Immunizing patients with metastatic melanoma using recombinant adenoviruses encoding MART-1 or gp100 melanoma antigens

Abstract

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.

Figures

Fig. 1

A 39-year-old female with metastatic melanoma who received four doses of 108 plaque-forming units of adenovirus MART-1 underwent complete regression of biopsy-proven breast and mediastinal metastases. The response is ongoing at 31 months.

Fig. 2

A) Pretreatment levels of antiadenoviral immunoglobulin G (IgG) (left) or neutralizing (right) antibody in the sera of patients undergoing immunization with recombinant adenovirus encoding MART-1 or gp100. Thirty-four of 45 sera showed an increase in titer of antiadenoviral IgG following administration of adenovirus. Patients receiving interleukin 2 (IL-2) exhibited a higher incidence of increase in IgG than those not receiving IL-2 (P = .004). B) Increase in antiadenoviral IgG and neutralizing antibody in sera of patients receiving recombinant adenovirus encoding MART-1 or gp100.