1435 Therapeutic mRNA cancer vaccine for GBM reaches complete response in a preclinical model
Bibliographic record
Abstract
Background Glioblastoma (GBM) is a fatal cancer that has limited response to chemotherapy and radiotherapy. Immunotherapy for GBM has been challenging due to low frequency of neoantigens and immunosuppressive tumor microenvironment. Here we report the efficacy of a novel EGFRvIII mRNA vaccine formulated in next generation lipid nanoparticles (LNP). EGFRvIII is a cancer-driver mutation detected in approximately 30% of GBM patients, it appears as an in-frame epidermal growth factor receptor (EGFR) deletion generating a constitutively active oncogenic protein therefore considered a neoantigen driver mutation. Methods A GBM implantable cell line was generated from C3H/HeJ mice by in vivo electroporation to introduce genetic alterations of EGFRvIII-OE, CDKN2A-KO and PTEN-KO into periventricular cells of early postnatal mice. Resulting tumors were propagated in vitro to create cell lines. Following orthotopic implantation in 6-week-old C3H/He mice resulted in syngeneic tumors that recapitulate histologic features of GBM and caused mortality of mice by day 30. Using this GBM model, mice were intramuscularly vaccinated with either formulation buffer (fb) or EGFRv-III mRNA-LNP on day 7or 10 post tumor implantation. Four more immunizations were done before MR imaging. Mice were monitored until day 150. Brains were fixed for histological evaluation and immuno-histochemistry to determine lymphocytes, macrophages and tumor cells. T cells from spleen, and lymph nodes were analyzed to determine KLRG1, IL-7R, PD1, Ly108, CD44 and CD62L populations by flow. Anti-EGFRvIII abs were determined by ELISA. In situ spatial profiling with 10x Xenium was done in tissues for a panel of immunological markers. Results Vaccinated mice cleared tumors with no detection by histology or MRI and stayed tumor free until day 150. In contrast, control mice were diseased by day 36. Moreover, surviving vaccinated mice re-challenged on day 42 with the tumor cells, controlled the tumor with no evidence of tumor growth until day 150. The vaccination regimen induced specific EGFRvIII T cells, high numbers of Ly108+ T cells and high amounts of anti EGFRvIII antibodies. T cells are detected in brain tissue of vaccinated mice. LNP mechanism of action involved in the tumor control will be discussed. Conclusions An mRNA vaccine encoding a driver mutation in a new LNP induce an immune response that clears tumors in 100% of mice with a high-grade glioma. The vaccine induced strong T cell and antibody responses involved in controlling tumor progression. These new LNP will help progress the development of cancer vaccines for solid tumors and difficult to treat cancers.
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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 | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".