Lipopeptide‐based melanoma cancer vaccine induced a strong MART‐27‐35‐cytotoxic T lymphocyte response in a preclinal study

Abstract

Key words: melanoma; cancer; vaccine; lipopeptides; CD8 ϩ T cell responses; peptides; immunotherapyCytotoxic T lymphocytes play a central role in the anti-tumor immune response by recognizing small antigenic peptides bound to major histocompatibility complex (MHC) class-I molecules on cancer cells. Identification of tumor antigens and their optimal antigenic peptides over the past decade opened new approaches to the understanding of melanoma antigenicity and allowed development of peptide-based vaccine strategies. 1 The results of most clinical trials, however, indicated that progress must be made before peptide-based vaccines can be added to the therapeutic arsenal against melanoma. [2][3][4] Many studies demonstrated that immunization with antigenic peptides alone is not sufficient to elicit an efficient cytotoxic T lymphocyte (CTL) response, or even any response at all. Formulation of the antigenic peptide is critical in vaccine development, because it conditions the vaccine capacity to induce effective and long-lasting anti-tumor immunity. Inappropriate modes of peptide delivery can even lead to antigen-specific tolerance instead of protection. 5 Lack of costimulation or T cell help activity has been proposed as a possible explanation for this phenomenon. Thus, to elicit specific CTL responses, peptide vaccine strategies must take into account additional factors, such as vectors, adjuvants and CD4 ϩ T cell help, all of which probably provide essential secondary signals. In this respect, professional antigen-presenting cells (APCs) are tools of choice in anti-tumor vaccine strategies. Encouraging results were obtained in a recent anti-melanoma vaccine trial using dendritic cells pulsed with tumor-associated antigenic peptides and a helper peptide. 6 Nevertheless, the procedure involved (in vitro generation, pulse and reinjection of these cells) was cumbersome and it increased the risk of bacterial contamination. Thus, we chose to develop a formulation that brings the benefits of synthetic peptides, assures T cell help via a strong CD4 epitope and might allow uptake by dendritic cells at the injection site.Lipopeptide formulations have been successfully used to induce anti-viral CTL responses in mice, 7-9 in monkeys 10 and in human clinical trials. [11][12][13] The influence of helper T lymphocytes (HTLs) stimulated by CD4 epitopes in inducing strong and long-lasting antigen-specific CTL responses in vivo 11,14 -16 and in vitro 17 has also been demonstrated. Therefore, to induce a strong melanoma specific CTL response, we included a CD4 epitope in our lipopeptide construct, which resulted in a simple vaccine formulation. MART-1 was selected as melanoma target antigen because of its very frequent expression in melanoma 18 and its well-known immunogenicity. 19 Moreover, the immunodominant peptide of this antigen, MART 27-35, is restricted to HLA-A2, expressed in 45% of the Caucasian population, which makes it a good candidate for vaccination. The TT830-843 peptide, derived from tetanus toxoid, was chosen as a s...

Lipopeptide epitopes extended by an Nϵ‐palmitoyl‐lysine moiety increase uptake and maturation of dendritic cells through a Toll‐like receptor‐2 pathway and trigger a Th1‐dependent protective immunity

“…The elucidation of cellular and molecular mechanisms by which lipopeptides interact with the adaptive immune system could led to significant improvement of lipopeptide‐based vaccines currently being developed for human pathogens and cancers 1, 10, 12. In the present study, we found that totally synthetic lipopeptides induced up‐regulation of a number of DC surface markers, including MHC class I, MHC class II, CD80 and CD86 molecules, and showed that the nature of the lipid moiety is a crucial factor in the effect of lipopeptide Ag on DC.…”

Definition of anti‐tyrosinase MAb T311 linear determinant by proteome‐based similarity analysis

“…As an additional consideration, immunogens with increased immunogenicity can be easily obtained by fusing peptides to cytokines utilizing recombinant DNA technology, by conjugating peptides to larger molecules, particularly if the carrier proteins contain strong T‐helper epitopes, and by direct peptide polymerization with glutaraldehyde and other chemical processes (4–6). These encouraging perspectives explain the high interest and commitment of investigators to the goal of developing effective anti‐cancer peptide vaccines.…”

Retargeting NK‐92 for anti‐melanoma activity by a TCR‐like single‐domain antibody

“…The TAP‐deficient cell line T2, the myeloid cell line K562 and the mouse melanoma cell line B16F10 were purchased from American Type Culture Collection (ATCC). B16AAD (B16F10 cells expressing a chimeric major histocompatibility complex class I molecule consisting of the α1 and α2 domains of HLA‐A2 and the α3 domain of H‐2D d ) was a kind gift from Professor Gahéry‐Ségard H 35 . All the above cell lines were maintained in RPMI‐1640 medium (Invitrogen, Grandland, NY, USA.)…”