Journal
CLINICAL CANCER RESEARCH
Volume 20, Issue 9, Pages 2457-2465Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-13-3017
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Funding
- NCI [P01 CA132681, U54 CA119347, P50 CA086306, RO1 CA129816]
- California Institute for Regenerative Medicine New Faculty Award [RN2-00902-1]
- Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA
- Samuel Waxman Foundation
- Keck Foundation
- Seaver Institute
- PhaseOne Foundation
- Louise Belley and Richard Schnarr Fund
- Wesley Coyle Memorial Fund
- Garcia-Corsini Family Fund
- Bila Alon Hacker Memorial Fund
- Fred L. Hartley Family Foundation
- Ruby Family Foundation
- Joy and Jerry Monkarsh Fund
- Caltech/UCLA Joint Center for Translational Medicine
- Melanoma Research Alliance
- V Foundation-Gil Nickel Family Endowed Fellowship in Melanoma Research
- NIH [CA-16042, AI-28697]
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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.
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