Early survival prediction framework in cd19‐specific car‐t cell immunotherapy using a quantitative systems pharmacology model

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 > 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.