journal contribution
posted on 2023-10-13, 07:40 authored by Tina Sarén, Mohanraj Ramachandran, Gustav Gammelgård, Tanja Lövgren, Claudio Mirabello, Åsa K. Björklund, Kristina Wikström, Jamileh Hashemi, Eva Freyhult, Håkan Ahlström, Rose-Marie Amini, Hans Hagberg, Angelica Loskog, Gunilla Enblad, Magnus Essand Supplementary Figure S5. Clinical response could not be predicted from CAR-T expansion invivo, transduction efficiency or CD8/CD4 ratio of the CAR-T product
Funding
Vetenskapsrådet (VR)
Cancerfonden (Swedish Cancer Society)
AFA Försäkring (AFA Insurance)
Lions Cancer Fund at Uppsala University Hospital
Swedish State Support for Clinical Research
Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation)
History
ARTICLE ABSTRACT
Although CD19 chimeric antigen receptor T cells (CAR-T) therapy has shown remarkable success in B-cell malignancies, a substantial fraction of patients do not obtain a long-term clinical response. This could be influenced by the quality of the individual CAR-T infusion product. To shed some light on this, clinical outcome was correlated to characteristics of CAR-T infusion products.
In this phase II study, patients with B-cell lymphoma (n = 23) or leukemia (n = 1) received one or two infusions of third-generation CD19-directed CAR-Ts (2 × 108/m2). The clinical trial was registered at clinicaltrials.gov: NCT03068416. We investigated the transcriptional profile of individual CD19 CAR-T infusion products using targeted single-cell RNA sequencing and multicolor flow cytometry.
Two CAR-T infusions were not better than one in the settings used in this study. As for the CAR-T infusion products, we found that effector-like CD8+CAR-Ts with a high polyfunctionality, high cytotoxic and cytokine production profile, and low dysfunctional signature were associated with clinical response. An extended ex vivo expansion time during CAR-T manufacturing negatively influenced the proportion of effector CD8+CAR-Ts in the infusion product.
We identified cell-intrinsic characteristics of effector CD8+CAR-Ts correlating with response that could be used as an indicator for clinical outcome. The results in the study also serve as a guide to CAR-T manufacturing practices.
