“The SPARK Award has provided me with invaluable public exposure and a deeper understanding of how scientific discoveries can directly impact patient lives. It has given me the confidence to pursue high-risk, high-reward projects. The personal connection I’ve made with donors, like Joani Nelson who shared her passion for blue penguins with me, has also been incredibly meaningful and inspiring. My experience with SPARK has strengthened my ability to translate scientific discoveries into real-world applications, which I plan to incorporate into my future research.”
2024 Tullie and Rickey Families Spark Awards Winner
Chen Sun, Ph.D.
Can we design better receptors for CAR-T cell therapy?
Funded: January 2024
Funded by: The generosity of various donors
Multiple myeloma is the second most common blood cancer, and while treatments have improved, a cure remains elusive. Since 2021, therapies developed with engineered immune cells, called CAR-T cell therapies, improved patient outcomes. My project aims to understand how CAR-T cells interact with cancer cells using cryo-Electron Tomography (cryo-ET). I am studying two FDA-approved CAR-T cells for multiple myeloma: Ide-cel and Cilta-cel. Both of these CAR-T therapies target the same protein on cancer cells, but they are not equally effective. Initial live cell imaging I’ve conducted shows that Cilta-cel binds to cancer cells faster than Ide-cel, which matches clinical data indicating Cilta-cel’s superior performance. Cilta-cel is also more effective even at lower doses.
We need to know more about how these therapies work. By using cryo-ET, I will freeze and thinly slice cancer cells to analyze how CAR-T cells connect and attack cancer cells. My research aims to reveal why Cilta-cel works better—and guide the development of more effective CAR-T therapies, offering new hope for cancer patients.
What was the goal of your SPARK project?
My goal was to study two types of CAR T cells, Ide-cel and Cilta-cel, both of which are FDA-approved treatments for a blood cancer called multiple myeloma. These CAR T cell therapies are not equally effective, and we need to know why. My initial experiments showed that Cilta-cel binds to cancer cells faster than Ide-cel, which matches clinical data indicating Cilta-cel’s superior performance. Cilta-cel is also more effective even at lower doses. For my SPARK project, I harnessed cryo-ET to analyze how CAR T cells target cancer cells. I hoped to reveal why Cilta-cel works better—and guide the development of more effective CAR T therapies. For my SPARK project, I harnessed cryo-ET to analyze how CAR T cells target cancer cells. I hoped to reveal why Cilta-cel works better—and guide the development of more effective CAR T therapies.
SPARK Project Results
My research produced the first-ever 3D tomogram of the immune synapse formed between a
CAR T cell and a target cell in a native cellular environment. With this high-resolution image, I identified features on the CAR T side which appear to be immune cell structures called lytic granules. Lytic granules release cancer-killing molecules. My 3D tomogram captures what is likely the late stage of a lytic granule being released into the cell-to-cell interface to kill a cancer cell. These findings have significant clinical potential. We can now see exactly how CAR T cells target cancer cells. This approach may reveal why some CAR T cell therapies are more effective than others—a vital step towards refining these therapies and bringing more effective options to patients with relapsed multiple myeloma.
What’s next for this project?
What’s next for this project? I plan to expand on these findings by investigating how structural differences in CAR T cell synapses contribute to treatment outcomes for patients with various hematologic malignancies, including blood cancers such as leukemias and lymphomas. This work may help scientists better understand a phenomenon called T cell exhaustion, where T cells fail to effectively eliminate tumors. Additionally, future research will integrate our structural discoveries to shed light on how CAR T cell therapies work in specific patient groups, ensuring that more individuals can benefit from these potentially life-saving treatments.
What’s next for Chen?
Next, I plan to characterize well-established protein markers of the canonical TCR immune synapse to assess the extent to which the CAR T cell immune synapse mirrors its organization. My goal is to identify a reliable protein marker that defines the boundary of the CAR T cell immune synapse, which could serve as a quantitative metric for evaluating CAR T cell quality.
