Limited antitumor T cell response in melanoma patients vaccinated with interleukin-2 gene-transduced allogeneic melanoma cells.
We have immunized advanced melanoma patients with a HLA-A2-compatible human melanoma line genetically modified to release interleukin-2 (IL-2), to elicit or increase a T cell-mediated anti-melanoma response that may affect distant lesions. Twelve stage-IV patients were injected subcutaneously at days 1, 13, 26, and 55 with IL-2 gene-transduced and irradiated melanoma cells at doses of 5 or 15 x 10(7) cells. Both local and systemic toxicities were mild, consisting of transient erythema at the vaccination site; fever occurred in a minority of patients. Three mixed responses were recorded. Seven patients were evaluable for immunological studies. Mixed tumor-lymphocyte cultures carried out with different allogeneic HLA-A2-matched melanoma lines as stimulators and targets revealed an increase in the MHC-unrestricted, but no changes in the MHC-restricted, cytotoxicity in peripheral blood lymphocytes (PBL) obtained after vaccination as compared with those obtained before vaccination. Increased recognition of the tyrosinase 368-376 peptide occurred in post-vaccination PBL of one patient, whereas a weak increase in recognition of the gp100 280-288 peptide was detectable in another patient; these 2 patients also recognized the gp100 457-466 peptide. After in vitro, stimulation with the only available autologous melanoma line, CD4+ cells with autologous tumor-specific cytotoxicity and ability to release interferon-gamma (IFN-gamma) were found in post- but not in pre-vaccination PBL. In the same patient, as well as in another patient, limiting dilution analysis showed that vaccination resulted in an increased frequency of melanoma-specific cytotoxic T lymphocyte (CTL) precursors. These results indicate that vaccination with cells releasing IL-2 locally can expand a T cell response against antigen(s) of autologous, untransduced tumor, although this response occurred in a minority of the melanoma patients studied.
Arienti
F
F
Division of Experimental Oncology D, Istituto Nazionale Tumori, Milan, Italy.
Sulé-Suso
J
J
Belli
F
F
Mascheroni
L
L
Rivoltini
L
L
Melani
C
C
Maio
M
M
Cascinelli
N
N
Colombo
M P
MP
Parmiani
G
G
D000328:Adult; D000368:Aged; D000906:Antibodies / Q000097:blood; D000951:Antigens, Neoplasm / Q000276:immunology; D002461:Cell Line, Transformed; D017690:Cell Transplantation; D003601:Cytotoxicity Tests, Immunologic; D005260:Female; D015316:Genetic Therapy; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000097:blood / Q000235:genetics / Q000627:therapeutic use*; D007519:Isoantigens / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008297:Male; D008545:Melanoma / Q000628:therapy*; D008875:Middle Aged; D010641:Phenotype; D010865:Pilot Projects; D013601:T-Lymphocytes; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014184:Transplantation, Homologous; D014407:Tumor Cells, Cultured; D014611:Vaccination
D000906:Antibodies; D000951:Antigens, Neoplasm; D015789:HLA-A2 Antigen; D007376:Interleukin-2; D007519:Isoantigens