Abstract
Chimeric antigen receptor (CAR) T-cell therapy has shown promise in the treatment of haematological cancers and is currently being investigated for solid tumours, including high-grade glioma brain tumours. There is a desperate need to quantitatively study the factors that contribute to the efficacy of CAR T-cell therapy in solid tumours. In this work, we use a mathematical model of predator–prey dynamics to explore the kinetics of CAR T-cell killing in glioma: the Chimeric Antigen Receptor T-cell treatment Response in GliOma (CARRGO) model. The model includes rates of cancer cell proliferation, CAR T-cell killing, proliferation, exhaustion, and persistence. We use patient-derived and engineered cancer cell lines with an in vitro real-time cell analyser to parametrize the CARRGO model. We observe that CAR T-cell dose correlates inversely with the killing rate and correlates directly with the net rate of proliferation and exhaustion. This suggests that at a lower dose of CAR T-cells, individual T-cells kill more cancer cells but become more exhausted when compared with higher doses. Furthermore, the exhaustion rate was observed to increase significantly with tumour growth rate and was dependent on level of antigen expression. The CARRGO model highlights nonlinear dynamics involved in CAR T-cell therapy and provides novel insights into the kinetics of CAR T-cell killing. The model suggests that CAR T-cell treatment may be tailored to individual tumour characteristics including tumour growth rate and antigen level to maximize therapeutic benefit.
Highlights
chimeric antigen receptor (CAR) T-cell therapy is a targeted immunotherapy, demonstrating remarkable anti-tumour efficacy, in the treatment of haematologic cancers [1,2]
To investigate the relationship between tumour growth rate and CAR T-cell killing k1 and exhaustion k2, we evaluated cell lines with antigen levels greater than 80% and treated with BBζ CAR T-cells at an effector to target ratio of 1 : 5. No significant correlation was found between the cancer cell proliferation rate r and killing rate (k1)
The CARRGO model is a simple representation of cancer cell–T-cell interactions
Summary
CAR T-cell therapy is a targeted immunotherapy, demonstrating remarkable anti-tumour efficacy, in the treatment of haematologic cancers [1,2]. Several clinical trials using CAR T-cells to treat GBM have been initiated all over the world [3,4,5,6]. At this early stage of clinical development, CAR T-cells offer much promise in solid tumours. The diversity of current clinical trials employing varying types of CARs for different solid tumours, target patient populations, preconditioning regimes and cell origins (autologous versus allogeneic) presents a significant challenge in identifying which aspects of a given CAR T-cell treatment protocol are most critical for its effectiveness. An additional critical challenge for CAR Tcell therapy is the potential for transient progression, where the cancer appears to progress before eventually responding to the treatment [7,8]
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