Induction of Therapeutically Relevant Cytotoxic T Lymphocytes in Humans by Percutaneous Peptide Immunization

Abstract

Percutaneous peptide immunization (PPI) is a simple and noninvasive immunization approach to induce potent CTL responses by peptide delivery via skin with the stratum corneum removed. After such a barrier disruption in human skin, epidermal Langerhans cells, although functionally matured through the up-regulation of HLA expression and costimulatory molecules, were found to emigrate with a reduced number of dendrites. CD8+ populations binding to MHC-peptide tetramers/pentamers and producing IFN-; appeared in the blood after PPI with HLA class I-restricted antigenic peptides. PPI with melanoma-associated peptides reduced the lesion size and suppressed further development of tumors in four of seven patients with advanced melanoma. These beneficial effects were accompanied by the generation of circulating CTLs with in vitro cytolytic activity and extensive infiltration of tetramer/pentamer-binding cells into regressing lesions. PPI elicited neither local nor systemic toxicity or autoimmunity, except for vitiligo, in patients with melanoma. Therefore, PPI represents a novel therapeutic intervention for cancer in the clinical setting.

Layer-by-Layer-Assembled Multilayer Films for Transcutaneous Drug and Vaccine Delivery

“…This barrier disruption process is painless, highly effective in augmenting the transfer of macromolecules such as proteins or DNA into skin, and has been successfully utilized in human clinical trials. 46,[48][49][50] An additional advantage is that physical barrier disruption itself has been shown to trigger activation of keratinocytes and LCs in skin, providing some level of 'built-in' adjuvant response. [44][45][46][49][50][51][52] We thus tested a model where the dorsal ears of anesthetized mice were tape-stripped followed by application of as-assembled, airdried (Poly-1/ova) 40 films on either glass or PDMS substrates, fixed in place by surgical tape against the exposed ear skin, mimicking a common strategy used in skin vaccination studies 45,46 (Figure 1a).…”

Dendritic cells recruitment in melanoma metastasis treated by electrochemotherapy

“…in situ DCs vaccination) [31][32][33]. In this way the effective local effects of ECT might be enhanced and turned in a systemic treatment by the activation of local recruited DCs.…”

Tumor Immunotherapy by Epicutaneous Immunization Requires Langerhans Cells

“…Barrier disruption proved to be essential to achieve optimal and long-lasting CD8 ϩ T cell activation and antitumor responses. Clinical studies have also shown that barrier disruption in combination with peptide immunization resulted in activation of specific T cell responses and reduction of lesion size in melanoma patients (8). In contrast, the clinical applicability of TLR ligands and cholera toxin as adjuvants remains to be proven.…”

“…ϩ T cell responses and showed regression of some lesions (8), further indicating that targeting of skin DC is a viable approach to tumor immunotherapy. However, the contribution of individual populations of skin DC, the epidermal Langerhans cells (LC) and the dermal DC, to the induction of immune responses through the skin remains undefined.…”