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According to data released by the International Agency for Research on Cancer (IARC) in 2024, liver cancer is the fifth most common cancer in the world, and the third highest number of deaths among all cancers. Hepatocellular carcinoma (HCC) is the most common primary liver cancer (about 70%). The 5-year survival rate for advanced HCC is still less than 10%, and treatment options are limited. Liver cancer is less sensitive to immunotherapy, and the response rate of PD-1 checkpoint inhibitor monotherapy is only about 20%.
Individualized therapeutic cancer vaccines have the potential to enhance tumor response to PD-1 inhibitors by inducing tumor-specific immunity. Recently, Nature Medicine published the results of a phase 1/2 clinical trial, showing that the personalized therapeutic cancer vaccine GNOS-PV02 in combination with PD-1 inhibitors has a good safety profile in the second-line treatment of advanced HCC, with a response rate nearly twice that of monotherapy history (30.6% vs 16.9%), and overall survival is also better than that of previous monotherapy.
截图来源：Nature Medicine
The vaccine, GNOS-PV02, is based on a DNA plasmid and is capable of encoding up to 40 neoantigens. Neoantigens are mutations in tumor genes that cause tumors to express abnormal proteins that are not present in normal host cells. By sequencing a patient's tumor, neoantigens produced by each patient's unique tumor mutations can be discovered, and DNA sequences expressing these neoantigens can then be imported into the DNA plasmid. As a result, when the vaccine is injected into the body, it stimulates the immune system to produce tumor-infiltrating lymphocytes (TILs) to recognize neoantigens and kill tumor cells.
Early studies have shown that patients who have an immune response to tumor neoantigens often have a stronger response to checkpoint inhibitors. Therefore, in this trial, the research team chose a combination of GNOS-PV02, the DNA plasmid-encoded cytokine IL-12 (as an adjuvant to enhance the body's response to neoantigens), and the PD-1 inhibitor pembrolizumab.
The trial was conducted in 36 patients with advanced HCC who had previously received TKIs, and the median number of vaccinations was 5 (range 1-18) and the median duration of treatment was 6.1 months as of the deadline for this data collection (18 August 2023).
The primary endpoints are safety and immunogenicity. The most common treatment-related adverse event was injection site reactions, which occurred in 41.6% (15/36 cases), and no dose-limiting toxicities or grade 3 treatment-related adverse events ≥ were observed. The addition of a vaccine to a PD-1 inhibitor was not observed to reduce safety tolerability.
Secondary endpoints are treatment efficacy and feasibility. Efficacy data support favorable clinical activity of vaccine combinations:
- There were 3 complete responses and 8 partial responses, respectively, with an objective response rate of 30.6% (11 cases/36 cases), which was statistically significant compared with the historical control value of response rate with pembrolizumab monotherapy (16.9%, reference KEYNOTE-240). In addition, the disease control rate was 55.6% (20 cases/36 cases).
- In terms of time to action, the median time from treatment to remission was 9.3 weeks, and the median duration of response was not yet reached and was still accumulating.
- Median progression-free survival was 4.2 months and median overall survival was 19.9 months. Disease remission is closely related to survival. It is worth mentioning that the current median overall survival data is also better than the previous PD-1 inhibitor single-agent second-line treatment data for liver cancer (12.9~15.1 months).
Further immunological analysis confirmed the therapeutic mechanism of action of this vaccine.
- Vaccination was able to induce neoantigen-specific responses: 19 of 22 evaluable patients (86.4%) demonstrated neoantigen-specific T cell responses.
- Vaccination promotes T cell clonal expansion and infiltration: 100% of the 14 evaluable patients had significant T cell clonal expansion in peripheral blood and tumor tissues. Single-cell sequencing analysis revealed that the vast majority of these T cell clones were CD8 T effector memory cells, which is key to inducing anti-tumor cytotoxicity.
- Data from two representative patients further confirmed the specific activity of tumor-infiltrating T cells against neoantigens.
Overall, the results of this trial support the ability of a personalized therapeutic cancer vaccine to induce anti-tumor T cell production and clinical activity in combination with pembrolizumab.
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References (scroll up and down)
[1] Yarchoan, M., Gane, E.J., Marron, T.U. et al. (2024). Personalized neoantigen vaccine and pembrolizumab in advanced hepatocellular carcinoma: a phase 1/2 trial. Nat Med, DOI: https://doi.org/10.1038/s41591-024-02894-y
[2] Global cancer burden growing, amidst mounting need for services. Retrieved April 10, 2024 from https://www.who.int/news/item/01-02-2024-global-cancer-burden-growing--amidst-mounting-need-for-services
[3] Cancer Facts & Figures 2024 Retrieved April 10, 2024 from https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/2024-cancer-facts-figures.html
[4] Geneos Therapeutics. Retrieved April 10, 2024 from https://www.geneostx.com/
[5] Geneos Therapeutics Announces Positive Phase 1/2 Data for GT-30 Trial of Personalized Therapeutic Cancer Vaccine. Retrieved April 10, 2024 from https://www.geneostx.com/geneos-therapeutics-announces-positive-phase-1-2-data-for-gt-30-trial-of-personalized-therapeutic-cancer-vaccine/
Source: New Perspectives in Medicine