- This study investigated change over time in patient-derived T cells and CAR T-cells from two different CD19 CAR products for treatment of large B-cell lymphoma, aiming to gain insights into the respective mechanisms of response or failure
- Single-cell transcriptome sequencing was performed on 105 pre- and post-treatment peripheral blood mononuclear cell samples and infusion products collected from 32 patients treated with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel)
- Large expansions of CD8+ CAR T-cells post-treatment were a hallmark of good response to tisa-cel
- Axi-cel nonresponders had higher frequencies of CAR-transduced regulatory T cells, and in vivo mouse modeling showed even small numbers of those cells contributed to relapse
- Determining the molecular features that predict response to each CAR T-cell product should make it possible to further optimize their design and manufacture and help identify which product is most likely to succeed in a given patient
Response to chimeric antigen receptor (CAR) T-cell therapy persists long-term in only about half of patients. There's limited understanding of the mechanisms of resistance to CAR T-cell therapy for aggressive large B-cell lymphoma (LBCL).
Subscribe to the latest updates from Cancer Center Advances in Motion
By monitoring cellular dynamics during CAR T-cell therapy at the single-cell level, Marcela V. Maus, MD, PhD, director of the Cellular Immunotherapy Program at the Mass General Cancer Center, Gad Getz, PhD, director of bioinformatics there, and colleagues detected molecular markers that varied according to how patients responded. In Nature Medicine they also report that CAR regulatory T cells (Treg cells) contributed to relapse.
The researchers performed single-cell RNA sequencing and single-cell T-cell receptor sequencing of 105 peripheral blood mononuclear cell samples from 32 patients with refractory LBCL being treated with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel). These therapies have comparable efficacy and both target CD19.
The principal goal of sequencing was to see how the CAR T-cells from the therapies changed over time, from pre-infusion to a week after treatment. There were substantial differences between the two products in cellular dynamics:
- Tisa-cel—A hallmark of good response was large expansions of rare CD8+ clones that contribute to the immune system's memory of specific antigens; this phenomenon was not seen with axi-cel
- Axi-cel—Increases in infusional CAR Treg cells were noted in patients who did not respond; substantially lower numbers of CAR Treg cells were found in tisa-cel products
CAR Treg Cells As Drivers of Relapse
Through in vitro experiments and in vivo mouse modeling, the researchers observed that CAR Treg cells expressing either product could suppress conventional CAR T-cell activity and thus facilitate clinical relapse. Even small numbers of CAR Treg cells (just 5% percent of the total number of cells infused) were capable of driving relapse.
Determining the molecular features that predict response to each CAR T-cell product should make it possible to optimize their design, match patients to the product most likely to induce response and develop strategies for combating relapse.
Refer a patient to the Mass General Cancer Center
Learn about the Mass General Cancer Center