Biomedical subjects

Nancy B Myers

Publications and source records attributed to Nancy B Myers.

4 recordsLinked to original sources

PubMed2026

Synthetic long peptide and DNA personalized cancer vaccines induce robust neoantigen-specific T cell responses in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is unresponsive to standard immunotherapies despite harboring cancer neoantigens capable of eliciting T cell responses. We completed two phase 1 clinical trials (NCT03956056 and NCT03122106) evaluating safety and immunogenicity of synthetic long peptide (SLP) and DNA personalized cancer vaccines (PCVs). PCVs were administered after resection and adjuvant chemotherapy. Tumor/normal whole-exome sequencing, RNA sequencing, and pVACtools were used to identify and prioritize candidate PCV neoantigens. PCVs were well tolerated without any grade ≥3 adverse events. Neoantigen-specific responses were demonstrated by interferon-γ enzyme-linked immunospot and intracellular cytokine staining. Expanded T cell receptor clonotypes were sequenced and transduced into autologous peripheral blood mononuclear cells to confirm neoantigen specificity. When compared with a contemporaneous institutional propensity-matched cohort, PCV patients demonstrated a trend toward prolonged median overall survival (4.4 versus 3.5 years, log-rank P = 0.23). Overall, PDAC PCVs are safe and feasible and elicit polyclonal T cell responses, linking prioritized cancer neoantigens to functional antitumor immunity.

Humans↗

PubMed2005

Applications of major histocompatibility complex class I molecules expressed as single chains.

Generation of CD8 T-cell responses to pathogens and tumors requires optimal expression of class I major histocompatibility complex/peptide complexes, which, in turn, is dependent on host cellular processing events and subject to interference by pathogens. To create a stable structure that is more immunogenic and resistant to immune evasion pathways, we have engineered class I molecules as single-chain trimers (SCTs), with flexible linkers connecting peptide, beta2m, and heavy chain. Herein we extend our earlier studies with SCTs to the K(b) ligand derived from vesicular stomatitis virus (VSV) to characterize further SCTs as probes of immune function as well as their potential in immunotherapy. The VSVp-beta2m-K(b) SCTs were remarkably stable at the cell surface, and immunization with DNA encoding SCTs elicited complex-specific antibody. In addition, SCTs were detected by cytotoxic T-lymphocytes specific for the native molecule, and the covalently bound peptide was highly resistant to displacement by exogenous peptide. SCTs can also prime CD8 T-cells in vivo that recognize the native molecule. Furthermore, SCTs were resistant to downregulation by the immune evasion protein mK3 of gamma herpesvirus 68. Moreover, owing to their preassembled nature, SCTs should be resistant to other immune evasion proteins that restrict peptide supply. Thus, SCTs possess therapeutic potential both for prophylactic treatment and for the treatment of ongoing infection.

Animals↗

PubMed2002

Polymorphism at position 97 in MHC class I molecules affects peptide specificity, cell surface stability, and affinity for beta2-microglobulin.

The two mouse MHC class I alleles, L(d) and L(q), share complete amino acid sequence identity except in the alpha2 domain, where they differ at six positions. Despite their similarity, L(q) has a stronger association with beta2-microglobulin (beta2m), is expressed at higher levels on the cell surface, demonstrates an increased cell surface half-life, and has fewer open forms on the cell surface than L(d). To determine the basis for their phenotypic differences, L(d) molecules containing chimeric L(d)-L(q) alpha2 domains were characterized, and these analyses implicated residue 97 (L(d)Trp and L(q)Arg) as the polymorphic site responsible for the disparity in beta2m association between the two alleles. Single substitution analysis at this site (L(d)W97R and L(q)R97W) confirmed this. Furthermore, the L(d)W97R mutant molecule has a longer cell surface half-life than either L(q) or L(d), and fewer open forms of L(d)W97R are observed on the cell surface. In addition, both L(d)W97R and L(q) possess decreased binding affinity for the L(d)-restricted tum(-) P91A(14-22) peptide compared with L(d). Collectively, these results and the known location of Trp(97) in the peptide binding cleft of L(d) strongly suggest that the substitution of Arg for Trp(97) in L(d) alters the peptide binding cleft, increasing its affinity for endogenous peptides, which results in greater cell surface stability and better retention of beta2m. Furthermore, these results imply that Trp(97) plays an important role in the ability of L(d) to efficiently participate in alternative MHC class I Ag presentation pathways.

Alleles↗

PubMed2002

Physical association of the K3 protein of gamma-2 herpesvirus 68 with major histocompatibility complex class I molecules with impaired peptide and beta(2)-microglobulin assembly.

To persist in the presence of an active immune system, viruses encode proteins that decrease expression of major histocompatibility complex class I molecules by using a variety of mechanisms. For example, murine gamma-2 herpesvirus 68 expresses the K3 protein, which causes the rapid turnover of nascent class I molecules. In this report we show that certain mouse class I alleles are more susceptible than others to K3-mediated down regulation. Prior to their rapid degradation, class I molecules in K3-expressing cells exhibit impaired assembly with beta(2)-microglobulin. Furthermore, K3 is detected predominantly in association with class I molecules lacking assembly with high-affinity peptides, including class I molecules associated with the peptide loading complex TAP/tapasin/calreticulin. The detection of K3 with class I assembly intermediates raises the possibility that molecular chaperones involved in class I assembly are involved in K3-mediated class I regulation.

Animals↗