Early Survival Prediction Framework in CD19-Specific CAR-T Cell Immunotherapy Using a Quantitative Systems Pharmacology Model

• Main Authors: Anna Mueller-Schoell, Nahum Puebla-Osorio, Robin Michelet, Michael R. Green, Annette Künkele, Wilhelm Huisinga, Paolo Strati, Beth Chasen, Sattva S. Neelapu, Cassian Yee, Charlotte Kloft
• Format: Article
• Language: English
• Published: MDPI AG 2021-06-01
• Series: Cancers
• Subjects: chimeric antigen receptor T cells; non-Hodgkin lymphoma; CAR-T cells; mathematical modeling; pharmacometrics
• Online Access: https://www.mdpi.com/2072-6694/13/11/2782

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 CCS_TN-value > 0.00136 (cells·µL⁻¹·mL⁻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.