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Phase I Trial of Adoptive Immunotherapy With Cytolytic T Lymphocytes Immunized Against a Tyrosinase Epitope

From the Center for Biological Therapy and Melanoma Research, University of California San Diego School of Medicine, San Diego, CA.

Address reprint requests to Malcolm S. Mitchell, MD, Hudson-Webber Cancer Research Center, Rm 740.2, Karmanos Cancer Institute, 110 East Warren Ave, Detroit, MI 48201; email: mitchell@ karmanos.org.

PURPOSE: To study distribution and toxicity of cytolytic T lymphocytes (CTLs) against a single melanoma epitope.

PATIENTS AND METHODS: CD8⁺ T cells obtained by leukapheresis from 10 patients with disseminated HLA-A2.1⁺, tyrosinase-positive melanomas were immunized in vitro against tyrosinase_369-377 (YMNGTMSQV). Drosophila cells transduced with HLA-A2.1, CD80, and CD54 (intracellular adhesion molecule-1) were used for priming, followed by two rounds of immunization with mononuclear cells as antigen-presenting cells. 1 x 10⁸ CTL were infused intravenously (IV) on day 1. CTL frequency was measured by limiting dilutions in five patients. ¹¹¹In labeling and scintigraphy measured distribution of CTL in next five. Five days later, 1 x 10⁸ CTLs were infused on 4 successive days to both groups. Immunohistology of response was judged by biopsies.

RESULTS: Infusions were nontoxic. CTLs were undetectable in the blood, going to lungs within 5 minutes. At 4, 24, and 72 hours, they were found in liver and spleen. Lesions were visualized by scintiscans in one responding patient where two subcutaneous nodules were noted at 4 and 24 hours. A second patient had a partial response and remains alive with disease 2 years later. CD8⁺ T cells were found in lesions of responders, associated with the presence of HLA-A2 molecules and tyrosinase. Two nonresponders without tyrosinase and HLA-A2 molecules had a paucity of CD8⁺ T cells in their lesions. Whether the CD8⁺ T cells in lesions of responders were those we had reinfused is uncertain.

CONCLUSION: CTLs immunized against a single melanoma epitope were nontoxic but did not specifically localize to tumor sites. Nevertheless, two patients had disease regression. Additional therapeutic studies with specifically immunized CTL seem justified.

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