A Deep Look at the Immune System

Imagine a future where immunotherapy, which engages a patient’s own immune system to fight disease, is as accessible as any prescription drug. But immunotherapy often has to be personalized, a painstaking and expensive process that puts it out of reach for some patients. Now scientists, including Sjoukje van der Stegen, a group lead at Chan Zuckerberg Biohub New York, are hoping that generating engineered immune cells from induced pluripotent stem cells can solve that problem. Her work is advancing CZI’s grand challenge to “harness the immune system for early detection, prevention and treatment of disease.”

Various approaches to immunotherapy have revolutionized cancer treatment, but some can be expensive and laborious both to create and to administer. One approach, known as adoptive cell therapy (ACT), involves removing immune cells from a patient’s blood, engineering them in the lab to target specific proteins found on diseased cells, then reinfusing them so they can attack those cells. CAR T therapy, one of the most common forms of ACT, has transformed the treatment of leukemia and other blood cancers, but the process is costly, and it can take weeks or months to properly modify a patient’s T cells.

Yet the biggest bottleneck in making ACT widely available is that, so far, it has been an “autologous” method, relying solely on a patient’s own immune cells as the raw material for engineering. This means not only that the clinical success of ACT depends on the quality and quantity of those cells — some immune cells are fairly sparse in the circulation — but also that the engineered cells cannot be used in any other patient (known as “allogeneic” treatment), because they can be rejected by the recipient unless the donor is carefully matched, like with organ transplantation.

Van der Stegen believes that induced pluripotent stem cells, or iPSCs, may hold the key to solving these problems, opening a path to more versatile, powerful, and accessible forms of ACT. iPSCs are made by turning adult skin or blood cells back to a stem-cell like state. With iPSCs it’s possible to produce large numbers of immune cells of many different varieties aside from T cells, but importantly, they can also be engineered so they don’t provoke an immune response in recipients — which would allow treatments to be produced en masse for “off-the-shelf” use, instead of needing to be personalized for each patient.

“The implementation of . . . iPSC technology ushers in the promise of a large-scale, ‘off-the-shelf,’ allogeneic treatment strategy that can harness the potential of various immune cells, including those scarcely found in peripheral blood,” van der Stegen wrote in a 2024 review article in the journal Experimental Hematology, with co-author Mame Diop.

At that time, van der Stegen was a research scientist at the Memorial Sloan Kettering Cancer Center, but she joined the Biohub last year to lead its Immune Cell Engineering and Development Platform. Van der Stegen’s research interests were a good match for the grand challenge to harness and bioengineer immune cells for the early detection, prevention, and treatment of a broad spectrum of age-related diseases, and to develop next-generation cell-based immunotherapies.

Creative cell design

The difficulty with immune cells derived from iPSCs is that they initially don’t have all the same functions as the body’s own immune cells. In the context of a fully functioning immune system, immune stem cells are exposed to countless biological signals and other cells that influence their development into mature immune cells. But scientists haven’t quite figured out how to replicate all of those signals in the lab when generating immune cells from iPSCs. “That’s where the challenge really lies,” van der Stegen says. “Our hope is that a deeper understanding of how these cells emerge will help us maximize the therapeutic capacity of iPSC-derived immune cells.”

The immune system is, by design, reactive: it recognizes and attacks anything that could pose a threat to our health, protecting us from illness but also presenting significant roadblocks when creating iPSC-derived immunotherapies. Scientists must ensure that the treatments don’t attack patients’ healthy cells, and that the patients’ immune systems don’t reject the engineered cells. A reaction in either direction could have disastrous consequences.

In the case of T cells, van der Stegen’s lab is working to create cells that lack the T cell receptor (TCR). The TCR plays a crucial role in allowing the immune system to distinguish disease from health, and “self” from “non-self.” Without the TCR, donor-derived T cells won’t attack a patient’s healthy cells — and these modified cells could then act as scaffolds for a broad range of therapeutic techniques. But on the other hand, TCRs are essential for T cells to develop properly. Van der Stegen’s lab is studying the main checkpoints of T cell development in hopes of creating functional cells without TCRs.

The lab also aims to use iPSC-derived immune cells to create disease models in the lab. For example, they could mimic the immune cell makeup of a tumor or an influenza-infected tissue, and study the immune response and disease progression. This would provide a close-up look at these immune cells, and fill in some of the knowledge and safety gaps between what we can learn from mouse models and what occurs in human disease settings.

Van der Stegen (center), Biohub leaders, and other attendees gathered at the 2025 Spring CZI Affiliate Symposium meeting. (Credit: Angelina Katsanis)

Innovative implementations

Once the lab can reliably develop highly functional immune cells from iPSCs, the sky’s the limit: they could create generic vehicles for immunotherapies, engineer cells that target tumors, or design cells that detect and report early signs of disease in at-risk patients.

“Augmenting in vitro differentiation to generate bona-fide immune effectors combined with engineering strategies to enhance their effector functions,” she and co-author Pieter Lindenbergh wrote last year in Transfusion Medicine and Hemotherapy, “could potentiate iPSC-derived adoptive cell therapy to reshape the current therapeutic landscape of oncology.”