Preferential expansion of CD8+ CD19-CAR T cells postinfusion and the role of disease burden on outcome in pediatric B-ALL

• Published in: Blood advances Vol. 6; no. 21; pp. 5737 - 5749
• Main Authors: Talleur, Aimee C., Qudeimat, Amr, Métais, Jean-Yves, Langfitt, Deanna, Mamcarz, Ewelina, Crawford, Jeremy Chase, Huang, Sujuan, Cheng, Cheng, Hurley, Caitlin, Madden, Renee, Sharma, Akshay, Suliman, Ali, Srinivasan, Ashok, Velasquez, M. Paulina, Obeng, Esther A., Willis, Catherine, Akel, Salem, Karol, Seth E., Inaba, Hiroto, Bragg, Allison, Zheng, Wenting, Zhou, Sheng M., Schell, Sarah, Tuggle-Brown, MaCal, Cullins, David, Patil, Sagar L, Li, Ying, Thomas, Paul G., Zebley, Caitlin, Youngblood, Benjamin, Pui, Ching-Hon, Lockey, Timothy, Geiger, Terrence L., Meagher, Michael M., Triplett, Brandon M., Gottschalk, Stephen
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.11.2022; The American Society of Hematology
• Subjects: Regular
• ISSN: 2473-9529; 2473-9537
• DOI: 10.1182/bloodadvances.2021006293

•CD8+ CD19-CAR T cells outcompete their CD4+ counterparts and undergo antigen-driven differentiation after infusion.•Our study highlights the role of disease burden on outcome after CD19-CAR T-cell therapy. [Display omitted] T cells expressing CD19-specific chimeric antigen receptors (CD19-CARs) have potent antileukemia activity in pediatric and adult patients with relapsed and/or refractory B-cell acute lymphoblastic leukemia (B-ALL). However, not all patients achieve a complete response (CR), and a significant percentage relapse after CD19-CAR T-cell therapy due to T-cell intrinsic and/or extrinsic mechanisms. Thus, there is a need to evaluate new CD19-CAR T-cell products in patients to improve efficacy. We developed a phase 1/2 clinical study to evaluate an institutional autologous CD19-CAR T-cell product in pediatric patients with relapsed/refractory B-ALL. Here we report the outcome of the phase 1 study participants (n = 12). Treatment was well tolerated, with a low incidence of both cytokine release syndrome (any grade, n = 6) and neurotoxicity (any grade, n = 3). Nine out of 12 patients (75%) achieved a minimal residual disease-negative CR in the bone marrow (BM). High disease burden (≥40% morphologic blasts) before CAR T-cell infusion correlated with increased side effects and lower response rate, but not with CD19-CAR T-cell expansion. After infusion, CD8+ CAR T cells had a proliferative advantage over CD4+ CAR T cells and at peak expansion, had an effector memory phenotype with evidence of antigen-driven differentiation. Patients that proceeded to allogeneic hematopoietic cell transplantation (AlloHCT) had sustained, durable responses. In summary, the initial evaluation of our institutional CD19-CAR T-cell product demonstrates safety and efficacy while highlighting the impact of pre-infusion disease burden on outcomes. This trial was registered at www.clinicaltrials.gov as #NCT03573700.