Researchers at Kobe University have generated off-the-shelf, mass-producible induced pluripotent stem cell (iPSC)-derived gamma delta T cells (γδT cells) that in a small preclinical study suppressed tumor growth in mouse colorectal cancer (CRC) xenograft models. The team says their development could point to the potential for developing faster, cheaper cancer immunotherapy.

Research lead Takashi Aoi, PhD, and colleagues reported on the work in Stem Cell Reports, in a paper titled “Allogeneic iPSC-derived γδT cells demonstrate antitumor efficacy against patient-derived tissues,” commenting “Our current findings provide robust preclinical evidence supporting the efficacy of T cell therapy for CRC.”

“Various immunotherapies have been developed to treat malignant tumors, and autologous CAR T-cell therapy is clinically used for certain malignancies,” the authors wrote. However, CAR T-cell therapies demonstrate limited efficacy against solid tumors, and current techniques for modifying T cells extracted from the patient are expensive and time consuming. “… obstacles such as the time and cost required to initiate autologous treatment impede their widespread adoption.”

Consequently, the authors noted, there is growing interest in allogeneic, or off-the-shelf, cell therapy. Researchers have considered turning to a subclass of T cells called gamma-delta (γδ) T cells that don’t need to be tailored toward each individual patient but can be harvested from a donor and used in other people. “… the development of novel therapies for CRC, a highly heterogeneous cancer, remains a paramount challenge in global healthcare, and γδT cells are considered a promising candidate modality,” the authors stated. “γδT cells represent approximately 3–5% of peripheral blood lymphocytes and are capable of targeting various types of tumors in an MHC-unrestricted manner with a single type of γδT cell receptor.”

However, these cells are much fewer, making the harvesting approach infeasible, and they also cannot be directly multiplied well in the lab. Aoi stated, “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.” In their paper the authors added “We focused on γδT cells as a potential therapeutic modality for colorectal cancer (CRC).”

Through their reported study the investigators showed that they could create iPS cells from the subclass of T cells that can be used across patients and reproducibly turn them back into those T cells with an overall 80,000-fold multiplication. Importantly, they achieved this without relying on animal cells or extracts, which is a requirement for clinical applications. “To the best of our knowledge, this is the first study to report the successful induction of differentiation of γδT cells from iPS cells under feeder-free, serum-free conditions.”

Their study was also the first to show, on a small preclinical scale, that the resulting iPSC-derived γδT cells (iγδT cells) attack and shrink human patient-derived colorectal cancer tumors that were implanted into mice, with tumor weights in treated animals reduced by up to 88%, when compared with control mice.

“We demonstrated that these iγδTs exhibit cytotoxic activity against CRC and leukemia cell lines, as well as against patient-derived CRC organoids in vitro, while also exerting antitumor effects in vivo in xenograft models,” they noted. “Cancers from cell culture lines don’t have the same drug insensitivities as actual cancers and also don’t emulate the physical barriers that actual tumors have,” explained first author Ryoko Futai, PhD. “That’s why patient-derived organoids are highly significant for evaluating new cancer treatment approaches,” explained first author.

When they designed the study, the Kobe University team imagined that their approach would be used fighting metastasizing cancers. They also checked whether their T cells would find their targets not only when administered close to the tumor but when administered intravenously a week after the tumor was implanted. And indeed, even in this setting tumor weights decreased 43%, 82% and 92% in the three treated mice. Futai noted, “This suggests potential for future systemic therapy. We believe this achievement represents an important step toward the development of a new immunotherapy for solid tumors.”

The study was conducted at a small scale, with only three or four mice in each experiment and tumor models derived from only two different patients. This is especially important because colorectal cancer tumors are known for their high variability. “This study is a preclinical investigation demonstrating the potential using iPS cell-derived T cells and is not yet at a stage where it can be used on patients,” cautions Futai.

But by conducting further studies using these easily multipliable and very standardized cells, the Kobe University development may also be used to elucidate where the variability comes from and what steps to take to counter it. Aoi commented, “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 tumors.” And in their paper the authors concluded, “Our findings will pave the way for the realization of off-the-shelf allogeneic γδT cell therapy.”

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