Phase I trial of adoptive immunotherapy with cytolytic T lymphocytes immunized against a tyrosinase epitope.
OBJECTIVE
To study distribution and toxicity of cytolytic T lymphocytes (CTLs) against a single melanoma epitope.


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 10(8) CTL were infused intravenously (IV) on day 1. CTL frequency was measured by limiting dilutions in five patients. (111)In labeling and scintigraphy measured distribution of CTL in next five. Five days later, 1 x 10(8) 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.


CONCLUSIONS
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.
Mitchell
Malcolm S
MS
Center for Biological Therapy and Melanoma Research, University of California San Diego School of Medicine, San Diego, CA, USA. mitchell@karmanos.org
Darrah
Denise
D
Yeung
David
D
Halpern
Samuel
S
Wallace
Anne
A
Voland
Joseph
J
Jones
Vicky
V
Kan-Mitchell
June
J
D000818:Animals; D018122:B7-1 Antigen / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D018572:Disease-Free Survival; D004330:Drosophila / Q000235:genetics; D000939:Epitopes; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D007114:Immunization; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007262:Infusions, Intravenous; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology; D008545:Melanoma / Q000276:immunology* / Q000628:therapy*; D012878:Skin Neoplasms / Q000276:immunology* / Q000628:therapy*; D014161:Transduction, Genetic; D016896:Treatment Outcome; D014443:Tyrosine / Q000235:genetics
D018122:B7-1 Antigen; D000939:Epitopes; D015789:HLA-A2 Antigen; D018799:Intercellular Adhesion Molecule-1; D014443:Tyrosine