75 Researchers at Kobe University have developed a method to mass-produce gamma-delta T cells from induced pluripotent stem cells, an advance that could overcome key barriers in cancer immunotherapy for solid tumours such as colorectal cancer. The human body relies on an army of immune cells to fight cancer, and T cells are among the major forces involved. They are also the target of modern cancer immunotherapies that aim to boost T cells’ ability to find and attack cancer cells. Current techniques require extracting a patient’s own T cells from blood, modifying them in the lab, and reintroducing them into the patient, a process that is expensive and time-consuming. Researchers have looked to a subclass of T cells called gamma-delta T cells as an alternative, since they do not need to be tailored to each individual patient and can instead be harvested from a donor and used in other people. They also have an innate ability to recognise stress signals on cancer cells in an MHC-unrestricted manner, making them attractive for immunotherapy. However, these cells are far fewer in number, making harvesting infeasible, and they cannot be readily multiplied in the lab. Kobe University stem cell researcher Aoi Takashi explains: “Based on our experience with induced pluripotent stem cells, also called iPS cells, we thought that we could approach this issue by creating such easily storable and growable cells from these specific T cells, and then only turning them back into T cells when actually needed.” Since T cells modify their DNA during development to target a specific threat, creating iPS cells from cancer-specific T cells means all their descendants retain that specificity, essentially creating an army of clones from one effective cancer fighter. In a new paper published in the journal Stem Cell Reports, Takashi and his team show that they could create iPS cells from this subclass of T cells and reproducibly turn them back into T cells, with an overall 80,000-fold multiplication, achieved without relying on animal cells or extracts, a requirement for clinical applications. The study was also the first to show, on a small preclinical scale, that the resulting T cells attack and shrink human patient-derived colorectal cancer tumours implanted into mice. Cancers from cell culture lines do not share the same drug insensitivity as actual cancers, nor do they replicate the physical barriers of real tumours. That is why patient-derived organoids are significant for evaluating new cancer treatments, explains the study’s first author Futai Ryoko. The Kobe University team designed the study with metastasising cancers in mind, so they also tested whether the T cells would find their targets when administered intravenously a week after the tumour was implanted, rather than close to the tumour itself. In this setting, tumour weights decreased by between 43% and 92% in the three mice tested. “This suggests potential for future systemic therapy,” Ryoko says. “We believe this achievement represents an important step toward the development of a new immunotherapy for solid tumours.” The study was conducted at a small scale, with only three or four mice in each experiment and tumour models derived from just two patients, a limitation the researchers note is significant given that colorectal cancer tumours are known for their high variability. “This study is a preclinical investigation demonstrating the potential of using iPS cell-derived T cells and is not yet at a stage where it can be used on patients,” Ryoko cautions. Further studies using these easily multipliable and standardised cells may help clarify where this variability comes from and what steps could counter it. Takashi adds: “Furthermore, by combining this approach with cell modification techniques such as CAR therapy, we hope that this research will eventually lead to the development of new therapeutic possibilities for patients with solid tumours.” The work addresses a major challenge in adoptive cell therapies. Traditional chimeric antigen receptor T cell approaches have shown remarkable success against blood cancers but face hurdles with solid tumours due to manufacturing complexity, cost, and the immunosuppressive tumour microenvironment. By deriving gamma-delta T cells from iPS cells under feeder-free and serum-free conditions, the Kobe team has created a pathway towards allogeneic, off-the-shelf products that could significantly reduce treatment delays and costs compared with autologous therapies. Larger studies will be needed to confirm efficacy and safety across more diverse tumour models and, eventually, in human trials, but the high multiplication factor and retention of anti-tumour activity in patient-derived tissues mark a notable step forward in iPS cell-based immunotherapies.