In April 2024 Geneos Therapeutics announced the publication of “positive” safety, immunogenicity, and efficacy data from a full cohort of patients in the GT-30 clinical trial. The paper, in Nature Medicine, presents the 36-patient, single-arm, open-label, multi-centre Phase I/II study of GNOS-PV02. This is a DNA plasmid encoded PTCV in combination with DNA plasmid encoded IL-12, and is administered in combination with pembrolizumab in second-line (2L) patients with advanced hepatocellular carcinoma (HCC) who had previously been treated with a multi-tyrosine kinase inhibitor. Geneos reports that the study “met” both primary and secondary endpoints.
HCC and the vaccines
The study describes hepatocellular carcinoma (HCC) as the “most common form of primary liver cancer”, a leading cause of cancer-related death globally. Although there have been “advancements” in systemic therapy for advanced HCC, the 5-year survival rate is <10%. Therefore, the team at Geneos conducted their study of a personalised therapeutic cancer vaccine (PTCV) in combination with pembrolizumab.
The PTCV comprised a DNA plasmid encoding up to 40 neoantigens (GNOS-PV02) identified through sequencing of each patient’s tumour DNA and RNA, as well as germline DNA. GNOS-PV02 is “coformulated” with a second DNA plasmid encoding the cytokine interleukin-12 (IL-12) as a vaccine adjuvant and is administered by intradermal injection before in vivo electroporation.
In study
Geneos states that PTCV-related adverse events were “all limited” to Grades 1 and 2, with no dose-limiting toxicities. The most common of these were injection site reactions, which were observed in 41.6% of patients. The ORR for GT-30 is currently at 30.6%, including three “complete responses” and eight partial responses, which is described as “statistically significant”.
“Immunological analysis confirmed both the induction of new T cell responses to vaccine-encoded antigens and an expansion of the TCR repertoire in both the peripheral blood and tumour.”
Although anti-PD-1 monotherapy can reverse T cell dysfunction in existing neoantigen-specific T cell clones, it is not known to induce new neoantigen-specific T cell clones. Thus, the study “provides evidence that a PTCV can enhance responses to anti-PD-1 therapy through the induction of neoantigen-specific T cells in the peripheral blood and tumour”.
Another feature of the current approach that is identified in the study is that it sought to include “all targetable neoantigens in each patients’ vaccine”: “drivers and passengers, truncal and branch, shared and private”.
Advancing the field
CEO and president of Geneos, Dr Niranjan Sardesai, commented that the current trial provides a “marked contrast” to other industry trials that have tested personalised cancer vaccines in “patients with highly immune-sensitive tumour phenotypes and no measurable disease”. The GT-30 trial “assess PTCVs in HCC, a cancer with very low tumour mutational burden and an immune-excluded phenotype, and in patients with significant late-stage unresectable and metastatic disease”.
“Despite the small size of this study, our results are important for the advancement of the field. We have not only met endpoints for safety, immunogenicity, and clinical efficacy based on ORR in this difficult to treat setting, but our mechanism of action data trace and confirm every step, from vaccination to tumour reduction, required to explain the immunological basis for the observed clinical responses.”
Dr Ildiko Csiki, chief medical officer of Geneos, believes that the study is the “first definitive demonstration of a personalised cancer vaccine enhancing clinical response to anti-PD-1 therapy by inducing new, neoantigen-specific T cells”.
“The fact that the PTCV regimen has produced this important result in a form of cancer as immunologically ‘cold’ as HCC, leading to multiple complete responses and a doubling of objective responses versus PD-1, is incredibly promising and shows the therapeutic potential of personalised cancer vaccines for cancer patients.”
We were glad to hear more from Dr Sardesai at the Congress in Washington this April and hope to follow Geneos’ progress on this front as they continue to push the field forward. For more updates on cancer therapy progress do make sure you subscribe to our weekly newsletters here!
