Back to Search
Start Over
Early Survival Prediction Framework in CD19-Specific CAR-T Cell Immunotherapy Using a Quantitative Systems Pharmacology Model
- Source :
- Cancers, Volume 13, Issue 11, Cancers, Vol 13, Iss 2782, p 2782 (2021)
- Publication Year :
- 2021
- Publisher :
- Freie Universität Berlin, 2021.
-
Abstract
- Chimeric antigen receptor (CAR)-T cell therapy has revolutionized treatment of relapsed/refractory non-Hodgkin lymphoma (NHL). However, since 36–60% of patients relapse, early response prediction is crucial. We present a novel population quantitative systems pharmacology model, integrating literature knowledge on physiology, immunology, and adoptive cell therapy together with 133 CAR-T cell phenotype, 1943 cytokine, and 48 metabolic tumor measurements. The model well described post-infusion concentrations of four CAR-T cell phenotypes and CD19+ metabolic tumor volume over 3 months after CAR-T cell infusion. Leveraging the model, we identified a low expansion subpopulation with significantly lower CAR-T cell expansion capacities amongst 19 NHL patients. Together with two patient-/therapy-related factors (autologous stem cell transplantation, CD4+/CD8+ T cells), the low expansion subpopulation explained 2/3 of the interindividual variability in the CAR-T cell expansion capacities. Moreover, the low expansion subpopulation had poor prognosis as only 1/4 of the low expansion subpopulation compared to 2/3 of the reference population were still alive after 24 months. We translated the expansion capacities into a clinical composite score (CCS) of ‘Maximum naïve CAR-T cell concentrations/Baseline tumor burden’ ratio and propose a CCSTN-value &gt<br />0.00136 (cellsµL−1mL−1 as predictor for survival. Once validated in a larger cohort, the model will foster refining survival prediction and solutions to enhance NHL CAR-T cell therapy response.
- Subjects :
- 0301 basic medicine
Oncology
Cancer Research
medicine.medical_specialty
CAR-T cells
medicine.medical_treatment
Population
600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::616 Krankheiten
Article
CD19
chimeric antigen receptor T cells
Cell therapy
03 medical and health sciences
0302 clinical medicine
Autologous stem-cell transplantation
Internal medicine
medicine
education
RC254-282
pharmacometrics
education.field_of_study
biology
business.industry
non-Hodgkin lymphoma
mathematical modeling
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Immunotherapy
medicine.disease
Chimeric antigen receptor
Lymphoma
030104 developmental biology
030220 oncology & carcinogenesis
biology.protein
600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::615 Pharmakologie, Therapeutik
business
CD8
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Cancers, Volume 13, Issue 11, Cancers, Vol 13, Iss 2782, p 2782 (2021)
- Accession number :
- edsair.doi.dedup.....b67bfd2fea1cc7b00e81a98744a5a7ed