DIPG-92. IMMUNE ACTIVATION STUDIES WITH THE NEOANTIGEN-BASED PEPTIDE VACCINE RHSC-DIPGVAX DEMONSTRATE ANTIBODY-MEDIATED RESPONSES AND EPITOPE SPREADING IN PEDIATRIC PATIENTS WITH DIFFUSE INTRINSIC PONTINE GLIOMAS (DIPG)
Bibliographic record
Abstract
Abstract BACKGROUND Approximately 80% of DIPGs carry gain-of-function lysine-to-methionine (K27M) mutations in histone H3 proteins that frequently co-occur with other protein aberrations, including p53, ACVR1, and PDGFRA. Because the DIPG microenvironment has few infiltrating immune cells, resolution of negative regulatory mechanisms through checkpoint blockade may be necessary to promote vaccine-induced anti-tumor responses. Accordingly, rHSC-DIPGVax is a neoantigen-based peptide vaccine combined with checkpoint inhibitors currently under investigation in clinical trial, NCT04943848. The vaccine contains 16 neoantigen peptides, QS-21 adjuvant, and recombinant heat shock protein, Hsc70. In this study, we investigate vaccine-induced antibody-mediated immunity and the phenomenon of epitope spreading, an extension of the immune response to secondary epitopes not directly targeted by the therapy, thus promoting distinct, individualized responses. METHODS rHSC-DIPGVax is administered every two weeks to patients with DIPG and blood is collected pre-treatment and prior to each dose. To investigate vaccine-induced immunoreactivity to neoantigens targeted by rHSC-DIPGVax, DIPG lysates resolved by two-dimensional gel electrophoresis are immunoblotted with pre- and post-vaccine patient plasma containing antibodies against vaccine antigens. Proteins are immunoprecipitated (IP) from DIPG lysates, followed by mass spectrometry (MS) identification and validation. RESULTS In eight subjects to date, vaccination with rHSC-DIPGVax consistently induces IgM and IgG antibodies against proteins directly targeted by the vaccine, including strong immunoreactivity to ACVR1. Furthermore, antibodies against several secondary proteins are also detected in post-vaccination plasma. Immunoblotting and IP-MS analysis identified several distinct candidates of epitope spreading, including the tumor antigens CEP290, DNAH3, HRNR, KDM6B, LAMA5, and TRPA1. CONCLUSIONS rHSC-DIPGVax induces antibody-mediated tumor-specific responses to DIPG neoantigens, including direct vaccine targets and secondary targets via intra- and inter-molecular epitope spreading. We also present an experimental protocol to investigate vaccine-induced immune activation. Our ongoing studies aim to validate epitope spreading candidates and determine the important biological correlates between antibody responses and clinical outcomes.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".