Abstract 1693: T cell responses to peptide-epitopes can be boosted by immune complexes of circulating anti-tetanus antibodies
Authors: Fletcher Erika A. , Maren Wendy van , Cordfunke Robert , Dinkelaar Jasper , Castelli Ricardo , Codee Jeroen , Marel Gijs van de , Melief Cornelis J. , Ossendorp Ferry , Drijfhout Jan Wouter , Mangsbo Sara 
Published: July 2017

Abstract
The ability of dendritic cells (DCs) to boost an antigen-specific immune response is utilized in several cancer immunotherapy strategies including therapeutic vaccination using long peptides. Naked peptides are rapidly degraded and oil-based delivery strategies trap immune cells to unwanted sites or have inappropriate adjuvant properties. To enhance the uptake of cancer or viral T cell epitopes and subsequent activation of DCs we make use of circulating antibodies to mount cellular responses against tumor antigens of interest by conjugating a B cell epitope to a T cell epitope. The conjugation of the two greatly improves antigen uptake and concomitant activation of the same DC in contrast to naked long peptides which are not conjugated. Our identified B cell epitope of choice is derived from tetanus toxin and can be targeted by tetanus-specific antibodies boosted by a standard tetanus toxoid vaccine. We have applied a modified chandler loop model preserving intact cascade systems to characterize how the tetanus-peptide conjugated vaccine is targeted to human immune cells. The B cell-T cell conjugate is taken up by human monocytes and blood DCs in an antibody-dependent manner. Rather than FcγRs, the internalization of the antigen appears to be partly mediated through the classical pathway of the complement system. Tetanus-CMV conjugates, containing a T cell epitope from the pp65 protein of cytomegalovirus (CMV), strongly reactivates memory T cells when analyzed in blood from donors with CMV-specific T cells. The CMV-specific T cells rapidly produce IFNγ and TNF in response to the conjugate illustrating that the uptake of the conjugate leads to activation of antigen-specific T cells. Uptake as well as T cell activation occurs at low concentrations of the SLP conjugate, superior to a conjugate lacking the tetanus-sequence as well as to SLPs with or without additional adjuvant (LPS). Of importance, when the B and T cell epitopes are separate entities but mixed, CMV-specific T cells are not activated, illustrating the requirement of conjugating the two. Our data show that we have a unique delivery system for peptide based vaccines that can aid induction of human T cell responses, and may potentiate immune responses in cancer patients.We are now actively working on a prostate cancer vaccine candidate using this novel loading/adjuvant technology.
Citation Format: Erika A. Fletcher, Wendy van Maren, Robert Cordfunke, Jasper Dinkelaar, Ricardo Castelli, Jeroen Codee, Gijs van de Marel, Cornelis J. Melief, Ferry Ossendorp, Jan Wouter Drijfhout, Sara Mangsbo. T cell responses to peptide-epitopes can be boosted by immune complexes of circulating anti-tetanus antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1693. doi:10.1158/1538-7445.AM2017-1693