In vivo inhibition of human CD19-targeted effector T cells by natural T regulatory cells in a xenotransplant murine model of B cell malignancy Journal Article

   

Authors:	Lee, J. C.; Hayman, E.; Pegram, H. J.; Santos, E.; Heller, G.; Sadelain, M.; Brentjens, R.
Article Title:	In vivo inhibition of human CD19-targeted effector T cells by natural T regulatory cells in a xenotransplant murine model of B cell malignancy
Abstract:	Human T cells genetically modified to express chimeric antigen receptors (CAR) specific to the B cell tumor antigen CD19 can successfully eradicate systemic human CD19+ tumors in immunocompromised SCID (severe combined immunodeficient)-Beige mice. However, in the clinical setting, CD4 + CD25hi T regulatory cells (Treg) present within the tumor microenvironment may be potent suppressors of tumor-targeted effector T cells. In order to assess the impact of Tregs on CAR-modified T cells in the SCID-Beige xenotransplant model, we isolated, genetically targeted and expanded natural T regulatory cells (nTreg). In vitro nTregs modified to express CD19-targeted CARs efficiently inhibited the proliferation of activated human T cells, as well as the capacity of CD19-targeted 19-28z+ effector T cells to lyse CD19+ Raji tumor cells. Intravenous infusion of CD19-targeted nTregs into SCID-Beige mice with systemic Raji tumors traffic to sites of tumor and recapitulate a clinically relevant hostile tumor microenvironment. Antitumor efficacy of subsequently infused 19-28z+ effector T cells was fully abrogated as assessed by long-term survival of treated mice. Optimal suppression by genetically targeted nTregs was dependent on nTreg to effector T-cell ratios and in vivo nTreg activation. Prior infusion of cyclophosphamide in the setting of this nTreg-mediated hostile microenvironment was able to restore the antitumor activity of subsequently infused 19-28z+ effector T cells through the eradication of tumor-targeted nTregs. These findings have significant implications for the design of future clinical trials utilizing CAR-based adoptive T-cell therapies of cancer. © 2011 American Association for Cancer Research.
Keywords:	controlled study; human cell; nonhuman; lymphocyte proliferation; mouse; animal tissue; animal experiment; animal model; cyclophosphamide; survival time; regulatory t lymphocyte; dna modification; cytotoxic t lymphocyte; adoptive transfer; effector cell; adoptive immunotherapy; t lymphocyte activation; lymphocyte depletion; cd19 antigen; burkitt lymphoma; tumor microenvironment; raji cell
Journal Title:	Cancer Research
Volume:	71
Issue:	8
ISSN:	0008-5472
Publisher:	American Association for Cancer Research
Date Published:	2011-04-15
Start Page:	2871
End Page:	2881
Language:	English
DOI:	10.1158/0008-5472.can-10-0552
PROVIDER:	scopus
PUBMED:	21487038
PMCID:	PMC3094720
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-79954573204&partnerID=40&md5=33803e53286bb436a94b366e82360121
Notes:	--- - "Export Date: 23 June 2011" - "CODEN: CNREA" - "Source: Scopus"

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