Mueller and Taitt et al. reported the safety and efficacy of an H3.3K27M-targeted peptide vaccine in patients with HLA-A*02:01+H3.3K27M+ diffuse midline gliomas (Stratum A) and diffuse intrinsic pontine glioma (Stratum B). The treatment was well tolerated with an OS of 44% for Stratum A and 39% for Stratum B at 12 months. Immunological responders (expansion of H3.3K27M-reactive CD8+ T cells) demonstrated an improved OS of 16.1 months compared to 9.8 months for non-responders. High myeloid-derived suppressor cells (MDSChi) or dexamethasone pretreatment showed inverse association with survival.
Contributed by Shishir Pant
BACKGROUND: Patients with diffuse midline gliomas (DMG), 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 safety and efficacy of an H3.3K27M-targeted peptide vaccine. PATIENTS AND METHODS: Newly diagnosed patients aged 3-21 years with HLA-A*02.01+ and H3.3K27M+ status were enrolled into Stratum A (DIPG) and Stratum B (non-pontine DMG). Vaccine was administered in combination with poly-ICLC every three weeks for eight cycles, followed by once every six weeks. Immuno-monitoring and imaging occurred every three months. Imaging was centrally reviewed. Immunological responses were assessed in peripheral blood mononuclear cells using mass cytometry. RESULTS: 19 patients 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 (TRAE). Injection site reaction was the most commonly reported TRAE. Overall survival (OS) at 12 months was 40% (95% CI, 22% to 73%) for Stratum A and 39% (95% CI, 16% to 93%) for Stratum B. The median OS was 16.1 months in patients exhibiting an expansion of H3.3K27M-reactive CD8+ T-cells compared to 9.8 months for their counterparts (p=0.05). DIPG patients with below-median baseline levels of myeloid-derived suppressor cells had prolonged OS compared to their counterparts (p<0.01). Immediate pre-treatment dexamethasone administration inversely associated with H3.3K27M-reactive CD8+ T-cell responses. CONCLUSION: Administration of the H3.3K27M-specific vaccine is well tolerated. Patients with H3.3K27M-specific CD8+ immunological responses demonstrated prolonged OS compared to non-responders.
Author Info: (1) Department of Neurological Surgery, University of California San Francisco, San Francisco, United States of America. (2) Department of Neurological Surgery, University of Calif
Author Info: (1) Department of Neurological Surgery, University of California San Francisco, San Francisco, United States of America. (2) Department of Neurological Surgery, University of California San Francisco, San Francisco, United States of America. (3) Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, United States of America. (4) Center for Genetic Medicine, The Children's National Medical Center, Washington, United States of America. (5) Department of Neurological Surgery, University of California San Francisco, San Francisco, United States of America. (6) Division of Pediatric Hematology/Oncology, The Warren Alpert Medical School of Brown University, Providence, United States of America. (7) Department of Hematology/Oncology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, United States of America. (8) Department of Neurological Surgery, University of California San Francisco, San Francisco, United States of America. (9) Pediatric Neuro-Oncology, Dana-Faber Cancer Institute, Boston, United States of America. (10) Division of Hematology/Oncology, University of Utah, Salt Lake City, United States of America. (11) Department of Neurosciences and Pediatrics, The University of California San Diego, San Diego, United States of America. (12) St. Louis Children's Hospital, Washington University, St. Louis, St. Louis, United States of America. (13) Doernbecher Children's Hospital, Oregon Health & Science Univ, Portland, United States of America. (14) Department of Neurosurgery, University of California San Francisco, San Francisco, United States of America. (15) The George Washington University School of Medicine and Health Sciences, The George Washington University, Washington, D.C., United States of America. (16) Department of Neurosurgery, University of California San Francisco, San Francisco, United States of America. (17) Oncovir Inc, Oncovir Inc, Washington, United States of America. (18) Department of Neurosurgery, University of California San Francisco, San Francisco, United States of America. (19) Genetic Medicine Research / Cancer & Immunology Research, Children's National Medical Center, Washington, D.C., United States of America. (20) Department of Neurosurgery, University of California San Francisco, San Francisco, United States of America. (21) Parker Institute for Cancer Immunotherapy, San Francisco, United States of America. (22) Department of Neurosurgery, University of California San Francisco, San Francisco, United States of America. (23) Department of Neurosurgery, University of California San Francisco, San Francisco, United States of America.
