Journal Article

Characteristics of anti-CD19 CAR T cell infusion products associated with efficacy and toxicity in patients with large B cell lymphomas

Jain, Neeraj, Yang, Haopeng, Zhang, Qi, Han, Guangchun, Ghosh, Sreejoyee, Fowler, Nathan, Strati, Paolo, Patchva, Sridevi, Lee, Hans C., Wang, Yuanxin, Wang, Ruiping, Westin, Jason, Nastoupil, Loretta J., Neelapu, Sattva S., Fayad, Luis, Chen, Runzhe, Deng, Qing, Chasen, Beth, Dai, Enyu, Zhang, Shaojun, Showell, Jordan, Eric Davis, R., Hagemeister, Frederick, Samaniego, Felipe, Ma, Man Chun John, Puebla-Osorio, Nahum, Sun, Ryan, Wang, Linghua, Dang, Minghao, Green, Michael R.

2020

Overview

Autologous chimeric antigen receptor (CAR) T cell therapies targeting CD19 have high efficacy in large B cell lymphomas (LBCLs), but long-term remissions are observed in less than half of patients, and treatment-associated adverse events, such as immune effector cell-associated neurotoxicity syndrome (ICANS), are a clinical challenge. We performed single-cell RNA sequencing with capture-based cell identification on autologous axicabtagene ciloleucel (axi-cel) anti-CD19 CAR T cell infusion products to identify transcriptomic features associated with efficacy and toxicity in 24 patients with LBCL. Patients who achieved a complete response by positron emission tomography/computed tomography at their 3-month follow-up had three-fold higher frequencies of CD8 T cells expressing memory signatures than patients with partial response or progressive disease. Molecular response measured by cell-free DNA sequencing at day 7 after infusion was significantly associated with clinical response ( P = 0.008), and a signature of CD8 T cell exhaustion was associated ( q = 2.8 × 10 −149 ) with a poor molecular response. Furthermore, a rare cell population with monocyte-like transcriptional features was associated ( P = 0.0002) with high-grade ICANS. Our results suggest that heterogeneity in the cellular and molecular features of CAR T cell infusion products contributes to variation in efficacy and toxicity after axi-cel therapy in LBCL, and that day 7 molecular response might serve as an early predictor of CAR T cell efficacy. Single-cell transcriptomics reveals that the heterogeneity of anti-CD19 CAR T cell infusion products contributes to variability in clinical response, early molecular response and development of immune effector cell-associated neurotoxicity syndrome in patients with large B cell lymphomas.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/1647/514/1949 / 631/250/1619/554 / 692/308/409 / 692/699/67/1059/2325 / 692/699/67/1990/291/1621/1915 / Adult / Aged / Antigen receptors, T cell / Antigens / B-cell lymphoma / Biomedical and Life Sciences / Biomedicine / Cancer Research / CD19 antigen / CD8 antigen / CD8-Positive T-Lymphocytes - immunology / CD8-Positive T-Lymphocytes - pathology / Cell- and Tissue-Based Therapy - adverse effects / Cell-Free Nucleic Acids - blood / Chimeric antigen receptors / Complications and side effects / Computed tomography / Deoxyribonucleic acid / DNA / DNA sequencing / Drug therapy / Exhaustion / Female / Heterogeneity / Humans / Immunological memory / Immunotherapy / Infectious Diseases / Lymphocytes / Lymphocytes T / Lymphoma / Lymphoma, Large B-Cell, Diffuse - genetics / Lymphoma, Large B-Cell, Diffuse - immunology / Lymphoma, Large B-Cell, Diffuse - pathology / Lymphoma, Large B-Cell, Diffuse - therapy / Male / Memory cells / Metabolic Diseases / Methods / Middle Aged / Molecular Medicine / Monocytes / Neurosciences / Neurotoxicity / Neurotoxicity Syndromes - etiology / Non-Hodgkin's lymphomas / Patients / Physiological aspects / Positron emission / Positron emission tomography / Receptors / Receptors, Antigen, T-Cell - genetics / Receptors, Antigen, T-Cell - immunology / Receptors, Antigen, T-Cell - therapeutic use / Ribonucleic acid / RNA / RNA-Seq / Single-Cell Analysis / T cells / Tomography / Toxicity / Transcription / Transcriptome - genetics / Transcriptomics