Multifunctional T-cell Analyses to Study Response and Progression in Adoptive Cell Transfer Immunotherapy
Abstract
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.
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. HeathAttached Files
Accepted Version - nihms478899.pdf
Supplemental Material - fig1-8.pdf
Supplemental Material - tab1-5.pdf
Files
Additional details
- PMCID
- PMC3716460
- Eprint ID
- 39123
- DOI
- 10.1158/2159-8290.CD-12-0383
- Resolver ID
- CaltechAUTHORS:20130627-100022739
- 5U54 CA119347
- National Cancer Institute
- P50 CA086306
- National Cancer Institute
- P01 CA132681
- National Cancer Institute
- R01 CA170689-01
- National Cancer Institute
- Jean Perkins Foundation
- RN2-00902-1
- California Institute for Regenerative Medicine (CIRM)
- UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research
- Seaver Institute
- PhaseOne Foundation
- Louise Belley and Richard Schnarr Fund
- Wesley Coyle Memorial Fund
- Garcia-Corsini Family Fund
- Caltech/UCLA Joint Center for Translational Medicine
- Melanoma Research Alliance
- Caltech Rosen Fellowship
- CA-16042
- NIH
- AI-28697
- NIH
- Created
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2013-06-27Created from EPrint's datestamp field
- Updated
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2021-11-09Created from EPrint's last_modified field