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Personalized NeoAntigen Cancer Vaccine with RT for Newly Diagnosed Glioblastoma

ABSTRACT: Personalized NeoAntigen Cancer Vaccine with RT for Newly Diagnosed Glioblastoma

PROVIDER: PRJNA429518 | ENA |

REPOSITORIES: ENA

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Personalized NeoAntigen Cancer Vaccine with RT for Newly Diagnosed Glioblastoma

Project description:Personalized NeoAntigen Cancer Vaccine with RT for Newly Diagnosed Glioblastoma

| PRJNA429519 | ENA

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

Project description: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.

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

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Personalized neoantigen-based T cell therapy triggers cytotoxic lymphocytes expressing polyclonal TCR against metastatic ovarian cancer

Project description:Neoantigen-reactive cytotoxic T lymphocytes play a vital role in precise cancer cell elimination. In this study, we demonstrate the effectiveness of personalized neoantigen-based T cell therapy in inducing tumor regression in two patients suffering from heavily-burdened metastatic ovarian cancer. Our approach involved the development of a robust pipeline for ex vivo expansion of neoantigen-reactive T lymphocytes. Neoantigen peptides were designed and synthesized based on the somatic mutations of the tumors and their predicted HLA binding affinities. These peptides were then presented to T lymphocytes through co-culture with neoantigen-loaded dendritic cells for ex vivo expansion. Subsequent to cell therapy, both patients exhibited significant reductions in tumor marker levels and experienced substantial tumor regression. One patient achieved repeated cancer regression through infusions of T cell products generated from newly identified neoantigens. Transcriptomic analyses revealed a remarkable increase in neoantigen-reactive cytotoxic lymphocytes in the peripheral blood of the patients following cell therapy. These cytotoxic T lymphocytes expressed polyclonal T cell receptors (TCR) against neoantigens, along with abundant cytotoxic proteins and pro-inflammatory cytokines. The efficacy of neoantigen targeting was significantly associated with the immunogenicity and TCR polyclonality. Notably, the neoantigen-specific TCR clonotypes persisted in the peripheral blood after cell therapy. Our findings indicate that personalized neoantigen-based T cell therapy triggers cytotoxic lymphocytes expressing polyclonal TCR against ovarian cancer, suggesting its promising potential in cancer immunotherapy.

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Integrating multisector molecular characterization into personalized peptide vaccine design for patients with newly diagnosed glioblastoma.

Project description:Integrating multisector molecular characterization into personalized peptide vaccine design for patients with newly diagnosed glioblastoma.

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Personalized Neoantigen Cancer Vaccine in Glioblastoma Multiforme

Project description:<p>Neoantigens, which are derived from tumour-specific protein-coding mutations, are exempt from central tolerance, can generate robust immune responses and can function as bona fide antigens that facilitate tumour rejection. We demonstrated that a strategy that uses multi-epitope, personalized neoantigen vaccination, which has previously been tested in patients with high-risk melanoma, is feasible for tumours such as glioblastoma, which typically have a relatively low mutation load and an immunologically ‘cold’ tumour microenvironment. Here we conducted whole-exome sequencing of tumor and normal cells from individual patients with glioblastoma to identify tumor-specific mutations. We assessed the expression of mutated alleles by RNA-sequencing of tumor. We used personalized neoantigen-targeting vaccines to immunize patients newly diagnosed with glioblastoma following surgical resection and conventional radiotherapy in a phase I/Ib study. Patients who did not receive dexamethasone-a highly potent corticosteroid that is frequently prescribed to treat cerebral oedema in patients with glioblastoma-generated circulating polyfunctional neoantigen-specific CD4+ and CD8+ T cell responses that were enriched in a memory phenotype and showed an increase in the number of tumour-infiltrating T cells. Using single-cell T cell receptor analysis, we provide evidence that neoantigen-specific T cells from the peripheral blood can migrate into an intracranial glioblastoma tumour. Neoantigen-targeting vaccines thus have the potential to favourably alter the immune milieu of glioblastoma.</p>

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Project description:We recently defined a gene expression-based signature of high-risk multiple myeloma; this predictive signature was developed with and independently validated for newly diagnosed patients treated with high dose therapy and stem cell rescue. Here we use Phase 3 clinical trial data to show that this signature also predicts short survival in relapsed disease treated with single agent bortezomib or high dose dexamethasone. In addition, a survival signature derived with relapsed myeloma samples identified newly diagnosed patients with short survival. Taken together these data suggest that a similar biology underlies poor outcome in both newly diagnosed and relapsed myeloma and provide strong evidence that the high-risk signature is a powerful tool to identify patients who are candidates for new therapeutic regimens. Keywords: Model validation

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