By Tiffany Williams –
Boston researchers may have cleared a major hurdle standing between today’s personalized CAR-T cancer treatments and a future in which immune cells could be manufactured at scale and potentially be ready when patients need them.
Researchers at the Center for Regenerative Medicine at Boston Medical Center and Boston University have developed a scalable method for generating CD4+ helper T cells from induced pluripotent stem cells, known as iPSCs. The findings, published in Stem Cell Reports, could help advance efforts to develop off-the-shelf CAR-T therapies.
CAR-T therapy works by collecting a patient’s T cells, genetically modifying those cells so they can recognize and attack cancer cells, and then returning them to the patient. The approach has transformed treatment for some blood cancers, but producing an individualized therapy for every patient can be expensive and time-consuming.
That is where iPSCs could change the equation. These stem cells can be generated from donated adult skin or blood cells, potentially providing a foundation for manufacturing large numbers of T cells that could eventually be used for multiple patients rather than creating a new therapy individually each time.
But researchers have faced a major obstacle: reliably producing functional CD4+ helper T cells. Those cells are critical because they help coordinate and regulate the immune response.
The Boston team, 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, focused on a molecular signaling pathway called Notch.
Notch signaling plays an important role during early T cell development. The researchers found that removing that signaling during later stages of maturation, while simultaneously reducing anti-T cell receptor signaling, 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.”
The findings also provided researchers with new information about T cell biology. The work showed how Notch signaling changes over time as developing cells move toward either the CD8 or CD4 lineage.
The research remains a step toward a potential therapy rather than a finished treatment. The team’s next move is to introduce a chimeric antigen receptor, or CAR, directly into the iPSC-derived CD4+ and CD8+ cells and test their ability to kill cancer in animal models.
Those experiments will be an important next stage in determining whether the system could eventually contribute to universal CAR-T therapies. If successful through the necessary additional research and development, the approach could move CAR-T manufacturing away from a process requiring each patient’s cells to be individually collected and engineered.
“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 individualized manufacturing, just treatment.”
For now, that remains the potential rather than the clinical reality. But the Boston researchers have developed a method for producing one of the critical immune-cell components at scale, opening another path toward a future in which CAR-T therapy could potentially be manufactured before the patient who needs it ever walks through the hospital door.