Conditional Superagonist CTL Ligands for the Promotion of Tumor-Specific CTL Responses

Abstract

While it has been demonstrated that cytotoxic T lymphocytes (CTL) can be raised against tumor-associated self-antigens, achieving consistent and effective clinical responses has proven challenging. Superagonist altered peptide ligands (APL) can often elicit potent anti-tumor CTL responses where the native tumor-associated epitope fails. Current methods have identified a limited number of superagonist APLs, including the prototypic 27L mutant of MART-1. However, more comprehensive screening strategies would be desirable. In this study we utilize a novel genetic screen, involving recombinant technology and class I antigen cross-presentation, to search for supraoptimal superagonists of the 27L MART-1 mutant by surveying the effectiveness of virtually every single amino acid substitution mutant of 27L to activate human antigen-specific CTL clones recognizing the wild-type MART-126-35 epitope. We identify 3 novel mutant epitopes with superagonist properties that are functionally superior to 27L; however, the ability of a given analog to act as superagonist varies among patients and suggest that a given superagonist altered peptide ligand may be ideally suited to different patients. These findings endorse the use of comprehensive methods to establish panels of potential superagonist APLs to individualize tumor peptide vaccines among patients.

Superagonism at G protein‐coupled receptors and beyond

“…In this regard, compounds, which hyperstimulate either immune‐inhibitory T reg s or pro‐inflammatory T eff s, may be of great therapeutic value for the treatment of autoimmune disorders or anti‐cancer therapy respectively. There are several examples for immunological ‘superagonists’ that, in comparison with the endogenous ligands, display enhanced biological activity for triggering immune cell activation and proliferation (Chen et al ., ; Beyersdorf et al ., ; Rubinstein et al ., ; Abdul‐Alim et al ., ).…”

Enhanced anti-colon cancer immune responses with modified eEF2-derived peptides

“…As most TAAs are selfantigens, antigen-specific CTL repertoires may be significantly reduced in the host during the negative selection process, leaving behind a T-cell repertoire that is poorly effective at mounting productive antitumor responses [5]. As a potential approach to enhance the immunogenicity of epitopes recognized by CTLs, modifications to the peptide sequences are applied to improve binding to MHC class I molecules [6][7][8][9]. However, replacing residues that are directed toward the TCR (T cell receptor) can also improve epitope immunogenicity [10][11][12].…”

Amino-Terminal Extended Peptide Single-Chain Trimers Are Potent Synthetic Agonists for Memory Human CD8+ T Cells

“…Single amino acid substitutions can create structural variants of antigenic peptide ligands, referred to as altered peptide ligands (APL), which allow manipulation of the strength of the TCR-p-MHC interaction. APL can induce a complete range of T cell functions (agonist), a subset of T cell functions (partial agonist) (9, 10) or in a few instances, be more potent (superagonist) than the native ligand (11, 12). It is also well established that memory T cells display a lower threshold for activation (13, 14) and are more sensitive to cell death compared to naïve resting T cells upon antigen exposure (15–17).…”