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Characterization of Postinfusion Phenotypic Differences in Fresh Versus Cryopreserved TCR Engineered Adoptive Cell Therapy Products

Nowicki, Theodore S. and Escuin-Ordinas, Helena and Avramis, Earl and Chmielowski, Bartosz and Chodon, Thinle and Berent-Maoz, Beata and Wang, Xiaoyan and Kaplan-Lefko, Paula and Yang, Lili and Baltimore, David and Economou, James S. and Ribas, Antoni and Comin-Anduix, Begoña (2018) Characterization of Postinfusion Phenotypic Differences in Fresh Versus Cryopreserved TCR Engineered Adoptive Cell Therapy Products. Journal of Immunotherapy, 41 (5). pp. 248-259. ISSN 1524-9557. PMCID PMC5959255. doi:10.1097/CJI.0000000000000216.

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Adoptive cell therapy (ACT) consisting of genetically engineered T cells expressing tumor antigen-specific T-cell receptors displays robust initial antitumor activity, followed by loss of T-cell activity/persistence and frequent disease relapse. We characterized baseline and longitudinal T-cell phenotype variations resulting from different manufacturing and administration protocols in patients who received ACT. Patients with melanoma who enrolled in the F5-MART-1 clinical trial (NCT00910650) received infusions of MART-1 T-cell receptors transgenic T cells with MART-1 peptide-pulsed dendritic cell vaccination. Patients were divided into cohorts based on several manufacturing changes in the generation and administration of the transgenic T cells: decreasing ex vivo stimulation/expansion time, increased cell dose, and receiving fresh instead of cryopreserved cells. T-cell phenotypes were analyzed by flow cytometry at baseline and longitudinally in peripheral blood. Transgenic T cells with shorter ex vivo culture/expansion periods displayed significantly increased expression of markers associated with less differentiated naive/memory populations, as well as significantly decreased expression of the inhibitory receptor programmed death 1 (PD1). Patients receiving fresh infusions of transgenic cells demonstrated expansion of central memory T cells and delayed acquisition of PD1 expression compared with patients who received cryopreserved products. Freshly infused transgenic T cells showed persistence and expansion of naive and memory T-cell populations and delayed acquisition of PD1 expression, which correlated with this cohort’s superior persistence of transgenic cells and response to dendritic cell vaccines. These results may be useful in designing future ACT protocols.

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Baltimore, David0000-0001-8723-8190
Additional Information:© 2018 The Author(s). Wolters Kluwer Health, Inc. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Received for publication November 7, 2017; accepted January 11, 2018. The authors gratefully acknowledge the NHLBI National Gene Vector Biorepository at Indiana University (PI Cornetta, P40HL116212) for assistance in the generation and maintenance of the F5 Vector. Flow cytometry was performed in the UCLA Jonsson Comprehensive Cancer Center (JCCC) and Center for AIDS Research Flow Cytometry Core Facility that is supported by National Institutes of Health awards P30 CA016042 and 5P30 AI028697, and by the JCCC, the UCLA AIDS Institute, and the David Geffen School of Medicine at UCLA. Conflicts of Interest/Financial Disclosures: Supported in part by NIH grants R01 CA129816 (to J.S.E.), P01 CA132681 (to D.B.), R35 CA197633 and P01 CA168585 (to A.R.), as well as the Parker Institute for Cancer Immunotherapy, the Ressler Family Fund, the Grimaldi Family Fund, the Samuels Family Fund and the Garcia-Corsini Family Fund (to A.R.). T.S.N. is supported by the NIH/NICHD grant K12-HD000850 (Pediatric Scientist Development Program). All authors have declared that there are no financial conflicts of interest with regard to this work.
Funding AgencyGrant Number
NIHP30 CA016042
NIH5P30 AI028697
UCLA Jonsson Comprehensive Cancer CenterUNSPECIFIED
David Geffen School of Medicine, UCLAUNSPECIFIED
NIHR01 CA129816
NIHP01 CA132681
NIHR35 CA197633
NIHP01 CA168585
Parker Institute for Cancer ImmunotherapyUNSPECIFIED
Ressler Family FundUNSPECIFIED
Grimaldi Family FundUNSPECIFIED
Samuels Family FundUNSPECIFIED
Garcia-Corsini Family FundUNSPECIFIED
National Heart, Lung, and Blood InstituteUNSPECIFIED
National Institute of Child Health and Human Development (NICHD)UNSPECIFIED
Subject Keywords:melanoma, adoptive cell therapy, T-cell phenotype, memory T cells, PD1
Issue or Number:5
PubMed Central ID:PMC5959255
Record Number:CaltechAUTHORS:20180227-091330026
Persistent URL:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:84970
Deposited By: Ruth Sustaita
Deposited On:27 Feb 2018 19:01
Last Modified:15 Nov 2021 20:24

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