CAR-T cell therapy genomic profiling and clinical association study.

External Partners:

• University of Sydney
• Fred Hutchinson Cancer Center

Overview: Our project focuses on developing advanced computational methods and statistical tools for analyzing single-cell multi-omics data in immunological and immunotherapeutic research. Through close collaboration with clinical teams, we aim to understand immune cell heterogeneity and improve CAR-T cell therapy outcomes. Our research utilizes cutting-edge technologies including CITE-seq, CUT&RUN, and scCUT&Tag to profile both transcriptomic and epigenomic landscapes of CAR-T cells from patients and healthy donors.

Motivation: Immunotherapy, particularly CAR-T cell therapy, has emerged as a revolutionary approach in treating various cancers. However, the complexity of immune cell responses and the heterogeneity of patient outcomes present significant challenges in optimizing these treatments. Our research addresses these challenges through:

1. Development of a computational framework specifically designed for processing and analyzing CAR-T cell therapy CITE-seq data
2. Profiling the epigenomic landscape of CAR-T cells to investigate cell type origins post-manufacturing stimulation
3. Identifying genomic markers associated with therapy efficacy and toxicity from both transcriptomic and epigenomic perspectives

We collaborate with multiple research groups at the Fred Hutchinson Cancer Center, including the Turtle Lab and Henikoff Lab, combining expertise in statistics, computational biology, molecular biology, and immunology. This interdisciplinary approach allows us to tackle complex immunological challenges and advance our understanding of immunotherapy responses.

The project’s success could lead to improved patient stratification, better prediction of treatment outcomes, and more personalized immunotherapy approaches. Long-term goals include developing robust computational tools that can be widely adopted by the immunotherapy research community and ultimately contribute to more effective cancer treatments.

Publications

⁺: co-corresponding author *: co-first author

1. Fiorenza S*, Zheng Y*, Purushe J, Bock T, Sarthy J, Janssens D, Sheih A, Kimble E, Kirchmeier D, Phi T, Gauthier J, Hirayama A, Riddell S, Wu Q, Gottardo R, Maloney D, Yang J, Henikoff S, Turtle C. Histone marks identify novel transcription factors that parse CAR-T subset-of-origin, clinical potential and expansion. Nature Communications. (2024).

2. Fiorenza S, Zheng Y, Sarthy J, Sheih A, Kimble E, Kirchmeier D, Janssens D, Phi T, Gauthier J, Hirayama A, Wu Q, Gottardo R,Riddell S, Maloney D, Henikoff S, Turtle C. Histone Methylation Mark Analyses Distinguish Carts Manufactured from Distinct Sources and Uncover Novel Transcription Factors Associated with In Vivo Function of Carts after Infusion into DLBCL Patients That Are Not Identified By RNA-Seq. Blood. (2023).

3. Chour, T., Hirayama, A., Zheng, Y., Sheih, A., Zhuang, S., Wilson, A., Wu, V., Gottardo, R., Turtle, C., Gardner, R. and Newell, E. Cellular profiling of leukapheresis and infusion products of patients enrolled in CD19 CAR T cell therapy identifies biomarkers associated with clinical outcomes. Cancer Research, 82(12_Supplement), pp.3910-3910. (2022).

4. Hirayama AV, Zheng Y, Dowling MR, Sheih A, Phi TD, Kirchmeier DR, Chucka AW, Gauthier J, Maloney DG, Gottardo R, Turtle CJ. Long-Term Follow-up and Single-Cell Multiomics Characteristics of Infusion Products in Patients with Chronic Lymphocytic Leukemia Treated with CD19 CAR-T Cells. Blood. (2021).