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Long-Lived Antitumor CD8⁺ Lymphocytes for Adoptive Therapy Generated Using an Artificial Antigen-Presenting Cell

Authors' Affiliations: Departments of ¹ Medical Oncology and ² Biostatistics and Computational Biology, Dana-Farber Cancer Institute, ³ Department of Medicine, Brigham and Women's Hospital, ⁴ Department of Genetics, ⁵ Harvard Medical School, and ⁶ Division of Molecular Medicine, Children's Hospital, Boston, Massachusetts

Requests for reprints: Marcus Butler, Dana-Farber Cancer Institute, Department of Medical Oncology, 44 Binney Street, Boston, MA 02115. Phone: 617-632-4589; Fax: 617-632-2255; E-mail: Marcus_Butler{at}dfci.harvard.edu.

Purpose: Antitumor lymphocytes can be generated ex vivo unencumbered by immunoregulation found in vivo. Adoptive transfer of these cells is a promising therapeutic modality that could establish long-term antitumor immunity. However, the widespread use of adoptive therapy has been hampered by the difficulty of consistently generating potent antitumor lymphocytes in a timely manner for every patient. To overcome this, we sought to establish a clinical grade culture system that can reproducibly generate antigen-specific cytotoxic T lymphocytes (CTL).

Experimental Design: We created an off-the-shelf, standardized, and renewable artificial antigen-presenting cell (aAPC) line that coexpresses HLA class I, CD54, CD58, CD80, and the dendritic cell maturation marker CD83. We tested the ability of aAPC to generate tumor antigen-specific CTL under optimal culture conditions. The number, phenotype, effector function, and in vitro longevity of generated CTL were determined.

Results: Stimulation of CD8⁺ T cells with peptide-pulsed aAPC generated large numbers of functional CTL that recognized a variety of tumor antigens. These CTLs, which possess a phenotype consistent with in vivo persistence, survived ex vivo for prolonged periods of time. Clinical grade aAPC³³, produced under current Good Manufacturing Practices guidelines, generated sufficient numbers of CTL within a short period of time. These CTL specifically lysed a variety of melanoma tumor lines naturally expressing a target melanoma antigen. Furthermore, antitumor CTL were easily generated in all melanoma patients examined.

Conclusions: With clinical grade aAPC³³ in hand, we are now poised for clinical translation of ex vivo generated antitumor CTL for adoptive cell transfer.

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