Phase I/II clinical trial of a nonreplicative vaccinia virus expressing multiple HLA-A0201-restricted tumor-associated epitopes and costimulatory molecules in metastatic melanoma patients.
We performed a phase I/II clinical trial in metastatic melanoma patients with an ultraviolet (UV)-inactivated nonreplicating recombinant vaccinia virus enabling the expression, from a single construct, of endoplasmic reticulum-targeted HLA-A0201-restricted Melan-A/MART-1(27-35), gp100(280-288), and tyrosinase(1-9) epitopes, together with CD80 and CD86 costimulatory proteins. Corresponding soluble peptides were used to boost responses and granulocyte-macrophage colony-stimulating factor was used as systemic adjuvant. Safety and immunogenicity, as monitored with in vitro-restimulated peripheral blood mononuclear cells by cytotoxic T lymphocyte precursor (CTLp) frequency analysis and tetramer staining, were specifically addressed. Of 20 patients entering the protocol, 2 had to withdraw because of rapidly progressing disease. Immune responses were evaluated in 18 patients (stage III, n = 5; stage IV, n = 13) and increases in specific CTLp frequencies were observed in 15. In 16 patients responsiveness against all 3 antigens could be analyzed: 7 (43%), including all stage III cases, showed evidence of induction of CTLs specific for the three epitopes, and 2 (12%) and 4 (25%), respectively, showed reactivity against two or one tumor-associated antigen. In three stage IV patients no specific CTL reactivity could be induced. Increases in CTLp frequency were detected mostly after viral vaccine injections. However, in a majority of patients final CTLp levels were comparable to initial levels. Tetramer characterization of Melan-A/MART-1(27-35)-specific CTLs during the protocol also suggested preferential expansion after recombinant virus administration. Vector-specific humoral responses, frequently undetectable in stage IV patients, did not appear to prevent tumor-associated antigen-specific CTL induction. Aside from a single occurrence of transient grade 3 leukopenia, no major clinical toxicity was reported. Seventeen of 18 patients completed the 3-month trial (one patient died before the last delayed-type hypersensitivity test). Three displayed regression of individual metastases, seven had stable disease, and progressive disease was observed in seven patients. This is the first report on the administration of a UV-inactivated recombinant vaccinia virus coexpressing five transgenes in cancer patients. The results described here, in terms of safety and immunogenicity, support the use of this reagent in active specific immunotherapy.
Zajac
P
P
Institute of Surgical Research and Hospital Management, Department of Research, University Hospital of Basel, ZLF, Laboratory 404, Hebelstrasse 20, CH-4031 Basel, Switzerland. pzajac@uhbs.ch
Oertli
D
D
Marti
W
W
Adamina
M
M
Bolli
M
M
Guller
U
U
Noppen
C
C
Padovan
E
E
Schultz-Thater
E
E
Heberer
M
M
Spagnoli
G
G
D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000276:immunology; D000951:Antigens, Neoplasm; D018122:B7-1 Antigen / Q000276:immunology; D051940:B7-2 Antigen; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000627:therapeutic use*; D003673:Defective Viruses; D000939:Epitopes / Q000276:immunology*; D005260:Female; D005500:Follow-Up Studies; D005822:Genetic Vectors; D015234:HLA-A Antigens / Q000276:immunology*; D006801:Humans; D058965:MART-1 Antigen; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000276:immunology; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000627:therapeutic use; D014616:Vaccinia virus / Q000276:immunology*
D015703:Antigens, CD; D000951:Antigens, Neoplasm; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497964:CD86 protein, human; D019496:Cancer Vaccines; D000939:Epitopes; D015234:HLA-A Antigens; D058965:MART-1 Antigen; C548667:MLANA protein, human; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D014614:Vaccines, Synthetic