AACR News: DNA Cancer Vaccine Enhances Immunotherapy for Advanced Liver Cancer

News

AACR News: DNA Cancer Vaccine Enhances Immunotherapy for Advanced Liver Cancer

AACR News: DNA Cancer Vaccine Enhances Immunotherapy for Advanced Liver Cancer

The 115th annual meeting of the American Association for Cancer Research (AACR 2024), a highly anticipated event in the field of cancer research, opened in San Diego, USA, on April 5, 2024. Scientists, clinical doctors, and cancer researchers from around the world gathered here to share the latest advances in cancer research and treatment.

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer and a leading cause of cancer-related deaths globally. Despite advances in the treatment of advanced HCC in recent years, the 5-year survival rate remains below 10%. Advanced HCC is a relatively immunosuppressive tumor type, typically characterized by low T-cell infiltration and moderate tumor mutation burden. The response rate to immune checkpoint inhibitors (ICI) targeting PD-1 as monotherapy is approximately 12%-18%.

Mutations in the tumor genome lead to the expression of abnormal proteins in the tumor, which are often not present in normal cells, known as tumor neoantigens. The advancement of second-generation sequencing technologies has facilitated the development of personalized immunotherapy for individual cancer patients. Patients with innate immunity to tumor neoantigens typically show a strong response to immune checkpoint inhibitors, providing a preliminary basis for combining immune checkpoint inhibitors with therapies that induce neoantigen-specific immunity.

On April 7, 2024, researchers from Geneos Therapeutics and Johns Hopkins University published a study titled “Personalized neoantigen vaccine and pembrolizumab in advanced hepatocellular carcinoma: a phase 1/2 trial” in the journal Nature Medicine.

AACR News: DNA Cancer Vaccine Enhances Immunotherapy for Advanced Liver Cancer

The results of a phase 1/2 clinical trial of the personalized therapeutic cancer vaccine GNOS-PV02 (encoding up to 40 tumor neoantigens in plasmids) in combination with pembrolizumab (anti-PD-1 monoclonal antibody) for the treatment of advanced liver cancer in 36 patients who had previously received multikinase inhibitors (mTKIs) showed an objective response rate of 30.6% (11/36 cases), including complete response in 3 patients and partial response in 8 patients.

The 30.6% objective response rate is nearly twice that of pembrolizumab monotherapy (16.9%), demonstrating that personalized cancer vaccines can enhance the clinical response of patients with advanced liver cancer to anti-PD-1 therapy.

In preclinical studies, therapeutic cancer vaccines targeting mutation-associated neoantigens induced tumor-specific T-cell responses and inhibited tumor growth.

Preliminary clinical trials of personalized therapeutic cancer vaccines (PTCV) have also demonstrated the induction of neoantigen-specific immune responses in cancer patients.

Recently, the phase 2b clinical trial data of Moderna’s cancer vaccine mRNA-4157 in combination with pembrolizumab (anti-PD-1 monoclonal antibody) for the treatment of advanced melanoma showed a significant improvement in patients’ recurrence-free survival (RFS) compared to pembrolizumab monotherapy, with a 49% reduction in the risk of recurrence or death and a 62% reduction in the risk of distant metastasis or death.

However, whether vaccine-induced T cells can enter existing tumors and synergistically induce tumor clearance with anti-PD-1 therapy in tumors with poor immune therapy response, such as liver cancer, has not been confirmed.

In this study, researchers conducted a single-arm, open-label, multicenter phase 1/2 clinical trial on 36 patients with advanced liver cancer who had previously received multikinase inhibitors (mTKIs) to study the efficacy of the personalized therapeutic cancer vaccine GNOS-PV02 in combination with pembrolizumab (anti-PD-1 monoclonal antibody). The primary endpoints of the clinical trial were safety and immunogenicity, with secondary endpoints including efficacy and feasibility.

The personalized therapeutic cancer vaccine GNOS-PV02 consists of a DNA plasmid encoding up to 40 tumor neoantigens, which are determined by DNA and RNA sequencing of each patient’s tumor sample and germline DNA sequencing. GNOS-PV02 is formulated with another plasmid encoding the cytokine interleukin-12 (pIL-12), which serves as a vaccine adjuvant, administered by intradermal injection and facilitated by in vivo electroporation. Intradermal injection of pIL-12 only resulted in local and transient IL-12 production at the injection site, promoting local induction of cellular responses to expressed antigens.

The most common treatment-related adverse event was injection site reaction, observed in 15 out of 36 patients (41.6%). No dose-limiting toxicities or treatment-related grade ≥3 adverse events were observed. The objective response rate was 30.6% (11/36 cases), with complete response in 8.3% (3/36 cases) of patients.

Clinical responses were correlated with the number of new antigens encoded in the vaccine, with patients receiving vaccines encoding a greater number of new antigens showing better treatment outcomes. Further assays showed that 19 out of 22 evaluable patients (86.4%) produced neoantigen-specific T-cell responses. Multi-parameter cellular analysis showed that vaccine-specific CD4+ and CD8+ effector T cells exhibited activity, proliferation, and cytotoxicity. T-cell receptor beta chain (TCRβ) sequencing showed clonal expansion and tumor infiltration of vaccine-enriched T-cell clones. Single-cell analysis showed clonal expansion of cytotoxic T-cell phenotypes after treatment. TCR complementarity-determining region (CDR) sequencing of expanded T-cell clones in tumors after vaccination confirmed reactivity to vaccine-encoded neoantigens.

These clinical trial results support the mechanism of action of personalized therapeutic cancer vaccines based on inducing anti-tumor T-cell responses, indicating that personalized therapeutic cancer vaccines in combination with pembrolizumab (anti-PD-1 monoclonal antibody) have clinical activity against advanced liver cancer.

Paper link: https://www.nature.com/articles/s41591-024-02894-y