Adoptive Transfer of MART-1 T-Cell Receptor Transgenic Lymphocytes and Dendritic Cell Vaccination in Patients with Metastatic Melanoma
- 30 April 2014
- journal article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 20 (9), 2457-2465
- https://doi.org/10.1158/1078-0432.ccr-13-3017
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. Clin Cancer Res; 20(9); 2457–65. ©2014 AACR.Other Versions
This publication has 36 references indexed in Scilit:
- Antitumor activity from antigen-specific CD8 T cells generated in vivo from genetically engineered human hematopoietic stem cellsProceedings of the National Academy of Sciences of the United States of America, 2011
- A human memory T cell subset with stem cell–like propertiesNature Medicine, 2011
- A clinical microchip for evaluation of single immune cells reveals high functional heterogeneity in phenotypically similar T cellsNature Medicine, 2011
- A Central Role for mTOR Kinase in Homeostatic Proliferation Induced CD8+ T Cell Memory and Tumor ImmunityImmunity, 2011
- Kinetic phases of distribution and tumor targeting by T cell receptor engineered lymphocytes inducing robust antitumor responsesProceedings of the National Academy of Sciences of the United States of America, 2010
- Case Report of a Serious Adverse Event Following the Administration of T Cells Transduced With a Chimeric Antigen Receptor Recognizing ERBB2Molecular Therapy, 2010
- Tumor-reactive CD4+ T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hostsThe Journal of Experimental Medicine, 2010
- Modular Nucleic Acid Assembled p/MHC Microarrays for Multiplexed Sorting of Antigen-Specific T CellsJournal of the American Chemical Society, 2009
- mTOR regulates memory CD8 T-cell differentiationNature, 2009
- Optimal two-stage designs for phase II clinical trialsControlled Clinical Trials, 1989