New drug could enhance efficacy of T-cell therapy for solid tumors

A groundbreaking study led by the Agency for Science, Technology and Research (A*STAR) has revealed a promising approach to enhancing the effectiveness of immune cells in fighting cancer. The research, published in the journal Nature Communications, focuses on inhibiting the function of two proteins, G9a and GLP, during the production of cell therapies. By doing so, the study suggests that immune cells can be empowered to combat solid tumor cancers more effectively.

Solid tumors are a leading cause of cancer-related deaths worldwide, and existing treatments like chemotherapy, radiation therapy, and surgery vary in their efficacy, particularly in advanced stages of the disease. While T-cell therapy has shown remarkable success in treating liquid tumors such as blood cancers, its effectiveness against solid tumors like breast, liver, or brain cancer has been limited.

In T-cell therapy, engineered immune cells are introduced into the patient’s bloodstream as part of the treatment. In the case of liquid tumors, this method works well since the immune cells can easily locate and target them. However, solid tumors present physical and molecular barriers that impede the function of engineered T cells, including navigating through dense tissue structures and encountering other cells and molecules that hinder their effectiveness.

To address this challenge, a collaborative team of researchers and clinicians from A*STAR’s Institute of Molecular and Cell Biology (IMCB), Singapore Immunology Network (SIgN), and Duke-NUS Medical School sought innovative strategies to improve the efficiency of T cells in recognizing and eliminating cancer cells.

Led by Dr. Andrea Pavesi, a Senior Scientist at A*STAR’s IMCB, the research team conducted an extensive analysis of epigenetic drugs that could enhance the anti-tumor activity of engineered T cells. They employed both 2D and novel 3D assays that replicated the physical environment encountered by T cells when locating and targeting cancer cells in the human body.

During the lab-based cell expansion process of cell therapy, the researchers administered a drug that targeted the G9a and GLP proteins to the immune cells. Subsequently, the drug was washed away before reintroducing the engineered immune cells into the patient’s body, eliminating any potential side effects. The findings demonstrated that the drug significantly enhanced the anti-tumor function of the engineered immune cells by boosting the production of granzymes, proteins that help identify and eliminate target tumor cells.

The study’s findings were further validated using established cell lines and patient-derived immune cells, leveraging the expertise of Dr. Giulia Adriani, a Principal Scientist at A*STAR’s SIgN, and patient samples from Duke-NUS. The results confirmed that blocking G9a and GLP activity improved the efficiency of T-cell therapy by enhancing the anti-tumor function of immune cells.

These discoveries hold tremendous potential for improving patient outcomes, including enhanced survival rates and improved quality of life. They also have wide-ranging implications for all cell therapies targeting solid tumors. Patients with weakened immune systems, who typically rely on immune cells from healthy donors for cell therapy, may also benefit from using their own immune cells. This reduces the risk of rejection by the patient’s body and minimizes complications associated with using incompatible cells. Moreover, the drug used to inhibit G9a and GLP activity presents an attractive option for further development and holds promise as a therapeutic agent for cancer treatments.

Dr. Andrea Pavesi, the lead author of the study, commented on the significance of their approach, stating that improving the individual anti-tumor activity of each immune cell can address several limitations in T-cell therapy and enhance treatment efficacy. He believes that their discovery will advance the development of effective therapeutics for solid tumor cancers, ultimately improving lives.

Professor Antonio Bertoletti, associated with Duke-NUS’ Emerging Infectious Diseases Programme, emphasized the high demand for producing suitable T cells for adoptive T-cell therapy, a form of cell therapy where engineered T cells are administered to patients to combat diseases like cancer. He expressed hope that this discovery would enhance cell therapies that utilize both patient-derived and donor-derived immune cells, benefiting a diverse range of patients. The research team aspires to progress towards successful clinical trials and bring this method to market, ultimately improving patient outcomes.

Source: Agency for Science, Technology and Research (A*STAR), Singapore

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