Immunizing patients with metastatic melanoma using recombinant adenoviruses encoding MART-1 or gp100 melanoma antigens.
BACKGROUND
The characterization of the genes encoding melanoma-associated antigens MART-1 or gp100, recognized by T cells, has opened new possibilities for the development of immunization strategies for patients with metastatic melanoma. With the use of recombinant adenoviruses expressing either MART-1 or gp100 to immunize patients with metastatic melanoma, we evaluated the safety, immunologic, and potential therapeutic aspects of these immunizations.


METHODS
In phase I studies, 54 patients received escalating doses (between 10(7) and 10(11) plaque-forming units) of recombinant adenovirus encoding either MART-1 or gp100 melanoma antigen administered either alone or followed by the administration of interleukin 2 (IL-2). The immunologic impact of these immunizations on the development of cellular and antibody reactivity was assayed.


RESULTS
Recombinant adenoviruses expressing MART-1 or gp100 were safely administered. One of 16 patients with metastatic melanoma receiving the recombinant adenovirus MART-1 alone experienced a complete response. Other patients achieved objective responses, but they had received IL-2 along with an adenovirus, and their responses could be attributed to the cytokine. Immunologic assays showed no consistent immunization to the MART-1 or gp100 transgenes expressed by the recombinant adenoviruses. High levels of neutralizing antibody were found in the pretreatment sera of the patients.


CONCLUSIONS
High doses of recombinant adenoviruses could be safely administered to cancer patients. High levels of neutralizing antibody present in patients' sera prior to treatment may have impaired the ability of these viruses to immunize patients against melanoma antigens.
Rosenberg
S A
SA
Surgery Branch, National Cancer Institute, Bethesda, MD, USA.
Zhai
Y
Y
Yang
J C
JC
Schwartzentruber
D J
DJ
Hwu
P
P
Marincola
F M
FM
Topalian
S L
SL
Restifo
N P
NP
Seipp
C A
CA
Einhorn
J H
JH
Roberts
B
B
White
D E
DE
D000256:Adenoviridae / Q000235:genetics*; D000914:Antibodies, Viral / Q000097:blood; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology; D002985:Clinical Protocols; D006801:Humans; D058965:MART-1 Antigen; D008545:Melanoma / Q000276:immunology* / Q000517:prevention & control* / Q000556:secondary; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D012878:Skin Neoplasms / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D058951:gp100 Melanoma Antigen
D000914:Antibodies, Viral; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D058965:MART-1 Antigen; C548667:MLANA protein, human; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C548637:PMEL protein, human; D058951:gp100 Melanoma Antigen