Mass cytometry detects H3.3K27M-specific vaccine responses in diffuse midline glioma
Sabine Mueller, … , Michael D. Prados, Hideho Okada
Sabine Mueller, … , Michael D. Prados, Hideho Okada
Published August 20, 2020
Citation Information: J Clin Invest. 2020;130(12):6325-6337. https://doi.org/10.1172/JCI140378.
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Clinical Medicine Immunology Oncology

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

Abstract

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).

Authors

Sabine Mueller, Jared M. Taitt, Javier E. Villanueva-Meyer, Erin R. Bonner, Takahide Nejo, Rishi R. Lulla, Stewart Goldman, Anu Banerjee, Susan N. Chi, Nicholas S. Whipple, John R. Crawford, Karen Gauvain, Kellie J. Nazemi, Payal B. Watchmaker, Neil D. Almeida, Kaori Okada, Andres M. Salazar, Ryan D. Gilbert, Javad Nazarian, Annette M. Molinaro, Lisa H. Butterfield, Michael D. Prados, Hideho Okada

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Figure 1

Mass cytometry–based phenotyping of H3.3K27M-reactive CD8+ T cell subpopulations reveals associations between immunological responses and prolonged OS or PFS.

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Mass cytometry–based phenotyping of H3.3K27M-reactive CD8+ T cell subpop...
(A and B) Kaplan-Meier survival curves contrasting the (A) OS and (B) PFS of patients enrolled in stratum A (red) and stratum B (blue) using log-rank tests. (C) Left: PBMCs derived from a healthy donor showed an absence of H3.3K27M dextramer staining. Right: The H3.3K27M dextramer exhibited sensitive detection of H3.3K27M-specific T cell receptor–transduced (TCR-transduced) CD8+ T cells. (D) Heatmap visualizing the relative expression (Z score) of subpopulation markers in patient-derived H3.3K27M-reactive CD8+ T cells. (E) Heatmap visualizing the patient-specific presence (blue) or absence (red) of an expansion of H3.3K27M-reactive CD8+ T cells in a subpopulation-specific manner. (F and G) Kaplan-Meier survival curves contrasting the (F) OS and (G) PFS of patients who had an immunological response (blue) compared with patients who did not (red) using log-rank tests. (H and I) Kaplan-Meier survival curves contrasting the (H) OS and (I) PFS of patients who had an expansion of effector memory H3.3K27M-reactive CD8+ T cells (blue) compared with patients who did not (red) using log-rank tests.