Peptide vaccine targeting mutatedGNAS: a potential novel treatment for pseudomyxoma peritonei

Abstract

BackgroundPseudomyxoma peritonei (PMP) is a rare, slow-growing abdominal cancer with no efficacious treatment options in non-resectable and recurrent cases. Otherwise, rare activating mutations in the GNAS oncogene are remarkably frequent in PMP and the mutated gene product, guanine nucleotide-binding protein α subunit (Gsα), is a potential tumor neoantigen, presenting an opportunity for targeting by a therapeutic cancer vaccine.MethodsTumor and blood samples were collected from 25 patients undergoing surgery for PMP (NCT02073500). GNAS mutation analysis was performed by next-generation targeted sequencing or digital droplet PCR. Responses to stimulation with Gsα mutated (point mutations R201H and R201C) 30 mer peptides were analyzed in peripheral blood T cells derived from patients with PMP and healthy donors. Fresh PMP tumor samples were analyzed by mass cytometry using a panel of 35 extracellular markers, and cellular subpopulations were clustered and visualized using the visual stochastic network embedding analysis tool.ResultsGNAS mutations were detected in 22/25 tumor samples (88%; R201H and R201C mutations detected in 16 and 6 cases, respectively). Strong T cell proliferation against Gsα mutated peptides was observed in 18/24 patients with PMP. Mass cytometry analysis of tumor revealed infiltration of CD3 +T cells in most samples, with variable CD4+:CD8 + ratios. A large proportion of T cells expressed immune checkpoint molecules, in particular programmed death receptor-1 and T cell immunoreceptor with Ig and ITIM, indicating that these T cells were antigen experienced.ConclusionThese findings point to the existence of a pre-existing immunity in patients with PMP towards mutated Gsα, which has been insufficient to control tumor growth, possibly because of inhibition of antitumor T cells by upregulation of immune checkpoint molecules. The results form a rationale for exploring peptide vaccination with Gsα peptides in combination with immune checkpoint inhibiton as a possible curative treatment for PMP and other GNAS mutated cancers.

Distinct cell states define the developmental trajectories of mucinous appendiceal neoplasms towards pseudomyxoma metastases

“…This result is supported by a recent study that identified immune enriched TME in a subset of PMP patients using spatial gene expression analysis [75]. Prior experiments have shown that PMP tumors respond to immune checkpoint blockade or cancer neoantigen vaccination based on a common mutation in GNAS [76, 77]. Despite the presence of these immune cells, their anti-tumor activity could be hindered by the presence of gelatinous mucin in PMP [78].…”

Comprehensive Understanding and Evolutional Therapeutic Schemes for Pseudomyxoma Peritonei

“…In another 2 relapsing panels of PMP patients that respectively accepted with capecitabine and bevacizumab, FOLFOX4 regimen both presented shorter median PFS if GNAS mutation was detected (5.1 vs. 13 mo) 107. GNAS mutation activates downstream protein factors in protein kinase A pathway and produces abnormal amounts of mucin 108. Existing researches have proven the powerful immunogen with guanine nucleotidebinding protein α subunti (Gsα) peptide which provokes de novo immunity targeting the tumor driver signaling molecule 108.…”

“… 107 GNAS mutation activates downstream protein factors in protein kinase A pathway and produces abnormal amounts of mucin. 108 Existing researches have proven the powerful immunogen with guanine nucleotidebinding protein α subunti (Gsα) peptide which provokes de novo immunity targeting the tumor driver signaling molecule. 108 That established a sound foundation to antitumor vaccination and open a novel affiliated therapy strategy.…”

“… 108 Existing researches have proven the powerful immunogen with guanine nucleotidebinding protein α subunti (Gsα) peptide which provokes de novo immunity targeting the tumor driver signaling molecule. 108 That established a sound foundation to antitumor vaccination and open a novel affiliated therapy strategy. The activation of the RAS-MAPK signaling pathway induces adverse molecular biological effects in whether KRAS or GNAS mutation, the medicine blocking this pathway could be another effective targeting treatment opportunity.…”

Therapy of genomic unstable solid tumours (WHO grade 3/4）in clinical stage III/IV using individualised neoantigen tumour peptides-INP trial (individualised neoantigen tumour peptides immunotherapy): study protocol for an open-label, non-randomised, prospective, single-arm trial

“… 5 12 18 25–28 Most of research on neoantigens has focused just on a unique tumour and a single mutated gene. 5 11 29 The safety and efficacy of neoantigen peptide mixtures derived from multiple gene mutation sites in the treatment of advanced solid malignancies with genomic instability are still unclear.…”