Researchers at the Centre for Regenerative Medicine (CReM) at Boston Medical Centre (BMC) and Boston University (BU) have developed a scalable method for generating CD4+ helper T cells from induced pluripotent stem cells (iPSCs), overcoming a longstanding challenge in the development of stem cell-based immunotherapies.

The findings, published in Stem Cell Reports, could help advance efforts to create off-the-shelf CAR-T cell therapies that can be produced at scale and made more readily available to patients.

CAR-T cell therapy works by isolating a patient's T cells, genetically modifying them to recognise and target cancer cells, and returning them to the patient.

While the approach has transformed treatment for some blood cancers, producing a personalised therapy for each patient can be costly and time-intensive.

IPSCs, which are generated from donated adult skin or blood cells, could enable the large-scale production of T cells that could be used "off the shelf" for many patients rather than being made individually for each one.

A key challenge, however, has been reliably generating functional CD4+ helper T cells, which play an important role in coordinating and regulating immune responses.

A team of researchers led by Gustavo Mostoslavsky, M.D., Ph.D., co-director of the CReM and professor of medicine and virology, immunology and microbiology at BU Chobanian & Avedisian School of Medicine, and doctoral student Julian Amirault found the key to producing CD4+ cells is in a molecular signalling pathway called Notch.

While Notch signalling is critical to early T cell development, the researchers found that removing it during later stages of maturation, while simultaneously reducing anti-T cell receptor signalling, allowed developing cells to survive and mature into CD4+ T cells at scale.

“Our protocol is simple, straightforward, and potentially scalable for treatment," Dr. Mostoslavsky said.

"And our system is making T cells that look like those from blood, with a full repertoire of the different subtypes."

Beyond the clinical implications, the work has also shed new light on T cell biology, revealing how Notch signalling shifts over time to direct cells toward either the CD8 or the CD4 lineage.

With a workable protocol in hand, the team's next step is to introduce the chimaeric antigen receptor (CAR) directly into their iPSC-derived CD4+ and CD8+ cells and test their ability to kill cancer in animal models, an important next step toward the potential development of universal CAR-T therapies.

“What we have developed represents a major advance in how the future of CAR-T could be done," said Dr. Mostoslavsky.

"The potential is that one day, these cells could be ready and waiting when a patient is diagnosed. No cell collection, no individualised manufacturing, just treatment."

Source: Boston Medical Center