BALTIMORE – Geneos Therapeutics' personalized cancer vaccine candidate GNOS-PV02 enhanced responses to Merck's PD-1 inhibitor Keytruda (pembrolizumab), inducing antitumor responses in patients with hepatocellular carcinoma (HCC), researchers reported at the American Society of Gene and Cell Therapy's annual meeting on Wednesday.
HCC tends to have low mutational burden and is challenging to treat, but the data presented at the meeting demonstrated the feasibility of treating this tumor type with a personalized cancer vaccine.
In a single-arm, open-label, multicenter Phase I/IIa trial, Plymouth Meeting, Pennsylvania-based Geneos enrolled 36 participants, 25 of whom had discontinued treatment as of the Aug. 18, 2023, data cutoff, most commonly due to disease progression. Study participants received GNOS-PVO2, designed based on up to 40 neoantigens unique to each patient's tumor, along with Keytruda and Inovio Pharmaceuticals' plasmid-encoded interleukin-12 adjuvant INO-9012.
The study met its primary endpoints, showing the regimen to be safe and tolerable, with a safety profile similar to single-agent Keytruda alone in HCC. Low-grade treatment-related adverse events occurred in 27 patients, and there were no grade 3 adverse events. Three patients reported an immune-related adverse event, and one patient discontinued Keytruda because of an adverse event, but no patients discontinued the vaccine due to an adverse event.
Three patients achieved a complete response, and eight achieved a partial response.
The company previously reported that eight of 34 patients had a complete molecular response based on circulating tumor DNA testing, and that three patients had complete responses, seven had partial responses, nine had stable disease, and 13 had progressive disease.
Researchers also tracked T-cell clonal expansion, as well as trafficking, neoantigen specificity, and clonal and subclonal genetic profiles as exploratory endpoints in this study. Four patients, one of whom also achieved a complete response, also achieved neoantigen-specific responses, in which CD4- and CD8-positive T cells became more active.
The updated analysis revealed induction of new T-cell responses to the vaccine accompanying the expansion of the T-cell receptor (TCR) repertoire in patients' peripheral blood and tumor. Although anti-PD-1 monotherapy is known to reverse T-cell dysfunction in existing neoantigen-specific T-cell clones, its ability to induce new neoantigen-specific responses was not previously known, according to Renzo Perales, immunology lead at Geneos, who presented the data at the meeting.
Additionally, single-cell RNA-seq analysis showed that the T-cell populations that expanded in response to the vaccine showed high expression of markers consistent with a cytotoxic phenotype and, to a lesser degree, with a pre-exhausted phenotype.
Perales concluded that these findings support the hypothesis that a personalized cancer vaccine can enhance patient responses to anti-PD-1 therapy. "The therapy is safe, there is evidence of T-cell localization to the tumor sites, and we observed objective responses … even at low-dose levels," Perales said.
The study is ongoing and is estimated to complete near the middle of next year.