TY - JOUR
T1 - Mass cytometry detects H3.3K27M-specific vaccine responses in diffuse midline glioma
AU - Mueller, Sabine
AU - Taitt, Jared M.
AU - Villanueva-Meyer, Javier E.
AU - Bonner, Erin R.
AU - Nejo, Takahide
AU - Lulla, Rishi R.
AU - Goldman, Stewart
AU - Banerjee, Anu
AU - Chi, Susan N.
AU - Whipple, Nicholas S.
AU - Crawford, John R.
AU - Gauvain, Karen
AU - Nazemi, Kellie J.
AU - Watchmaker, Payal B.
AU - Almeida, Neil D.
AU - Okada, Kaori
AU - Salazar, Andres M.
AU - Gilbert, Ryan D.
AU - Nazarian, Javad
AU - Molinaro, Annette M.
AU - Butterfield, Lisa H.
AU - Prados, Michael D.
AU - Okada, Hideho
N1 - Funding Information:
The authors thank the following individuals and organizations: the study participants and their families; all PNOC staff for their assistance; all PNOC principal investigators supporting the study; members of the IMCPL at the University of Pittsburgh for preparation and distribution of the vaccine (supported in part by award P30 CA047904); the UCSF Parnassus Flow Cytometry Core for mass cytometry–related services (P30 DK063720) and use of the CyTOF2 “Charmander” (S10 1S10OD018040-01); the USCF data safety monitoring committee; Lawrence Fong and the Cancer Immunotherapy Laboratory (CIL) at UCSF for the processing and banking of patient-derived peripheral blood samples; Maryam Shahin for contributions to the optimization of the CyTOF analytical platform; Marie-Eve Koziol of SEPPIC Inc. for training research nurses in the preparation of Montanide emulsions; Nich- olas Bayless and Pier Federico Gherardini at the Parker Institute for Cancer Immunotherapy (PICI) for computational analyses of the mass cytometric data; and the Ian’s Friends Foundation.
Funding Information:
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). The authors thank the following individuals and organizations: the study participants and their families; all PNOC staff for their assistance; all PNOC principal investigators supporting the study; members of the IMCPL at the University of Pittsburgh for preparation and distribution of the vaccine (supported in part by award P30 CA047904); the UCSF Parnassus Flow Cytometry Core for mass cytometry?related services (P30 DK063720) and use of the CyTOF2 ?Charmander? (S10 1S10OD018040-01); the USCF data safety monitoring committee; Lawrence Fong and the Cancer Immunotherapy Laboratory (CIL) at UCSF for the processing and banking of patient-derived peripheral blood samples; Maryam Shahin for contributions to the optimization of the CyTOF analytical platform; Marie-Eve Koziol of SEPPIC Inc. for training research nurses in the preparation of Montanide emulsions; Nicholas Bayless and Pier Federico Gherardini at the Parker Institute for Cancer Immunotherapy (PICI) for computational analyses of the mass cytometric data; and the Ian?s Friends Foundation.
Funding Information:
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).
Publisher Copyright:
© 2020, American Society for Clinical Investigation.
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI140378
DO - 10.1172/JCI140378
M3 - Article
C2 - 32817593
AN - SCOPUS:85096447180
VL - 130
SP - 6325
EP - 6337
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 12
ER -