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Adoptive Transfer of MART-1 T-Cell Receptor Transgenic Lymphocytes and Dendritic Cell Vaccination in Patients with Metastatic Melanoma

Chodon, Thinle and Baltimore, David (2014) Adoptive Transfer of MART-1 T-Cell Receptor Transgenic Lymphocytes and Dendritic Cell Vaccination in Patients with Metastatic Melanoma. Clinical Cancer Research, 20 (9). pp. 2457-2465. ISSN 1078-0432. PMCID PMC4070853. doi:10.1158/1078-0432.CCR-13-3017. https://resolver.caltech.edu/CaltechAUTHORS:20140613-144829921

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Abstract

Purpose: It has been demonstrated that large numbers of tumor-specific T cells for adoptive cell transfer (ACT) can be manufactured by retroviral genetic engineering of autologous peripheral blood lymphocytes and expanding them over several weeks. In mouse models, this therapy is optimized when administered with dendritic cell (DC) vaccination. We developed a short 1-week manufacture protocol to determine the feasibility, safety, and antitumor efficacy of this double cell therapy. Experimental Design: A clinical trial (NCT00910650) adoptively transferring MART-1 T-cell receptor (TCR) transgenic lymphocytes together with MART-1 peptide-pulsed DC vaccination in HLA-A2.1 patients with metastatic melanoma. Autologous TCR transgenic cells were manufactured in 6 to 7 days using retroviral vector gene transfer, and reinfused with (n = 10) or without (n = 3) prior cryopreservation. Results: A total of 14 patients with metastatic melanoma were enrolled and 9 of 13 treated patients (69%) showed evidence of tumor regression. Peripheral blood reconstitution with MART-1–specific T cells peaked within 2 weeks of ACT, indicating rapid in vivo expansion. Administration of freshly manufactured TCR transgenic T cells resulted in a higher persistence of MART-1–specific T cells in the blood as compared with cryopreserved. Evidence that DC vaccination could cause further in vivo expansion was only observed with ACT using noncryopreserved T cells. Conclusion: Double cell therapy with ACT of TCR-engineered T cells with a very short ex vivo manipulation and DC vaccines is feasible and results in antitumor activity, but improvements are needed to maintain tumor responses.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1158/1078-0432.CCR-13-3017DOIArticle
https://clincancerres.aacrjournals.org/content/20/9/2457/suppl/DC1PublisherSupplementary Data
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4070853PubMed CentralArticle
ORCID:
AuthorORCID
Baltimore, David0000-0001-8723-8190
Additional Information:© 2014 American Association for Cancer Research. Received November 4, 2013; revised January 21, 2014; accepted February 17, 2014; published Online First March 14, 2014. This work was funded by the NCI grants P01 CA132681 (to D. Baltimore, J.S. Economou, O.N. Witte, A. Ribas, D.B. Kohn, and J.A. Glaspy), U54 CA119347 (to J.R. Heath and A. Ribas), P50 CA086306 (to A. Ribas), and RO1 CA129816 (to J.S. Economou), the California Institute for Regenerative Medicine New Faculty Award RN2-00902-1 (to A. Ribas), the Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA (to O.N. Witte and A. Ribas), the Samuel Waxman Foundation (to J.S. Economou, D. Baltimore, and O.N. Witte), the Keck Foundation (to J.S. Economou, D. Baltimore, and O.N. Witte), 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 Bila Alon Hacker Memorial Fund (to A. Ribas), the Fred L. Hartley Family Foundation (to A. Ribas), the Ruby Family Foundation (to A. Ribas), the Joy and Jerry Monkarsh Fund (to J.S. Economou), the Caltech/UCLA Joint Center for Translational Medicine (to D. Baltimore, O.N. Witte, and A. Ribas), and the Melanoma Research Alliance (to A. Ribas, D. Baltimore, and J.R. Heath). O.N. Witte is an investigator of the Howard Hughes Medical Institute. R.C. Koya was supported in part by the V Foundation-Gil Nickel Family Endowed Fellowship in Melanoma Research. The UCLA Jonsson Comprehensive Cancer Center (JCCC) Flow Cytometry Core Facility is supported by NIH awards CA-16042 and AI-28697. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Acknowledgments: The authors thank Steven A. Rosenberg, Richard Morgan, Laura Johnson, and Mark Dudley (all from the NCI Surgery Branch, Bethesda, MD) for their guidance in establishing the TCR-engineered ACT protocol at UCLA and allowing access to their clinical grade retroviral vectormaster cell bank. They also acknowledge the contributions of Erika von Euw, Joanne Cox, and Narsis Attar in some of the cell therapy preparations. Authors' Contributions: Conception and design: T. Chodon, B. Chmielowski, R.C. Koya, D.W. Gjertson, B. Mukherji, L. Yang, J.A. Zack, O.N. Witte, D. Baltimore, J.S. Economou, A. Ribas Development of methodology: T. Chodon, B. Chmielowski, R.C. Koya, C.G. Radu, D.W. Gjertson, A.J. Cochran, K. Cornetta, B. Mukherji, L. Yang, D. Baltimore, A. Ribas Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): T. Chodon, B. Comin-Anduix, B. Chmielowski, R.C. Koya, Z. Wu, M. Auerbach, C. Ng, E. Avramis, T.A. McCannel, A. Ishiyama, J. Czernin, K. Cornetta, D.J.L. Wong, P. Kaplan-lefko, O. Hamid, W. Samlowski, P.A. Cohen, G.A. Daniels, J.R. Heath, J.A. Glaspy, A. Ribas Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): T. Chodon, B. Comin-Anduix, B. Chmielowski, R.C. Koya, M. Auerbach, E. Avramis, J. Czernin, X. Wang, D.W. Gjertson, A.J. Cochran, J.R. Heath, J.A. Glaspy, J.S. Economou, A. Ribas Writing, review, and/or revision of the manuscript: T. Chodon, B. Chmielowski, R.C. Koya, M. Auerbach, E. Avramis, T.A. McCannel, J. Czernin, X.Wang, A.J. Cochran, K. Cornetta, W. Samlowski, G.A. Daniels, J.A. Zack, D.B. Kohn, D. Baltimore, A. Ribas Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): T. Chodon, Z. Wu, E. Avramis, E. Seja, A. Villanueva, T.A. McCannel, P. Kaplan-lefko, O.N. Witte, D. Baltimore, A. Ribas Study supervision: T. Chodon, B. Chmielowski, R.C. Koya, A.J. Cochran, J.S. Economou, A. Ribas.
Funders:
Funding AgencyGrant Number
NIHP01 CA132681
NIHU54 CA119347
NIHP50 CA086306
NIHRO1 CA129816
California Institute for Regenerative Medicine (CIRM)RN2-00902-1
UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell ResearchUNSPECIFIED
Samuel Waxman FoundationUNSPECIFIED
W. M. Keck FoundationUNSPECIFIED
Seaver InstituteUNSPECIFIED
PhaseOne FoundationUNSPECIFIED
Louise Belley and Richard Schnarr FundUNSPECIFIED
Wesley Coyle Memorial FundUNSPECIFIED
Garcia-Corsini Family FundUNSPECIFIED
Bila Alon Hacker Memorial FundUNSPECIFIED
Fred L. Hartley Family FoundationUNSPECIFIED
Ruby Family FoundationUNSPECIFIED
Joy and Jerry Monkarsh FundUNSPECIFIED
Caltech/UCLA Joint Center for Translational MedicineUNSPECIFIED
Melanoma Research AllianceUNSPECIFIED
V Foundation-Gil Nickel Family Endowed Fellowship in Melanoma ResearchUNSPECIFIED
NIHCA-16042
NIHAI-28697
National Cancer InstituteUNSPECIFIED
Issue or Number:9
PubMed Central ID:PMC4070853
DOI:10.1158/1078-0432.CCR-13-3017
Record Number:CaltechAUTHORS:20140613-144829921
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20140613-144829921
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:46269
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:13 Jun 2014 22:23
Last Modified:10 Nov 2021 17:23

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