HONG KONG – Researchers from the Li Ka Shing Faculty of Medicine at The University of Hong Kong (HKU) have developed a DNA vaccine against malignant mesothelioma that elicited complete and long-lasting protection against malignancy, while curing pre-existing tumors in mouse models.

The culmination of a five-year study, the new vaccine harnesses the immune system and reinstates immune surveillance by overcoming tumor-associated immunosuppression, which has important implications for cancer prevention and immunotherapy, the researchers reported in the Nov. 1, 2014, print edition of Cancer Research.

The use of vaccines for cancer prevention and immunotherapy is attractive, because "if such vaccines can be made against human cancer-specific antigens, it may become possible to induce a large number of functional killer T cells for the elimination of cancer," said study leader Chen Zhiwei, director of the AIDS Institute and a professor in the Department of Microbiology at HKU.

"Our study further indicated that a high frequency of functional killer T cells is necessary for vaccine efficacy," Chen added.

The eradication of malignant cancer cells using vaccine-elicited host immunity has long represented a major medical challenge, largely due to the lack of an effective vaccination for the induction of immune surveillance, as this requires a large number of functional cytolytic CD8+ killer T cells to eliminate malignant cells.

Normally, the activation of oncogenes by carcinogens induces malignant cells, while rendering them vulnerable to immune cells, especially killer T cells. However, if the immune system fails to eliminate malignant cells, they may avoid ineffective immune responses, promoting cancer growth and progression.

Cancer cells express inhibitory molecules on their surface to disrupt killer T-cell function, although the growing cancer evades killer T cells by sustaining immunosuppressive cells, particularly within the microenvironment of the tumor.

To date, few cancer prevention vaccine strategies have successfully been able to overcome such a tumor-associated immunosuppressive microenvironment, even in small animal models.

However, the HKU researchers focused on malignant human mesothelioma, the major risk factor for which is occupational exposure to asbestos and which is almost inevitably incurable, with patients frequently dying within just one year of diagnosis.

"China including Hong Kong is one of the largest producers and users of asbestos, which is well known as the causative agent of mesothelioma," said Chen, noting that this part of the world will therefore be facing an unprecedented peak in the incidence of this malignancy in the near future.

"For this reason, the Hong Kong Pneumoconiosis Compensation Fund Board (PCFB) provided us with research funding, with the focus on mesothelioma," Chen told BioWorld Today.

The HKU team first developed a quantitative model of malignant mesothelioma in immunocompetent BALB/c mice, an albino inbred strain that is widely used in animal experimentation and which allowed efficacy testing of the novel programmed death-1 (PD-1)-based DNA vaccine.

They found that, unlike with a nonprotective tumor antigen Wilms' tumor 1 (WT1)-based DNA vaccine, repeated vaccinations of the model PD-1-based DNA vaccine elicited complete and long-lasting protection against lethal mesothelioma challenge in the mouse models. Importantly, the new vaccine also remained highly immunogenic in tumor-bearing animals and led to the therapeutic cure of mice with pre-existing malignant mesothelioma.

Moreover, the HKU researchers demonstrated that vaccine-induced killer T cells conferred protection in a dose-dependent manner and functioned by releasing the cytotoxic inflammatory cytokines, gamma interferon (IFN-γ) and tumor necrosis factor-alfa (TNF-α), in the vicinity of target cells, as well as by initiating TNF-related apoptosis-inducing ligand (TRAIL)-directed tumor cell apoptosis.

Importantly, they also established that the PD-1-based DNA vaccine achieved an active functional state, not only by preventing the rise of functionally exhausted killer T cells, but also by suppressing tumor-induced immunosuppressive cells including myeloid-derived suppressor and regulator T cells, with the frequency of antigen-specific killer T cells being inversely correlated with tumor mass.

Chen pointed out that his group's research is important in terms of achieving a clearer understanding of the mechanisms underlying cancer immunotherapy, as it provides valuable new insights into the quantitative and qualitative requirements of vaccine-elicited functional killer T cells for cancer prevention and immunotherapy.

"The discovery will encourage researchers to explore new ways of active vaccination for the development of both preventive and therapeutic strategies against cancer," he said.

Chen noted that the new vaccine would likely be used as an adjunctive therapy to other cancer treatment modalities including chemo/radiotherapy and/or surgery. "If successful, [the vaccine] could be used in combination with other existing methods," he said.

Fellow researcher Yuen Kwok-yung, the Henry Fok Professor in Infectious Diseases and chair professor of the Department of Microbiology commented, "This study demonstrated that a novel vaccination strategy initially invented for fighting the AIDS virus is quite helpful to the search for an effective cancer immunotherapy."

"This research will likely promote the search for active vaccination methods as a major strategy for cancer prevention and therapy," Chen told BioWorld Today.

"Our next step will involve looking for research funding to bring at least one PD-1-based vaccine into human studies, either against HIV or cancer."