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Multifunctional T-cell Analyses to Study Response and Progression in Adoptive Cell Transfer Immunotherapy

Ma, Chao and Cheung, Ann F. and Chodon, Thinle and Koya, Richard C. and Wu, Zhongqi and Ng, Charles and Avramis, Earl and Cochran, Alistair J. and Witte, Owen N. and Baltimore, David and Chmielowski, Bartosz and Economou, James S. and Comin-Anduix, Begonya and Ribas, Antoni and Heath, James R. (2013) Multifunctional T-cell Analyses to Study Response and Progression in Adoptive Cell Transfer Immunotherapy. Cancer Discovery, 3 (4). pp. 418-429. ISSN 2159-8274. PMCID PMC3716460.

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Adoptive cell transfer (ACT) of genetically engineered T cells expressing cancer-specific T-cell receptors (TCR) is a promising cancer treatment. Here, we investigate the in vivo functional activity and dynamics of the transferred cells by analyzing samples from 3 representative patients with melanoma enrolled in a clinical trial of ACT with TCR transgenic T cells targeted against the melanosomal antigen MART-1. The analyses included evaluating 19 secreted proteins from individual cells from phenotypically defined T-cell subpopulations, as well as the enumeration of T cells with TCR antigen specificity for 36 melanoma antigens. These analyses revealed the coordinated functional dynamics of the adoptively transferred, as well as endogenous, T cells, and the importance of highly functional T cells in dominating the antitumor immune response. This study highlights the need to develop approaches to maintaining antitumor T-cell functionality with the aim of increasing the long-term efficacy of TCR-engineered ACT immunotherapy. Significance: A longitudinal functional study of adoptively transferred TCR–engineered lymphocytes yielded revealing snapshots for understanding the changes of antitumor responses over time in ACT immunotherapy of patients with advanced melanoma.

Item Type:Article
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URLURL TypeDescription CentralArticle
Witte, Owen N.0000-0003-4461-4533
Baltimore, David0000-0001-8723-8190
Heath, James R.0000-0001-5356-4385
Additional Information:© 2013 American Association for Cancer Research. Received August 20, 2012; revised January 8, 2013; accepted January 11, 2013; published Online First March 21, 2013. Grant Support: This work was funded by National Cancer Institute grants 5U54 CA119347 (to J.R. Heath), P50 CA086306 (to A. Ribas), P01 CA132681 (to D. Baltimore, A. Ribas, and J.R. Heath), and R01 CA170689-01 (to J.R. Heath and A. Ribas); the Jean Perkins Foundation (to J.R. Heath); the California Institute for Regenerative Medicine New Faculty Award RN2-00902-1 (to A. Ribas); the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA (to O.N. Witte and A. Ribas); The Seaver Institute (to A. Ribas); the PhaseOne Foundation (to A. Ribas); the Louise Belley and Richard Schnarr Fund (to A. Ribas); the Wesley Coyle Memorial Fund (to A. Ribas); the Garcia-Corsini Family Fund (to A. Ribas); the Caltech/UCLA Joint Center for Translational Medicine (to A. Ribas and J.R. Heath); the Melanoma Research Alliance (to A. Ribas, D. Baltimore, and J.R. Heath); and a Rosen Fellowship (to C. Ma). The UCLA Jonsson Comprehensive Cancer Center Flow Cytometry Core Facility is supported by NIH awards CA-16042 and AI-28697. Acknowledgments: The authors thank Steven A. Rosenberg, Richard Morgan, Laura Johnson, and Mark Dudley (all from the National Cancer Institute Surgery Branch) for access to the clinical grade retroviral vector master cell bank and their guidance in establishing the TCR-engineered ACT protocol; Carl June and Michael Kalos at University of Pennsylvania; and Jonathan Braun at UCLA for valuable discussions. The authors also thank Erika von Euw, Joanne Cox, and Narsis Attar for the manufacture of cell therapies; Elizabeth Seja and Arturo Villanueva for study coordination and data management at UCLA; Li Cheung and Rochelle Diamond at the Caltech flow cytometry facility; Bruz Marzolf at the Institute for Systems Biology (Seattle, WA); the UCLA Institute of Molecular Medicine; and the UCLA fl ow cytometry core. Finally, the authors thank the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at UCLA for clinical trial materials. Authors’ Contributions: Conception and design: C. Ma, A. Ribas, J.R. Heath Development of methodology: C. Ma, A.F. Cheung Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): C. Ma, A.F. Cheung, T. Chodon, R.C. Koya, B. Comin-Anduix, A. Ribas Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): C. Ma, A. Ribas Writing, review, and/or revision of the manuscript: C. Ma, A. Ribas, J.R. Heath Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): Z. Wu, C. Ng, E. Avramis, A.J. Cochran Study supervision: C. Ma, O.N. Witte, D. Baltimore, B. Chmielowski, J.S. Economou, A. Ribas, J.R. Heath
Funding AgencyGrant Number
National Cancer Institute5U54 CA119347
National Cancer InstituteP50 CA086306
National Cancer InstituteP01 CA132681
National Cancer InstituteR01 CA170689-01
Jean Perkins FoundationUNSPECIFIED
California Institute for Regenerative Medicine (CIRM)RN2-00902-1
UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell ResearchUNSPECIFIED
Seaver InstituteUNSPECIFIED
PhaseOne FoundationUNSPECIFIED
Louise Belley and Richard Schnarr FundUNSPECIFIED
Wesley Coyle Memorial FundUNSPECIFIED
Garcia-Corsini Family FundUNSPECIFIED
Caltech/UCLA Joint Center for Translational MedicineUNSPECIFIED
Melanoma Research AllianceUNSPECIFIED
Caltech Rosen FellowshipUNSPECIFIED
Issue or Number:4
PubMed Central ID:PMC3716460
Record Number:CaltechAUTHORS:20130627-100022739
Persistent URL:
Official Citation:Multifunctional T-cell Analyses to Study Response and Progression in Adoptive Cell Transfer Immunotherapy Chao Ma, Ann F. Cheung, Thinle Chodon, Richard C. Koya, Zhongqi Wu, Charles Ng, Earl Avramis, Alistair J. Cochran, Owen N. Witte, David Baltimore, Bartosz Chmielowski, James S. Economou, Begonya Comin-Anduix, Antoni Ribas, and James R. Heath Cancer Discovery April 2013 3:418-429; Published OnlineFirst March 21, 2013; doi:10.1158/2159-8290.CD-12-0383
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:39123
Deposited By: Jason Perez
Deposited On:27 Jun 2013 20:19
Last Modified:03 Oct 2019 05:04

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