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ABSTRACT: Exome sequencing of primary human glioblastoma resected tissue before and after a personalized, neoantigen-based vaccine plus poly-ICLC (NeoVax) tissues from a Phase 1 clinical trial

PROVIDER: PRJNA999679 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25449378_1.fastq.gz	Fastqsanger.gz
	SRR25449378_2.fastq.gz	Fastqsanger.gz
	SRR25449379_1.fastq.gz	Fastqsanger.gz
	SRR25449379_2.fastq.gz	Fastqsanger.gz
	SRR25449380_1.fastq.gz	Fastqsanger.gz

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RNA-sequencing of primary human glioblastoma resected tissue before and after a personalized, neoantigen-based vaccine plus poly-ICLC (NeoVax) tissues from a Phase 1 clinical trial

Project description:RNA-sequencing of primary human glioblastoma resected tissue before and after a personalized, neoantigen-based vaccine plus poly-ICLC (NeoVax) tissues from a Phase 1 clinical trial

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RNA-sequencing of primary human glioblastoma resected tissue before and after a personalized, neoantigen-based vaccine plus poly-ICLC (NeoVax); tissues from a Phase 1 clinical trial

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Project description:Adjuvants are critical for the success of vaccines, and agonists for microbial pattern recognition receptors are promising new candidates. A mechanism for the immune enhancing role of adjuvants is to stimulate innate immunity. We studied the innate immune response in humans to synthetic double stranded RNA (poly ICLC), a ligand for TLR3 and MDA-5 cytosolic RNA helicase. Transcriptional analysis of blood samples from eight volunteers, after subcutaneous administration of poly ICLC showed upregulation of genes involved in multiple innate immune pathways in all subjects, including interferon and inflammasome signaling. Blocking of type I interferon receptor ex vivo significantly dampened the response to poly IC. Comparative transcriptional analysis showed that several innate pathways were similarly induced in volunteers immunized with the highly efficacious Yellow Fever Vaccine. Therefore a chemically defined microbial agonist like poly ICLC can be a reliable and authentic microbial mimic for inducing innate immunity, here for a live attenuated viral vaccine in humans. GSM813292-GSM813386: RNA expression obtained at different time points from Human blood after poly ICLC administration compared to RNA expression obtained from Human blood after placebo administration GSM813387-GSM813410: Blocking of type I interferon receptor ex vivo followed by poly IC stimulation

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Project description:Personalized cancer vaccines aim to activate and expand cytotoxic anti-tumor CD8+ T cells to recognize and kill tumor cells. However, the role of CD4+ T cell activation in the clinical benefit of these vaccines is not well defined. We previously established a personalized neoantigen vaccine (PancVAX) for the pancreatic cancer cell line Panc02, which activates tumor-specific CD8+ T cells but required combinatorial checkpoint modulators to achieve therapeutic efficacy. To determine the effects of neoantigen-specific CD4+ T cell activation, we generated a new vaccine (PancVAX2) targeting both MHCI- and MHCII-specific neoantigens. Tumor-bearing mice vaccinated with PancVAX2 had significantly improved control of tumor growth and long-term survival benefit without concurrent administration of checkpoint inhibitors. PancVAX2 significantly enhanced priming and recruitment of neoantigen-specific CD8+ T into the tumor with lower PD1 expression after reactivation compared to the CD8+ vaccine alone. Vaccine-induced neoantigen- specific Th1 CD4+ T cells in the tumor were associated with decreased T regulatory cells (Tregs). Consistent with this, PancVAX2 was associated with more pro-immune myeloid-derived suppressor cells and M1-like macrophages in the tumor demonstrating a less immunosuppressive tumor microenvironment. This study demonstrates the biological importance of prioritizing and including CD4 T cell-specific neoantigens for personalized cancer vaccine modalities.

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