Developing Nonactivated CAR T Therapy for Greater Persistence, Reduced Exhaustion and Enhanced In Vivo Expansion
Dr Saba Ghassemi, University of Pennsylvania, tells us about the paradigm-shifting advances in CAR T therapy and in cell therapy manufacturing she is pursuing at the Ghassemi Lab.
What is the work you’re leading at the Ghassemi Lab?
At my lab, we focus on making better CAR T cells to be simpler, more potent, and more effective. A core area of our research is developing one-day, nonactivated CAR T cells, which is a significant departure from the traditional expansion process of 10-14 days. We’re pioneering strategies to harness their natural state, potentially outperforming conventional activated CAR T cells. By studying their unique behavior, we aim to enhance their therapeutic efficacy.
Beyond cell engineering, we are also innovating on decentralized manufacturing. We envision a model where CAR T cells can be produced more efficiently at smaller hubs rather than large centralized facilities. To make CAR T therapy faster, more accessible, and more affordable, we are developing a streamlined manufacturing platform that eliminates unnecessary steps, bringing us closer to the goal of democratizing CAR T therapy for all.
"We’re pioneering strategies to harness [T-cells'] natural state, potentially outperforming conventional activated CAR T cells."
How did you arrive at the hypothesis that nonactivated T cells could be used as a therapy?
The idea emerged from observations in the field that T cell exhaustion correlates with poor clinical outcomes in CAR T therapy. Instead of extensive activation steps, we hypothesized that preserving T cell fitness could enhance therapeutic potential.
Ironically, my inspiration came from the HIV field, where researchers always worked with nonactivated primary cells. In that case, they were trying to limit HIV transduction, while I wanted the opposite: better transduction in our HIV-based lentivirus for T cells. This paradigm shift led me to question whether keeping cells in their natural state could improve function.
What is the potential benefit of nonactivated CAR T cells?
Quiescent (nonactivated) CAR T cells are untouched and minimally manipulated, preserving their natural power. They exhibit greater persistence, reduced exhaustion, and enhanced in vivo expansion compared to traditionally activated CAR T cells. By skipping prolonged activation, we maintain their native metabolic and stemlike transcriptional state, leading to stronger, longer-lasting responses post-infusion.
In contrast, activated CAR T cells, while effective, can terminally differentiate due to prolonged ex vivo manipulation limiting their durability. Our research shows that keeping CAR T cells in a rested, naïve-like state improves their function while potentially reducing toxicity. Through rigorous testing, we developed a one-day CAR T cell manufacturing process and rigorously evaluated its impact in preclinical models, comparing quiescent versus activated cells.
What were the results of your research with quiescent CAR T cells?
Quiescent CAR T cells demonstrated stronger expansion, superior tumor control, and reduced exhaustion. This led to further mechanistic studies and validation efforts, and now, we are advancing toward clinical translation.
Despite initial skepticism, accumulating data and growing interest in minimal-manipulation T cell therapies have reinforced the potential of this approach.
"Pursuing quiescent CAR T cells requires a paradigm shift in how we think about T cell engineering and manufacturing."
What changes in the existing engineering paradigm if one pursues quiescent CAR T cells versus activated CAR T cells?
Pursuing quiescent CAR T cells requires a paradigm shift in how we think about T cell engineering and manufacturing. Instead of activating and expanding cells for several days, we must rethink how to efficiently transduce and prepare T cells in a short timeframe while preserving their natural state. Lentiviral transduction must also be optimized to work effectively within this minimal-manipulation framework.
Additionally, the field must move away from the assumption that more cells are always better – prioritizing potency over sheer quantity. These changes will impact regulatory strategies, logistics, and how clinical trials are designed, but they offer a path toward more effective and accessible CAR T therapies.
Tell us more about how you’re innovating in cell therapy manufacturing.
In my lab, we are pushing the boundaries of cell manufacturing by developing a one-day process that maintains cell potency while simplifying production. We are also engineering CAR T cells with specific genes or cytokines to improve their efficacy based on the tumor environment they encounter. For example, in nutrient-poor or hypoxic tumors, we equip CAR T cells with metabolic gene enhancements that help them survive and function optimally.
When working with nonactivated CAR T cells, we engineer them to respond more rapidly upon infusion, ensuring that they remain highly potent despite minimal ex vivo manipulation. Overall, our goal is to create more resilient, effective, and accessible CAR T cell therapies.
What are the advances in technology or our understanding of cell therapy that are enabling you to innovate the cell therapy engineering process?
Several recent advances are driving innovation in CAR T cell engineering. Improved metabolic and epigenetic profiling is needed for the design of T cells that are more resilient and long-lasting. Advances in gene delivery, both viral and non-viral, are making transduction more efficient, especially for rapid manufacturing approaches.
Additionally, single-cell multiomics technologies are providing deeper insights into the functional heterogeneity of CAR T cells, helping us identify which cell populations contribute most to long-term efficacy.
Computational modeling and AI-driven analysis are also playing a growing role in optimizing cell therapy design. Altogether, these technological breakthroughs are making it possible to create next-generation CAR T cells that are more potent, durable, and adaptable to diverse tumor environments.
"We are pushing the boundaries of cell manufacturing by developing a one-day process that maintains cell potency while simplifying production."
How does your work contribute to the larger picture of fighting cancer?
The next frontier in cell therapy lies in making these treatments more precise, durable, and accessible. One major area of focus is the transition from centralized to decentralized manufacturing, allowing CAR T cells to be produced closer to the point of care.
Additionally, integrating synthetic biology approaches will enable the creation of “smart” CAR T cells that can sense and respond dynamically to their environment. Ultimately, the goal is to simplify and refine these therapies so they can be delivered to more patients with fewer barriers.
What keeps you passionate about this field?
What keeps me passionate is the realization that we can still do better. My passion comes from both the scientific challenge and the real-world impact of CAR T therapy. With my engineering background, I love optimizing, problem-solving, and making things more efficient. But beyond that, the patient impact is what truly drives me.
Despite the challenges, the fact that our work can change lives makes every obstacle feel small. That motivation is real – it keeps me pushing forward every day.
What was a piece of career advice that helped you during your career that you would pass on to young people, particularly young women, entering careers in science?
Women in science often have to prove themselves in ways that others don’t. One of the best pieces of advice I received was that the dynamic changes over time.
Once you’ve built a solid foundation – through trust, persistence, and good science – the work starts to speak for itself. So trust your intuition, push forward, and keep going. A strong paper, solid data, and perseverance can shift the narrative in your favor. The most exciting breakthroughs often come from challenging conventional wisdom.
I also advise young women to seek out sponsors who believe in you and invest in your success. Also, patience is key. It’s not always easy, but it’s essential – not just in science, but in life.
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