Systems Immunology for CAR T-cell Therapy

During my PhD research, I developed an interest in applying molecular technologies and computational methods to better understand and improve Chimeric Antigen Receptor (CAR) T-cell therapy, a form of cancer immunotherapy.

Longitudinal analysis of long-persisting CAR T cells

By longitudnally studying CAR T cells from the first two succesfully treated cancer patients, we identified two unexpected populations of CAR T cells: a gamma-delta CAR T-cell population, and a persistent CD4+ CAR T-cell population that dominated later time points. Single-cell analysis revealed that the intriguing CD4+ CAR T-cell population was highly proliferative, strongly activated, and expressed a distinct cytotoxic profile with GZMA and GZMK expression. These findings led us to re-think the CAR T-cell populations involved in long-term anti-cancer response, and have key implications in understanding the basis of effective CAR T-cell therapy.

An excerpt of Figs. 3 and 4, showing a UMAP embedding of 5' CITE-Seq data with TCR clonotyping.

Melenhorst JJ*#, Chen GM*, Wang M*, Porter DL*, Chen C, Collins MA, Gao P, Bandyopadhyay S, Sun H, Zhao Z, Lundh S, Pruteanu-Malinici I, Nobles CL, Maji S, Frey NV, Gill SI, Tian L, Kulikovskaya I, Gupta M, Ambrose DE, Davis MM, Fraietta JA, Brogdon JL, Young RM, Chew A, Levine BL, Siegel DL, Alanio C, Wherry EJ, Bushman FD, Lacey SF, Tan K#, June CH#. Decade-long leukemia remissions with persistence of CD4+ CAR T cells.
Nature (2022).

A bulk and single-cell atlas of pre-manufacture T cells used in CAR T-cell therapy for pediatric ALL

In this project, we profiled the pre-manufacture T cells in pediatric patients on trial to received CAR T-cell therapy using bulk RNA-Seq, CITE-Seq, and single-cell ATAC-Seq. We observed several T-cell factors associated with favorable clinical outcomes, including proportion of naive and early memory T cells, expression of TCF7 among effector T-cells, and lower expression of IRF7 and interferon response genes. These data help to clarify the characteristics of patient T cells that confer favorable CAR T-cell outcomes in patients.

An excerpt of Fig. 1 showing our subtype-specific RNA-Seq atlas of pre-manufacture T cells used in CAR T-cell therapy for pediatric ALL.

Chen GM*, Chen C*, Das RK*, Gao P, Chen C, Bandyopadhyay S, Ding YY, Uzun Y, Yu W, Zhu Q, Myers RM, Grupp SA, Barrett DM#, Tan K#. Integrative bulk and single-cell profiling of pre-manufacture T-cell populations reveals factors mediating long-term persistence of CAR T-cell therapy.
Cancer Discovery (2021).