Article
Author: Fletcher, Erika A K ; Westhrin, Marita ; Franken, Kees L M C ; Ahmad, Murrium ; Ullenhag, Gustav ; Lindqvist, Frida ; Dillmann, Inken ; Rasch, Wenche ; Lord, Martin ; Nasi, Aikaterini ; Haggman, Michael ; Valentijn, Rob R P M ; Bergqvist, Anna ; Törnqvist, Gunilla ; Neefjes, Jacques J ; Drijfhout, Jan Wouter ; Johansson, Silvia ; Bouwman, Neanke ; Lampinen, Maria ; Mangsbo, Sara M ; Ossendorp, Ferry ; Lilleby, Wolfgang ; Ladjevardi, Sam ; Leja-Jarblad, Justyna ; McArdle, Stephanie ; Cordfunke, Robert A
Peptide-based vaccines can be used to deliver tumor-specific antigens to dendritic cells (DCs), leading to tumor-directed T cell responses. We previously developed a peptide-peptide conjugate technology enabling in vivo cross-linking of pre-existing tetanus toxin-directed antibodies, facilitating antigen delivery to, and activation of DCs. To achieve this, multiple identical tetanus toxin-derived B cell epitopes (MTTEs) are conjugated to synthetically produce target antigens of choice. Herein, we describe the generation of a prostate cancer vaccine candidate (TENDU) based on this technology. It includes long synthetic peptides harboring epitopes (CD4 and CD8) from prostate-specific antigen (PAP) and prostate-specific membrane antigen (PSMA). The preclinical efficacy of TENDU was assessed in experimental systems, and safety was evaluated in a rabbit toxicity study and a human whole blood loop assay. We also report the first clinical safety assessment of TENDU. Experimental studies showed that prostate cancer patients mounted anti-MTTE antibodies in response to tetanus vaccination with recall T cell responses detected in two patients. Transgenic humanized HLA-DR4 mice displayed T cell responses and increased anti-MTTE IgG levels after vaccination with a peptide construct including an HLA-DR4 epitope. The vaccine candidate was found safe, and a positive correlation between T cell responses and anti-MTTE antibodies was noted in the first-in-human study.