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• W2959500507 abstract "Prophylactic cancer vaccines have traditionally only succeeded in preventing viral-induced malignancies, such as hepatitis B-associated hepatocellular carcinoma or papilloma virus-associated cervical cancer. Conceptually, treating cancers with tumor vaccines starts with identifying specific tumor-associated antigens for “educating” an individual's immune system to elicit an antitumor response.1 Notably, the recent description of an individualized tumor-specific (ie, “neoantigen”) vaccine for melanoma patients has sparked interest in a potential role for this therapeutic strategy in other solid tumors.2 Glioblastoma multiforme (GBM) is the most common and aggressive primary intracranial malignancy with a median survival of 15 mo for newly diagnosed patients, and is a challenging cancer for immunotherapy due to its relatively low mutagenic load.3-5 Keskin et al4 are the first to report on a human trial of neoantigen vaccines for GBM. In this phase I/Ib trial, tumor samples from 10 newly diagnosed GBMs harboring unmethylated methylguanine methyltransferase (MGMT) promoters (an indicator of worse prognosis) were analyzed for neoantigens in comparison with normal blood cells.6 For each specimen, whole-exome sequencing and RNA sequence analysis confirmed tumor specific single-nucleotide variants and coding mutations in many GBM-associated genes (ie, EGFR, RB1, PTEN). Neoantigen vaccines were developed, consisting of up to 20 long peptides divided into pools of 3 to 5 peptides (pools A-D) based on a median of 64.5 human leukocyte antigen (HLA) binding predictions (range 30-264) per tumor. For the 8 patients who completed enrollment, median 24 amino acid long peptides (15-30 aa range) and median 12 peptides (range 7-20) per vaccine were administered. Treatment scheduling and outcome data for the final cohort is summarized in the Figure. Only 3 patients completed the full course of 5 planned priming and 3 booster vaccinations.FIGURE.: A, Somatic mutations were identified by Clinical Laboratory Improvement Amendments (CLIA)-certified whole-exome sequencing of DNA from surgically resected glioblastoma (GBM) and matched normal cells (PBMCs) and their expression was confirmed by tumor RNA-seq. Immunizing peptides were selected based on HLA class I binding predictions. Each patient was vaccinated with up to 20 long peptides, administered in nonrotating pools of 3 to 5 peptides. B, Clinical event timeline for the 8 patients who received at least 1 vaccine dose, from surgery until time of death due to progressive disease. Blue bars, dexamethasone dose and duration. Gray bars, salvage therapy administered following progression. Median progression-free survival (PFS) and overall survival (OS) was 7.6 mo (90% confidence interval, 6.2-9.5) and 16.8 mo (90% confidence interval, 9.6-21.3), respectively. Reprinted by permission from Springer Nature: Springer Nature, Nature, Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial, Keskin DB, Anandappa AJ, Jing S, et al, ©2019. [https://www.nature.com/articles/s41586-018-0792-9]Of the 5 patients who received at least 1 booster vaccine, circulating immune responses to immunizing peptides were analyzed and peripheral blood mononuclear cells (PBMCs) were tested for neoepitope reactivity. Patients who did not receive dexamethasone during the vaccination period (n = 2) generated robust immune responses against predicted neoantigens. Conversely, patients who received intravenous steroids during the vaccine priming period (n = 3) did not show sufficient interferon-γ (IFNγ) response. Two patients demonstrated a robust peripheral CD4+ and CD8+ T cell response following vaccination, with activity against mutated ARHGAP35, GCP1, SLX4, SHANK2, SEVP1, and COX18 neoepitopes. The same 2 patients showed a significant increase in tumor infiltrating CD8+ T cells within surgical specimens at repeat resection for local disease recurrence. To confirm that these infiltrating T cells were reactive to administered neoantigen vaccines, the authors tested whether CDR3α and ß T cell receptor (TCR) sequences for neoantigen-specific T cell clones were present in resected tumor. TCRαß T cell clones were identified by stimulating T cells with mutated SHANK2 and SVEP1 peptides in vitro; the frequency of the identified α and ß TCR chains from bulk sequencing data was measured from de novo and recurrent tumor RNAs. TCR α and ß chains from the neoantigen-reactive clones stimulated in vitro were detected at week 16, but not detectable prevaccination in peripheral blood. Further, only SHANK2 TCR α and ß chain sequences were detectable in recurrent tumor RNA—indicating that some vaccine-induced neoantigen-specific T cells can successfully migrate into recurrent GBM. To further illustrate the neoantigen-reactivity of infiltrating T cells, the authors performed single-cell RNA-sequencing (scRNA-seq) on isolated CD3+ lymphocytes from postvaccination tumor tissue in 1 patient and acquired gene expression data for CD4+ and CD8+ tumor-associated T cells. Computationally reconstructed TCR sequences from the scRNA-seq data were then used to identify unique TCR clonotypes for CD3+ tumor-associated T cells. TCR sequences from 4 CD4+ and 2 CD8+ circulating neoantigen-reactive T cell clonotypes were identical to those of tumor infiltrating T cells. The authors concluded that neoantigen vaccination is feasible for tumors with a “cold” immune microenvironment like GBM. Though the median overall survival for patients who received at least the first vaccination dose (16.8 mo) was not significantly different than patients receiving standard-of-care, this study demonstrates that some patients mount a robust, neoantigen-active, circulating immune response. Notably, these were patients who did not receive dexamethasone during vaccine priming, indicating a possible negative corticosteroid interaction with neoantigen-reactive vaccine therapies. It is also important to note that although increased levels of infiltrating CD4+ T cells have been observed in more aggressive GBMs, only patients with neoantigen-specific immune responses were found to have increased levels of infiltrating T cells in recurrent GBM specimens in this small cohort.7 This promising study suggests the need for many future studies for neoantigen vaccines and GBM molecular subtypes in order to design and clinically implement this type of immunotherapy. Disclosures The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article." @default.
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• W2959500507 date "2019-07-15" @default.
• W2959500507 modified "2023-10-17" @default.
• W2959500507 title "Neoantigen-Targeting Vaccine Promotes T-Cell Response in Glioblastoma" @default.
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• W2959500507 doi "https://doi.org/10.1093/neuros/nyz164" @default.
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