CD8+ CTL Priming by Exact Peptide Epitopes in Incomplete Freund’s Adjuvant Induces a Vanishing CTL Response, whereas Long Peptides Induce Sustained CTL Reactivity

Abstract

Therapeutic vaccination trials, in which patients with cancer were vaccinated with minimal CTL peptide in oil-in-water formulations, have met with limited success. Many of these studies were based on the promising data of mice studies, showing that vaccination with a short synthetic peptide in IFA results in protective CD8+ T cell immunity. By use of the highly immunogenic OVA CTL peptide in IFA as a model peptide-based vaccine, we investigated why minimal CTL peptide vaccines in IFA performed so inadequately to allow full optimization of peptide vaccination. Injection of the minimal MHC class I-binding OVA257–264 peptide in IFA transiently activated CD8+ effector T cells, which eventually failed to undergo secondary expansion or to kill target cells, as a result of a sustained and systemic presentation of the CTL peptides gradually leaking out of the IFA depot without systemic danger signals. Complementation of this vaccine with the MHC class II-binding Th peptide (OVA323–339) restored both secondary expansion and in vivo effector functions of CD8+ T cells. Simply extending the CTL peptide to a length of 30 aa also preserved these CD8+ T cell functions, independent of T cell help, because the longer CTL peptide was predominantly presented in the locally inflamed draining lymph node. Importantly, these functional differences were reproduced in two additional model Ag systems. Our data clearly show why priming of CTL with minimal peptide epitopes in IFA is suboptimal, and demonstrate that the use of longer versions of these CTL peptide epitopes ensures the induction of sustained effector CD8+ T cell reactivity in vivo.

Long-peptide vaccination with driver gene mutations in p53 and Kras induces cancer mutation-specific effector as well as regulatory T cell responses

“…This process is indispensable for proper priming and activation of TSA-specific naïve T cells. 33, 34 Second, long peptides can provide several MHC class I alleles with ligands, thus permitting a broader cohort of patients to benefit from a vaccine. Third, long peptides can comprise both MHC class I and II epitopes.…”

“…Following this line of thought, cancer vaccination with long synthetic peptides 33 , presents a versatile and easily applicable therapeutic platform. Indeed, peptide vaccination was effective in eliciting tumor-protective immunity in animal studies.…”

CD20 alternative splicing isoform generates immunogenic CD4 helper T epitopes

“…Previous studies indicate that the use of synthetic long peptides can induce more effective cytotoxic T cell (CTL) responses than minimal MHC Class I restricted peptide-based vaccine. 24 We then evaluated the capacity of the D393-CD20 28-47 long peptide (LP) to prime HLA-A2-restricetd CTL response. To this end, mice were immunized either with the D393-CD20 [28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47] LP or with the HLA-A2-restricted D393-CD20 derived short peptide D393-CD20 [33][34][35][36][37][38][39][40][41] (SP).…”

Advances in Peptide-based Human Papillomavirus Therapeutic Vaccines

“…Tindle et al identified E7 [48][49][50][51][52][53][54] (DRAHYNI) as a Th-cell-stimulating epitope that helped to elicit antibody responses to HPV-16 E7 in a mouse model [97]. Recently, multiple studies have indicated that the use of longer versions of CTL peptide epitopes, covering the Th-cell epitope, ensures the induction of sustained CD8 + T cell reactivity in vivo, when compared with using the minimal CTL peptide epitope (E7 [49][50][51][52][53][54][55][56][57] ) [98,99]. Extension of the CTL peptides to longer variants may offer an excellent alternative when external specific CD4 + helper T cell epitopes are not readily available [99].…”