1499 TCR clonotype features correlate with responses to personalized neoantigen cancer vaccine in pancreatic ductal adenocarcinoma

Background

Neoantigen cancer vaccines have demonstrated promising therapeutic benefit in multiple clinical trials. However, long term efficacy data and mechanisms underlying immune responses to vaccination are lacking. Herein, we report late breaking results of a phase 1b trial of a personalized neoantigen cancer vaccine PCNAT-01 in patients with pancreatic ductal adenocarcinoma (PDAC) following chemotherapy (registered at ClinicalTrials.gov [NCT03558945].

Methods

The primary clinical endpoint for analysis is safety assessed by the incidence and severity (based on NCI-CTCAE V5.0) of all treatment emergent adverse events (TEAEs), serious adverse events (SAEs), PCNAT-01-related adverse events (TRAEs). Efficacy of the neoantigen vaccine was evaluated as secondary endpoint and measured by recurrence-free survival (RFS) and overall survival rates (OS) over an extended time period (3-, 4-, 5-years) in order to define the long-term effects of the vaccine. Exploratory measures were to conduct immune profiling analyses in order to investigate mechanisms underlying responses to vaccination.

Results

Results showed that only 5 subjects (21.74% [5/23]) experienced at least one grade 3 of all treatment emergent adverse events (TEAE). Patients achieved favorable survival outcomes, with a 3-, 4-, 5-year recurrence-free survival rate of 60%, 52.5% and 43.8%, respectively, and a 3-, 4-, 5-year overall survival rate of 80%, 66% and 66%, respectively. Leveraging single cell mRNA sequencing combined with single cell TCR sequencing technologies, we found that both cytotoxic CD4 and CD8 T cell clusters were enriched in expanded clonotypes and had higher frequencies in non-relapsed versus relapsed patients at the boosting stage. Functional gene enrichment analyses of expanded clones revealed that TCR genes are highly variable between non-relapsed and relapsed patients. Significant correlations between TCR gene usage and clinical efficacy measures (OS, RFS) were also found at baseline and at different priming and boosting timepoints suggesting that TCR gene usage may potentially predispose for the ability to respond to personalized neoantigen cancer vaccine.

Conclusions

Taken together, our results claim that neoantigen cancer vaccines may act by inducing the expansion of T clones with specific TCR gene usage signature that might predispose for the efficacy of the vaccine.