targeted CARs designed to deliver combined activating and costimulatory signals to the T cell was generated and tested in vitro to identify an optimal second-generation CAR. Antitumor efficacy of T cells expressing this optimal costimulatory CAR, 19-28z, was analyzed in mice bearing systemic costimulatory ligand-deficient NALM-6 tumors. Results: Expression of the 19-28z CAR, containing the signaling domain of the CD28 receptor, enhanced systemic T-cell antitumor activity when compared with 19z1 in treated mice. A treatment schedule of 4 weekly T-cell injections, designed to prolong in vivo T-cell function, further improved long-term survival. Bioluminescent imaging of tumor in treated mice failed to identify a conserved site of tumor relapse, consistent with successful homing by tumor-specific T cells to systemic sites of tumor involvement. Conclusions: Both in vivo costimulation and repeated administration enhance eradication of systemic tumor by genetically targeted T cells. The finding that modifications in CAR design as well as T-cell dosing allowed for the complete eradication of systemic disease affects the design of clinical trials using this treatment strategy.

UR - http://www.scopus.com/inward/record.url?scp=34848842554&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34848842554&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-07-0674

DO - 10.1158/1078-0432.CCR-07-0674

M3 - Article

VL - 13

SP - 5426

EP - 5435

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 18

ER -