Mass cytometry detects H3.3K27M-specific vaccine responses in diffuse midline glioma

Autor: Erin R Bonner, Lisa H. Butterfield, Annette M. Molinaro, Nicholas S Whipple, Michael D. Prados, Jared Taitt, Andres M. Salazar, Ryan Gilbert, Sabine Mueller, Javad Nazarian, Neil D. Almeida, Anu Banerjee, Hideho Okada, Susan N. Chi, Karen Gauvain, Javier Villanueva-Meyer, Kellie J. Nazemi, John Robertson Crawford, Rishi Lulla, Payal Watchmaker, Takahide Nejo, Kaori Okada, Stewart Goldman
Přispěvatelé: University of Zurich, Okada, Hideho
Rok vydání: 2022
Předmět:
0301 basic medicine
Oncology
Male
Cancer immunotherapy
2700 General Medicine
CD8-Positive T-Lymphocytes
Brain cancer
Medical and Health Sciences
Histones
0302 clinical medicine
Brain Stem Neoplasms
Child
Stroke
Cancer
Pediatric
Vaccines
Immunity
Cellular
Brain Neoplasms
General Medicine
Glioma
Flow Cytometry
Neoplasm Proteins
medicine.anatomical_structure
6.1 Pharmaceuticals
030220 oncology & carcinogenesis
Child
Preschool
Female
Corrigendum
medicine.drug
Adult
medicine.medical_specialty
Adolescent
T cell
Immunology
Clinical Trials and Supportive Activities
Mutation
Missense
610 Medicine & health
Peripheral blood mononuclear cell
Cancer Vaccines
Vaccine Related
03 medical and health sciences
Rare Diseases
Clinical Research
Internal medicine
Injection site reaction
medicine
Humans
Preschool
Adverse effect
Dexamethasone
business.industry
Immunity
Neurosciences
Evaluation of treatments and therapeutic interventions
medicine.disease
Brain Disorders
Good Health and Well Being
030104 developmental biology
Amino Acid Substitution
10036 Medical Clinic
Mutation
Immunization
Cellular
Missense
Clinical Medicine
business
CD8
Zdroj: J Clin Invest
The Journal of clinical investigation, vol 130, iss 12
ISSN: 0296-0230
DOI: 10.5167/uzh-224674
Popis: BACKGROUND: Patients with diffuse midline gliomas (DMGs), including diffuse intrinsic pontine glioma (DIPG), have dismal outcomes. We previously described the H3.3K27M mutation as a shared neoantigen in HLA-A*02.01(+), H3.3K27M(+) DMGs. Within the Pacific Pediatric Neuro-Oncology Consortium, we assessed the safety and efficacy of an H3.3K27M-targeted peptide vaccine. METHODS: Newly diagnosed patients, aged 3–21 years, with HLA-A*02.01(+) and H3.3K27M(+) status were enrolled in stratum A (DIPG) or stratum B (nonpontine DMG). Vaccine was administered in combination with polyinosinic-polycytidylic acid-poly-I-lysine carboxymethylcellulose (poly-ICLC) every 3 weeks for 8 cycles, followed by once every 6 weeks. Immunomonitoring and imaging were performed every 3 months. Imaging was centrally reviewed. Immunological responses were assessed in PBMCs using mass cytometry. RESULTS: A total of 19 patients were enrolled in stratum A (median age,11 years) and 10 in stratum B (median age, 13 years). There were no grade-4 treatment-related adverse events (TRAEs). Injection site reaction was the most commonly reported TRAE. Overall survival (OS) at 12 months was 40% (95% CI, 22%–73%) for patients in stratum A and 39% (95% CI, 16%–93%) for patients in stratum B. The median OS was 16.1 months for patients who had an expansion of H3.3K27M-reactive CD8(+) T cells compared with 9.8 months for their counterparts (P = 0.05). Patients with DIPG with below-median baseline levels of myeloid-derived suppressor cells had prolonged OS compared with their counterparts (P < 0.01). Immediate pretreatment dexamethasone administration was inversely associated with H3.3K27M-reactive CD8(+) T cell responses. CONCLUSION: Administration of the H3.3K27M-specific vaccine was well tolerated. Patients with H3.3K27M-specific CD8(+) immunological responses demonstrated prolonged OS compared with nonresponders. TRIAL REGISTRATION: ClinicalTrials.gov NCT02960230. FUNDING: The V Foundation, the Pacific Pediatric Neuro-Oncology Consortium Foundation, the Pediatric Brain Tumor Foundation, the Mithil Prasad Foundation, the MCJ Amelior Foundation, the Anne and Jason Farber Foundation, Will Power Research Fund Inc., the Isabella Kerr Molina Foundation, the Parker Institute for Cancer Immunotherapy, and the National Institute of Neurological Disorders and Stroke (NINDS), NIH (R35NS105068).
Databáze: OpenAIRE
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