Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts
RJ Brentjens, E Santos, Y Nikhamin, R Yeh… - Clinical cancer …, 2007 - AACR
RJ Brentjens, E Santos, Y Nikhamin, R Yeh, M Matsushita, K La Perle, A Quintás-Cardama…
Clinical cancer research, 2007•AACRPurpose: 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 …
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 …
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.
AACR