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

SIMPLE SUMMARY: Treatment with chimeric antigen receptor (CAR)-T cells has improved the prognosis of patients with non-Hodgkin lymphoma (NHL) substantially. Yet, as up to 60% of patients eventually relapse, insights into factors determining treatment response are highly warranted. We used mathematical modeling to characterize typical and individual concentration–time profiles of four different CAR-T cell subtypes and tumor burden in 19 NHL patients and investigated patient-/therapy-related factors associated with poor survival. A low CAR-T cell maximum expansion capacity and no previous autologous stem cell transplantation were associated with a poor prognosis. We next translated our most important model parameter into a clinical composite score, which leverages but does not require the use of the model. Based on our clinical data, we propose a clinical composite score cut-off value for early survival prediction. Additional data will be needed to update and refine the developed model and the proposed clinical composite score cut-off value. 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 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.