Our Science
Next-generation CAR T-cell therapy
Our Science
Next-generation CAR T-cell therapy
The Challenge
Our body’s immune system, specifically T cells, has the ability to recognize cancer cells as abnormal and kill them. Therapies based on genetically engineered patient-derived T cells have shown success in treating hematologic malignancies. But cell therapies have had limited success in solid tumors, which represent approximately 90% of cancers. Two primary barriers limit consistent and durable responses to cell therapy in solid tumors:
T-cell exhaustion
The dysfunctional state that T cells enter hindering their ability to respond to foreign antigens on cancer cells and eliminate them
Lack of durable stemness
This includes the inability of T cells to persist and self-renew to drive durable tumor cytotoxicity
A clinical study previously conducted at the Fred Hutchinson Cancer Center demonstrated that T-cell exhaustion is a major barrier to successful cell therapy in solid tumors. In this study, autologous ROR1-targeted CAR T cells infused into patients with chronic lymphocytic leukemia underwent rapid expansion and retained T-cell effector function, leading to tumor cell clearance and clinical responses. However, when CAR T cells generated with the same method were infused into patients with solid tumors such as triple-negative breast cancer or non-small cell lung cancer, these T cells often failed to expand adequately, rapidly upregulated cell surface markers of T-cell exhaustion and adopted a dysfunctional state.
Our Approach
At Lyell, it’s all about the cells. We are reprogramming T cells designed to outlast and eradicate solid tumors.
To achieve success in solid tumors, our cell therapies aim to:
Resist Exhaustion, Retain Function
Maintain cancer cell-killing ability in the immunosuppressive tumor microenvironment
Enhance Durable Stemness
Increase ability to self-renew and persist to drive durable tumor cytotoxicity
Our Technology
Our proprietary, stackable genetic and epigenetic reprogramming technologies are designed to create potent T cells with long-lasting functionality.
Genetic Reprogramming Technologies
Lyell’s genetic reprogramming technologies are designed to delay T-cell exhaustion and create more potent T cells with enhanced, durable antitumor activity in the immunosuppressive tumor microenvironment. Our technologies target the activator protein 1 (AP-1) transcription factor pathway, which plays a key role in T-cell effector function.
c-Jun
Reprogramming T cells through c-Jun overexpression delays exhaustion and results in increased proliferation, sustained cytokine production, and durable antitumor activity.
NR4A3
Combining NR4A3 knockout with c-Jun overexpression further reduces T-cell exhaustion, leading to improved antitumor activity.
Epigenetic Reprogramming Technologies
Our epigenetic reprogramming technologies are designed to improve the stemness, persistence and function of T-cell products without gene editing.
Epi-R™
Our Epi-R™ manufacturing protocol includes proprietary media, optimized cytokine composition and well-defined cell activation and expansion protocols. Epi-R is designed to consistently and reliably generate populations of stem-like T cells with improved proliferation, antitumor activity, and reduced exhaustion.
Stim-R™
Our Stim-R™ technology enables precise and optimized delivery of immune-activating molecules during manufacturing, in a way that more closely mimics the body’s natural process. This technology is designed to allow for greater control over T-cell stimulation and expansion, resulting in the generation of more potent T-cell products.
Collaborations
We welcome collaborations. To speak with a member of our team, contact us at businessdevelopmentlyell.com.
Additional Resources
Lyell Publications & Presentations
Access publications on our scientific and clinical research.