Vaccination of melanoma patients with peptide- or tumorlysate-pulsed dendritic cells

Abstract

Melanoma is the main cause of death in patients with skin cancer. Cytotoxic T lymphocytes (CTLs) attack melanoma cells in an HLA-restricted and tumor antigen-specific manner. Several melanoma-associated tumor antigens have been identified. These antigens are suitable candidates for a vaccination therapy of melanoma. Dendritic cells (DCs) are antigen-presenting cells (APCs) specialized for the induction of a primary T-cell response. Mouse studies have demonstrated the potent capacity of DCs to induce antitumor immunity. In the present clinical pilot study, DCs were generated in the presence of granulocyte/macrophage-colony stimulating factor (GM-CSF) and interleukin 4 (IL-4) and were pulsed with tumor lysate or a cocktail of peptides known to be recognized by CTLs, depending on the patient's HLA haplotype. Keyhole limpet hemocyanin (KLH) was added as a CD4 helper antigen and immunological tracer molecule. Sixteen patients with advanced melanoma were immunized on an outpatient basis. Vaccination was well tolerated. No physical sign of autoimmunity was detected in any of the patients. DC vaccination induced delayed-type hypersensitivity (DTH) reactivity toward KLH in all patients, as well as a positive DTH reaction to peptide-pulsed DCs in 11 patients. Recruitment of peptide-specific CTLs to the DTH challenge site was also demonstrated. Therefore, antigen-specific immunity was induced during DC vaccination. Objective responses were evident in 5 out of 16 evaluated patients (two complete responses, three partial responses) with regression of metastases in various organs (skin, soft tissue, lung, pancreas) and one additional minor response. These data indicate that vaccination with autologous DCs generated from peripheral blood is a safe and promising approach in the treatment of metastatic melanoma. Further studies are necessary to demonstrate clinical effectiveness and impact on the survival of melanoma patients.

Dendritic cells acquire the MAGE-3 human tumor antigen from apoptotic cells and induce a class I-restricted T cell response

“…DCs pulsed with class I-restricted synthetic peptides (5) and proteins (6), or with natural peptides eluted from the tumor (7), have been shown to induce an effective and long-lasting antitumor immunity in various murine tumor models (8,9). The relevance of these animal experiments to the treatment of human cancer has recently been confirmed (5,10,11). Alternative strategies to deliver the antigenic epitope into the class I pathway of DCs have been exploited, including viral vectors, naked and plasmid DNA, and RNA and liposomes with nucleic acid (4).…”

Dendritic cell vaccination for cancer therapy

“…Migratory capacity and also the number of DC which ®nally reach the lymph node in an active T cell stimulatory mode will be a critical issue for future studies. Since convincing data about the migratory capacity of human DCs are di cult to obtain, we developed in 1993 the concept to inject our DC preparation directly under ultrasound control in a normal appearing inguinal lymph node (Nestle et al, 1998). As discussed above the lymph node is the appropriate meeting point for a DC-T cell cross talk and is at least from a theoretical point of view the preferred injection site for antigen loaded DC.…”

“…An additional method is delayed type hypersensitivity (DTH) testing for peptide speci®c immune responses. Peptide DTH testing has been successfully used in various mouse models and recruitment of peptide speci®c T cells to the injection site was demonstrated in humans (Nestle et al, 1998). Peptide alone or DC pulsed with peptide are injected intradermally and induration as well as erythema is read after 48 h. This technique is easy to perform even though objective read out might be a problem and is observer dependent.…”

Telomerase as a universal tumor-associated antigen for cancer immunotherapy

“…This once suspect notion that tumor antigen-speci®c immune responses can lead to tumor regression has now been borne out extensively in animal models (Gilboa, 1999) and is being actively tested in human clinical trials. In particular, e orts to develop antigen-speci®c therapeutic vaccination strategies against cancer have greatly accelerated, particularly in light of early reports in melanoma and hematologic malignancies suggesting that vaccination against tumor-associated antigens is safe and potentially e ective (Hsu et al, 1996;Nestle et al, 1998;Rosenberg et al, 1998). To be sure, the promise of therapeutic strategies aimed at these tumor-associated antigens has thus far outweighed clinical results, but knowledge gained from early trials coupled with the impressive development of novel adjuvants and delivery modalities justi®es continued enthusiasm.…”