Getting Melanoma Cells to Stimulate With Frequency

Abstract

Strategies for the delivery of antigenic peptides to patients with advanced malignant melanoma include a variety of novel approaches, such as the administration of recombinant DNA-encoding antigenic-peptide sequences; mRNA transcripts and peptides collected directly from patient tumors; recombinant replication-deficient adenoviral and retroviral vectors encoding tumor antigens; synthetic peptides modified for enhanced binding to antigenpresenting cell (APC) and human leukocyte antigen (HLA) molecules; allogeneic tumor cell lysates; peptide-loaded dendritic cells; tumor cell-dendritic cell fusion products; and irradiated autologous tumor cell preparations. Thus far, it is not clear that any one method is superior for the generation of antigen-specific T cells, and the induction of durable clinical responses has remained an elusive goal. It may develop that multiple methods of vaccination will be employed depending upon the specific disease setting or the type of antigen that is being delivered. One area of research thatmayenhance the successof vaccinationstrategies is the development of improved vaccine adjuvants. The development of an effective immune response and long-lasting immunologic memory in response to the delivery of an antigenic peptide requires the generation of a pool of antigen-specific T cells. Coadministration of an adjuvant with the vaccine can enhance the activity of weak immunogens. Vaccine adjuvants may function in several ways. An adjuvant may act as a depot for the vaccine, thus prolonging the time period over which an antigen is presented to APCs. Alternatively, an adjuvant may be employed as a means to change the character, number, or activation state of APCs at the vaccination site. Finally, an adjuvant may be used to alter the immunologic pathway by which the protein is being presented or processed, thus steering the immune system toward either a cellbased or an antibody-based response to the antigen. Cytokines are of particular interest to this field because they affect which arm of the immune system is stimulated to respond to the antigenic stimulus. Interleukin-12, interleukin-2 (IL-2), and interferonare examples of cytokines that have been tested as adjuvants in the setting of metastatic malignant melanoma. However, laboratory and clinical studies indicate that granulocyte-macrophage colony-stimulating factor (GM-CSF) may have particular advantages as a vaccine adjuvant. GM-CSF stimulates the activation, maturation, and migration of dendritic cells (DCs) and macrophages and induces their expression of class II major histocompatibility complex molecules. Using a murine model, Disis et al showed that GM-CSF was comparable to complete Freund’s adjuvant in augmenting the immune response to both tetanus toxoid and a peptide sequence derived from the rat neu protein (homologue of human c-erb-B2). Importantly, peptides administered without GM-CSF were essentially nonimmunogenic. Dranoff et al used a murine melanoma model to evaluate seven different cytokines for their ability to enhance the immunogenicity of irradiated B16 tumor cells, which alone do not stimulate significant antitumor immunity. Tumor cells transduced with a retroviral construct for GM-CSF exerted potent, long-lasting, and specific antitumor immunity that required both CD4 and CD8 T cells. Tumor cells expressing other cytokines were either poorly immunogenic (IL-2, IL-5, interferon[IFN], tumor necrosis factor[TNF]), or weakly immunogenic (IL-4 and IL-6). Vaccination of stage IV melanoma patients with irradiated, autologous melanoma cells engineered to secrete GM-CSF by adenovirus gene transfer led to an antigen-specific T-cell response (as measured by a delayed-type hypersensitivity reaction to nontransduced tumor cells) and measurable lymphocytic infiltration of tumor deposits in a significant proportion of patients, as well as one complete response. Likewise, a multipeptide melanoma vaccine elicited superior T-cell immunity when injected as an emulsion with GM-CSF as compared VOLUME 23 d NUMBER 35 d DECEMBER 1