Detection of neoantigen-specific T cells following a personalized vaccine in a patient with glioblastoma

Abstract

Neoantigens represent promising targets for personalized cancer vaccine strategies. However, the feasibility of this approach in lower mutational burden tumors like glioblastoma (GBM) remains unknown. We have previously reported the use of an immunogenomics pipeline to identify candidate neoantigens in preclinical models of GBM. Here, we report the application of the same immunogenomics pipeline to identify candidate neoantigens and guide screening for neoantigen-specific T cell responses in a patient with GBM treated with a personalized synthetic long peptide vaccine following autologous tumor lysate DC vaccination. Following vaccination, reactivity to three HLA class I-and five HLA class II-restricted candidate neoantigens were detected by IFN-γ ELISPOT in peripheral blood. A similar pattern of reactivity was observed among isolated post-treatment tumor-infiltrating lymphocytes. Genomic analysis of pre-and post-treatment GBM reflected clonal remodeling. These data demonstrate the feasibility and translational potential of a therapeutic neoantigen-based vaccine approach in patients with primary CNS tumors.

Tumor antigens heterogeneity and immune response-targeting neoantigens in breast cancer

“…Ott et al [137] in melanoma patients demonstrated that a vaccine developed to target as many as 20 predicted personal tumor neoantigens is safe, feasible and creates a strong immunogenic response that had been absent before the vaccination, inducing polyfunctional CD8 + and CD4 + T cells able to discriminate between mutated and wild-type antigens. The results from Johanns et al [138] support the hypothesis that targeting neoantigens is also feasible for tumors with lower mutational burden. In fact, in glioblastoma, on the basis of an immunogenomics pipeline to identify candidate neoantigens (WES and affinity calculation algorithms), a peptide vaccine was designed and administered to patients after treatment with an autologous tumor lysate DC vaccine.…”

Intranodal Administration of Neoantigen Peptide-loaded Dendritic Cell Vaccine Elicits Epitope-specific T Cell Responses and Clinical Effects in a Patient with Chemorefractory Ovarian Cancer with Malignant Ascites

“…Using TCR repertoire analysis, we provided evidence that neoantigen peptide-loaded DC vaccine induced infiltration of T cells with mutant-specific TCR into the tumor site. Recent reports by Keskin et al and Johanns et al also demonstrated that a neoantigen vaccine induced neoantigen-specific T cell infiltration into the tumor site in patients with glioblastoma, which usually has a relatively low mutational load (Johanns et al 2019;Keskin et al 2019).…”

Trial watch: TLR3 agonists in cancer therapy

“…181 This regimen generated strong intratumoral T-cell responses even though glioblastoma is generally viewed as an immunological 'desert', 182 suggesting that robustly adjuvanted neoepitope-targeting vaccines may constitute a valid approach for the treatment of glioblastoma, especially in combination with immune checkpoint blockers. 183 Apparently at odds with this notion, Boydell and colleagues reported that a multipeptide vaccine (IMA950) admixed with Hiltonol™, administered prior to the vascular endothelial growth factor A (VEGFA)-targeting antibody bevacizumab, 184,185 failed to improve the therapeutic activity of the latter in high-grade glioma patients, as assessed by progression-free and overall survival (NCT01920191). 186 Melssen et al investigated the safety, immunogenicity and preliminary efficacy of a multipeptide vaccine 187,188 admixed with (1) Hiltonol™ and/or incomplete Freund's adjuvant (IFA), or (2) the mixed TLR2/TLR4 agonist lipopolysaccharide (LPS) 189,190 and/or IFA in melanoma patients (NCT01585350).…”