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Computational model of CAR T-cell immunotherapy dissects and predicts leukemia patient responses at remission, resistance, and relapse.
Liu, Lunan; Ma, Chao; Zhang, Zhuoyu; Witkowski, Matthew T; Aifantis, Iannis; Ghassemi, Saba; Chen, Weiqiang.
Afiliação
  • Liu L; Department of Mechanical and Aerospace Engineering, New York University, Brooklyn, New York, USA.
  • Ma C; Department of Mechanical and Aerospace Engineering, New York University, Brooklyn, New York, USA.
  • Zhang Z; Department of Biomedical Engineering, New York University, Brooklyn, New York, USA.
  • Witkowski MT; Department of Mechanical and Aerospace Engineering, New York University, Brooklyn, New York, USA.
  • Aifantis I; Perlmutter Cancer Center, NYU Langone Health, New York City, New York, USA.
  • Ghassemi S; Department of Pathology, NYU Langone Health, New York City, New York, USA.
  • Chen W; Perlmutter Cancer Center, NYU Langone Health, New York City, New York, USA.
J Immunother Cancer ; 10(12)2022 12.
Article em En | MEDLINE | ID: mdl-36600553
ABSTRACT

BACKGROUND:

Adaptive CD19-targeted chimeric antigen receptor (CAR) T-cell transfer has become a promising treatment for leukemia. Although patient responses vary across different clinical trials, reliable methods to dissect and predict patient responses to novel therapies are currently lacking. Recently, the depiction of patient responses has been achieved using in silico computational models, with prediction application being limited.

METHODS:

We established a computational model of CAR T-cell therapy to recapitulate key cellular mechanisms and dynamics during treatment with responses of continuous remission (CR), non-response (NR), and CD19-positive (CD19+) and CD19-negative (CD19-) relapse. Real-time CAR T-cell and tumor burden data of 209 patients were collected from clinical studies and standardized with unified units in bone marrow. Parameter estimation was conducted using the stochastic approximation expectation maximization algorithm for nonlinear mixed-effect modeling.

RESULTS:

We revealed critical determinants related to patient responses at remission, resistance, and relapse. For CR, NR, and CD19+ relapse, the overall functionality of CAR T-cell led to various outcomes, whereas loss of the CD19+ antigen and the bystander killing effect of CAR T-cells may partly explain the progression of CD19- relapse. Furthermore, we predicted patient responses by combining the peak and accumulated values of CAR T-cells or by inputting early-stage CAR T-cell dynamics. A clinical trial simulation using virtual patient cohorts generated based on real clinical patient datasets was conducted to further validate the prediction.

CONCLUSIONS:

Our model dissected the mechanism behind distinct responses of leukemia to CAR T-cell therapy. This patient-based computational immuno-oncology model can predict late responses and may be informative in clinical treatment and management.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Leucemia / Receptores de Antígenos Quiméricos Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Humans Idioma: En Revista: J Immunother Cancer Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Leucemia / Receptores de Antígenos Quiméricos Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Humans Idioma: En Revista: J Immunother Cancer Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Estados Unidos