Adoptive transfer of MART-1 T-cell receptor transgenic lymphocytes and dendritic cell vaccination in patients with metastatic melanoma.

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.

• Authors: Thinle Chodon, Begoña Comin-Anduix, Bartosz Chmielowski, Richard C Koya, Zhongqi Wu, Martin Auerbach, Charles Ng, Earl Avramis, Elizabeth Seja, Arturo Villanueva, Tara A McCannel, Akira Ishiyama, Johannes Czernin, Caius G Radu, Xiaoyan Wang, David W Gjertson, Alistair J Cochran, Kenneth Cornetta, Deborah J L Wong, Paula Kaplan-Lefko, Omid Hamid, Wolfram Samlowski, Peter A Cohen, Gregory A Daniels, Bijay Mukherji, Lili Yang, Jerome A Zack, Donald B Kohn, James R Heath, John A Glaspy, Owen N Witte, David Baltimore, James S Economou, Antoni Ribas
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 20 Issue 9 Pg. 2457-65 (May 01 2014) ISSN: 1557-3265 [Electronic] United States
• PMID: 24634374 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2014 AACR.

Chemical References

• Cancer Vaccines
• MART-1 Antigen
• Peptide Fragments
• Receptors, Antigen, T-Cell

Topics

• Adult
• Cancer Vaccines (administration & dosage, adverse effects, immunology)
• Dendritic Cells (immunology, metabolism)
• Female
• Humans
• Immunotherapy, Adoptive (adverse effects)
• MART-1 Antigen (genetics, immunology)
• Male
• Melanoma (diagnosis, immunology, mortality, therapy)
• Middle Aged
• Neoplasm Metastasis
• Neoplasm Staging
• Peptide Fragments (genetics, immunology)
• Positron-Emission Tomography
• Receptors, Antigen, T-Cell (genetics)
• T-Lymphocytes (immunology, metabolism)
• Tomography, X-Ray Computed
• Transduction, Genetic
• Treatment Outcome
• Vaccination