Vaccination of melanoma patients with an allogeneic, genetically modified interleukin 2-producing melanoma cell line.
Thirty-three metastatic melanoma patients were vaccinated according to a phase I-II study with an allogeneic melanoma cell line that was genetically modified by transfection with a plasmid containing the gene encoding human interleukin 2 (IL-2). The cell line expresses the major melanoma-associated antigens and the HLA class I alleles HLA-A1, -A2, -B8, and Cw7. All patients shared one or more HLA class I alleles with this cell line vaccine. Patients were immunized by three vaccinations, each consisting of 60 x 106 irradiated (100 Gy) melanoma cells (secreting 120 ng of IL-2/10(6) cells/24 hr) administered subcutaneously at weekly intervals for 3 consecutive weeks. Side effects of treatment consisted of swelling of locoregional lymph nodes and induration at the site of injection, i.e., a delayed-type hypersensitivity (DTH) reaction. In three patients, vaccination induced inflammatory responses in distant metastases containing necrosis or apoptosis along with T cell infiltration. Apoptosis occurred only in Bcl-2-negative areas, not in Bcl-2-expressing parts of the metastases. Two other patients experienced complete or partial regression of subcutaneous metastases. Seven patients had protracted stabilization (4 to >46 months) of soft tissue metastases, including one patient who developed vitiligo after vaccination. Immune responses to the vaccine could be detected in 67% of the 27 patients measured. Vaccination was shown to induce a variable change in the number of anti-vaccine cytotoxic T lymphocytes (CTLs) in peripheral blood, which did not correlate with response to treatment. However, in two of five patients the frequency of anti-autologous tumor CTLs measured was significantly higher than before vaccination. This study demonstrates the feasibility, safety, and therapeutic potential of vaccination of humans with allogeneic, gene-modified tumor cells, and that frequencies of vaccine-specific CTLs among patient lymphocytes can be determined by using a modified limited dilution analysis (LDA).
Osanto
S
S
Department of Clinical Oncology, Leiden University Medical Center, The Netherlands. osanto@mail.medfac.LeidenUniv.nl
Schiphorst
P P
PP
Weijl
N I
NI
Dijkstra
N
N
Van Wees
A
A
Brouwenstein
N
N
Vaessen
N
N
Van Krieken
J H
JH
Hermans
J
J
Cleton
F J
FJ
Schrier
P I
PI
D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000235:genetics; D019496:Cancer Vaccines / Q000235:genetics / Q000494:pharmacology*; D005260:Female; D015788:HLA-A1 Antigen / Q000378:metabolism; D015789:HLA-A2 Antigen / Q000378:metabolism; D015795:HLA-B8 Antigen / Q000378:metabolism; D015236:HLA-C Antigens / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D007249:Inflammation / Q000276:immunology; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D058965:MART-1 Antigen; D008297:Male; D008545:Melanoma / Q000401:mortality / Q000556:secondary* / Q000628:therapy*; D058950:Melanoma-Specific Antigens; D008875:Middle Aged; D014442:Monophenol Monooxygenase / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D015996:Survival Rate; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; C092706:BAGE protein, human; D019496:Cancer Vaccines; C095365:GAGE1 protein, human; C095366:GAGE2A protein, human; D015788:HLA-A1 Antigen; D015789:HLA-A2 Antigen; D015795:HLA-B8 Antigen; D015236:HLA-C Antigens; C040178:HLA-C*70 antigen; D007376:Interleukin-2; C072011:MAGEA1 protein, human; C072013:MAGEA3 protein, human; C072012:MAGEB2 protein, human; D058965:MART-1 Antigen; C548667:MLANA protein, human; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins; D014442:Monophenol Monooxygenase