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Adjuvant personalized multivalent neoantigen DNA vaccination for MGMT unmethylated glioblastoma: a phase I trial [RNA-seq]

ABSTRACT: Glioblastoma is a devastating disease with a prognosis of less than 24 months. Recent studies have shown encouraging results using neoantigen-based vaccines to stimulate glioblastoma-directed immune responses, but overall immunogenicity has been low. Here, we report the results of a phase 1 clinical trial (NCT04015700) to assess the safety and efficacy of GNOS-PV01, a personalized DNA vaccine platform, in patients with newly diagnosed MGMT unmethylated glioblastoma following surgery and radiation. Results show GNOS-PV01 is able to safely immunize against up to 40 neoantigens per patient (range 17-40) with neoantigen-specific T cell responses detectable in all evaluated subjects post-vaccination (7 of 7). Furthermore, we developed a novel T cell enrichment method for single nuclei RNA-sequencing to transcriptionally characterize tumor-infiltrating T cells after vaccination. Survival outcomes were encouraging with one-third of vaccinated patients (3 of 9) alive beyond 24 months. Moreover, induction of neoantigen-specific responses was associated with subsequent reactivity to PD-1 blockade therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE292045 | GEO | 2026/02/10

REPOSITORIES: GEO

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Project description:Abstract Glioblastoma (GBM) is the most common and aggressive primary brain cancer. Current standard-of-care includes surgery, radiation and treatment with temozolomide (TMZ), however nearly all tumors recur and the prognosis for recurrent GBM is dismal. Resistance to TMZ is correlated with expression of the DNA repair enzyme O6-methylguanine-DNA-methyltransferase (MGMT), which is highly expressed in a majority of GBM tumors. Dianhydrogalactitol (VAL-083) is a first-in-class bi-functional DNA-targeting agent that exhibited activity against GBM in NCI-sponsored clinical trials both as a single agent and in combination with radiotherapy. VAL-083 readily crosses the blood-brain barrier and accumulates in brain tumor tissue. We have demonstrated that VAL-083 targets N7-Guanine and rapidly induces interstrand DNA cross-links, leading to DNA double-strand breaks, S/G2 cell-cycle arrest and cell death in GBM cell lines and GBM cancer stem cells (CSCs) in vitro. This unique N7-guanine targeting mechanism not only circumvents MGMT-mediated chemo-resistance but also maintains cytotoxic activity in cancer cells deficient in mismatch repair (MMR). These data suggest VAL-083 may offer a superior chemotherapeutic alternative in the treatment of MGMT-unmethylated or MMR deficient GBM. Here, we provide an update of ongoing clinical trials with VAL-083 in MGMT-unmethylated GBM: i) a single-arm, biomarker-driven, Phase II study to determine if VAL-083 treatment of MGMT-unmethylated adult GBM patients at first recurrence/progression, prior to bevacizumab improves survival compared to historical lomustine control (clinicaltrials.gov identifier: NCT02717962); ii) a single-arm, biomarker-driven, Phase II study to confirm the tolerability and efficacy of VAL-083 in combination with radiotherapy in newly diagnosed MGMT-unmethylated GBM patients (clinicaltrials.gov identifier: NCT03050736). The results of these studies may support a new treatment paradigm in for the treatment of MGMT-unmethylated GBM.

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Adjuvant personalized multivalent neoantigen DNA vaccination for MGMT unmethylated glioblastoma: a phase I trial [RNA-seq]

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