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

Autor: Aimee C. Talleur, Amr Qudeimat, Jean-Yves Métais, Deanna Langfitt, Ewelina Mamcarz, Jeremy Chase Crawford, Sujuan Huang, Cheng Cheng, Caitlin Hurley, Renee Madden, Akshay Sharma, Ali Suliman, Ashok Srinivasan, M. Paulina Velasquez, Esther A. Obeng, Catherine Willis, Salem Akel, Seth E. Karol, Hiroto Inaba, Allison Bragg, Wenting Zheng, Sheng M. Zhou, Sarah Schell, MaCal Tuggle-Brown, David Cullins, Sagar L Patil, Ying Li, Paul G. Thomas, Caitlin Zebley, Benjamin Youngblood, Ching-Hon Pui, Timothy Lockey, Terrence L. Geiger, Michael M. Meagher, Brandon M. Triplett, Stephen Gottschalk
Rok vydání: 2022
Předmět:
Zdroj: Blood Advances. 6:5737-5749
ISSN: 2473-9537
2473-9529
DOI: 10.1182/bloodadvances.2021006293
Popis: 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.
Databáze: OpenAIRE
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