Rapid Expansion of Highly Functional Antigen-Specific T Cells from Patients with Melanoma by Nanoscale Artificial Antigen-Presenting Cells
Open Access
- 1 April 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 26 (13), 3384-3396
- https://doi.org/10.1158/1078-0432.CCR-19-3487
Abstract
Purpose: Generation of antigen-specific T cells from patients with cancer employs large numbers of peripheral blood cells and/or tumor-infiltrating cells to generate antigen-presenting and effector cells commonly requiring multiple rounds of restimulation ex vivo. We used a novel paramagnetic, nanoparticle-based artificial antigen-presenting cell (nano-aAPC) that combines anti-CD28 costimulatory and human MHC class 1 molecules that are loaded with antigenic peptides to rapidly expand tumor antigen-specific T cells from patients with melanoma. Experimental Design: Nano-aAPC-expressing HLA-A*0201 molecules and costimulatory anti-CD28 antibody and HLAA*0201 molecules loaded with MART-1 or gp100 class I-restricted peptides were used to stimulate CD8 T cells purified from the peripheral blood of treatment-naive or PD-1 antibody-treated patients with stage IV melanoma. Expanded cells were restimulated with fresh peptide-pulsed nano-aAPC at day 7. Phenotype analysis and functional assays including cytokine release, cytolysis, and measurement of avidity were conducted. Results: MART-1-specific CD8 T cells rapidly expanded up to 1,000-fold by day 14 after exposure to peptide-pulsed nano-aAPC. Expanded T cells had a predominantly stem cell memory CD45RA(+)/CD62L(+)/CD95(+) phenotype; expressed ICOS, PD-1, Tim3, and LAG3; and lacked CD28. Cells from patients with melanoma were polyfunctional; highly avid; expressed IL2, IFN gamma and TNF alpha; and exhibited cytolytic activity against tumor cell lines. They expanded 2- to 3-fold after exposure to PD-1 antibody in vivo, and expressed a highly diverse T-cell receptor V beta repertoire. Conclusions: Peptide-pulsed nano-aAPC rapidly expanded polyfunctional antigen-specific CD8 T cells with high avidity, potent lytic function, and a stem cell memory phenotype from patients with melanoma.Other Versions
Funding Information
- NCI (R01CA175732)
- NIH (R33-CA229042)
- NIH (P41-EB028239)
This publication has 60 references indexed in Scilit:
- Transferred WT1-Reactive CD8 + T Cells Can Mediate Antileukemic Activity and Persist in Post-Transplant PatientsScience Translational Medicine, 2013
- An Artificial Antigen-presenting Cell with Paracrine Delivery of IL-2 Impacts the Magnitude and Direction of the T Cell Response*Online Journal of Public Health Informatics, 2011
- Determinants of Successful CD8+ T-Cell Adoptive Immunotherapy for Large Established Tumors in MiceClinical Cancer Research, 2011
- A panel of human cell-based artificial APC enables the expansion of long-lived antigen-specific CD4+ T cells restricted by prevalent HLA-DR allelesInternational Immunology, 2010
- Rapid detection, enrichment and propagation of specific T cell subsets based on cytokine secretionClinical and Experimental Immunology, 2010
- Dynamic regulation of functionally distinct virus-specific T cellsProceedings of the National Academy of Sciences of the United States of America, 2010
- Adoptive cell therapy for the treatment of patients with metastatic melanomaCurrent Opinion in Immunology, 2009
- Dysfunctional DC subsets in RCC patients: Ex vivo correction to yield an effective anti-cancer vaccineMolecular Immunology, 2009
- Manufacturing Validation of Biologically Functional T Cells Targeted to CD19 Antigen for Autologous Adoptive Cell TherapyJournal of Immunotherapy, 2009
- Treatment of Metastatic Melanoma with Autologous CD4+ T Cells against NY-ESO-1The New England Journal of Medicine, 2008