Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains

Carmine Carpenito, Michael C. Milone, Raffit Hassan, Jacqueline C. Simonet, Mehdi Lakhal, Megan M. Suhoski, Angel Varela-Rohena, Kathleen M. Haines, Daniel F. Heitjan, Steven M. Albelda, Richard G. Carroll, James L. Riley, Ira Pastan, Carl H. June

Research output: Contribution to journalArticle

475 Citations (Scopus)

Abstract

Mesothelin is a cell-surface molecule over-expressed on a large fraction of carcinomas, and thus is an attractive target of immunotherapy. A molecularly targeted therapy for these cancers was created by engineering T cells to express a chimeric receptor with high affinity for human mesothelin. Lentiviral vectors were used to express a single-chain variable fragment that binds mesothelin and that is fused to signaling domains derived from T-cell receptor zeta, CD28, and CD137 (4-1BB). When stimulated by mesothelin, lentivirally transduced T cells were induced to proliferate, express the antiapoptotic gene Bcl-XL, and secrete multiple cytokines, all features characteristic of central memory T cells. When transferred intratumorally or intravenously into NOD/scid/IL2rγ-/- mice engrafted with large pre-established tumors, the engineered T cells reduced the tumor burden, and in some cases resulted in complete eradication of the tumors at low effector-to-target ratios. Incorporation of the CD137 signaling domain specifically reprogrammed cells for multifunctional cytokine secretion and enhanced persistence of T cells. These findings have important implications for adoptive immunotherapy of cancer, especially in the context of poorly immunogenic tumors. Genetically redirected T cells have promise of targeting T lymphocytes to tumor antigens, confer resistance to the tumor microenvironment, and providing immunosurveillance.

Original languageEnglish (US)
Pages (from-to)3360-3365
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number9
DOIs
StatePublished - Mar 3 2009

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Heterografts
T-Lymphocytes
Neoplasms
Cytokines
Adoptive Immunotherapy
Immunologic Monitoring
Single-Chain Antibodies
Tumor Microenvironment
Neoplasm Antigens
T-Cell Antigen Receptor
Tumor Burden
Immunotherapy
Carcinoma
mesothelin
Genes

Keywords

  • Adoptive immunotherapy
  • Chimeric receptor
  • Mesothelin

ASJC Scopus subject areas

  • General

Cite this

Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains. / Carpenito, Carmine; Milone, Michael C.; Hassan, Raffit; Simonet, Jacqueline C.; Lakhal, Mehdi; Suhoski, Megan M.; Varela-Rohena, Angel; Haines, Kathleen M.; Heitjan, Daniel F.; Albelda, Steven M.; Carroll, Richard G.; Riley, James L.; Pastan, Ira; June, Carl H.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 9, 03.03.2009, p. 3360-3365.

Research output: Contribution to journalArticle

Carpenito, C, Milone, MC, Hassan, R, Simonet, JC, Lakhal, M, Suhoski, MM, Varela-Rohena, A, Haines, KM, Heitjan, DF, Albelda, SM, Carroll, RG, Riley, JL, Pastan, I & June, CH 2009, 'Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains', Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 9, pp. 3360-3365. https://doi.org/10.1073/pnas.0813101106
Carpenito, Carmine ; Milone, Michael C. ; Hassan, Raffit ; Simonet, Jacqueline C. ; Lakhal, Mehdi ; Suhoski, Megan M. ; Varela-Rohena, Angel ; Haines, Kathleen M. ; Heitjan, Daniel F. ; Albelda, Steven M. ; Carroll, Richard G. ; Riley, James L. ; Pastan, Ira ; June, Carl H. / Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 9. pp. 3360-3365.
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AU - Lakhal, Mehdi

AU - Suhoski, Megan M.

AU - Varela-Rohena, Angel

AU - Haines, Kathleen M.

AU - Heitjan, Daniel F.

AU - Albelda, Steven M.

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