Mathematical deconvolution of CAR T-cell proliferation and exhaustion from real-time killing assay data

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.

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Mathematical deconvolution of CAR T-cell proliferation and exhaustion from real-time killing assay data

10.1101/786020 ◽

2019 ◽

Author(s):

Prativa Sahoo ◽

Xin Yang ◽

Daniel Abler ◽

Davide Maestrini ◽

Vikram Adhikarla ◽

...

Keyword(s):

Cell Proliferation ◽

T Cell ◽

Cell Therapy ◽

Cell Killing ◽

T Cell Proliferation ◽

Tumor Growth Rate ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T

AbstractChimeric antigen receptor (CAR) T-cell therapy has shown promise in the treatment of hematological cancers and is currently being investigated for solid tumors including high-grade glioma brain tumors. There is a desperate need to quantitatively study the factors that contribute to the efficacy of CAR T-cell therapy in solid tumors. 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, CAR T-cell proliferation and exhaustion, and CAR T-cell persistence. We use patient-derived and engineered cancer cell lines with an in vitro real-time cell analyzer to parameterize 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 as compared to higher doses. Furthermore, the exhaustion rate was observed to increase significantly with tumor 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 tumor characteristics including tumor growth rate and antigen level to maximize therapeutic benefit.Statement of SignificanceWe utilize a mathematical model to deconvolute the nonlinear contributions of CAR T-cell proliferation and exhaustion to predict therapeutic efficacy and dependence on CAR T-cell dose and target antigen levels.

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Kinetics of Immune Reconstitution after CD19 CAR-T Cell Therapy in ALL Patients

Blood ◽

10.1182/blood-2019-127808 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1301-1301 ◽

Cited By ~ 1

Author(s):

Ying Wang ◽

Jiang Cao ◽

Yan Zhiling ◽

Jianlin Qiao ◽

Deipeng Li ◽

...

Keyword(s):

T Cell ◽

Cell Therapy ◽

Lymphocyte Subsets ◽

T Cell Therapy ◽

Cd8 Cells ◽

Car T Cells ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T ◽

Kinetics Of

Background: Chimeric antigen receptor (CAR)-T cell therapy has achieved significant efficacy in relapsed or refractory(R/R) hematologic malignancies. CD19 CAR-T cells, which kill B lymphoblasts, but also target normal B lymphocytes, resulting in dysplasia of B cells and suppression of humoral immunity. There were no detailed reports on the profile of immune reconstitution in patients after CD19 CAR-T cell treatment. Our study focused on the kinetics of lymphocyte subsets and immunoglobulin reconstruction in 21 patients with acute lymphoblastic leukemia (ALL) after CD19 CAR-T cell therapy. Methods: Patients with R/R ALL received CD19 CAR-T cell therapy who obtaining complete response at 1 month after CAR-T cell infusion from April 1, 2016 to Feb 28, 2019 were enrolled (Clinical Trials: NCT02782351). Blood was collected before lymphodepletion therapy and at intervals after CAR-T cell infusion for analysis of complete blood counts, lymphocyte subsets, immunoglobulin, and the amplification of CAR T cells. Results: We found that the reconstitution of different immune cell subsets occurred at different rates after CD19 CAR-T cell infusion: CD8+ cells were the first to recover, followed by CD16+CD56+ cells and CD3+ cells, and finally CD4+ cells. CD4/CD8 ratio was inverted, sustaining for at least 1 year. B cell dysplasia occurred in all patients and CD19+ cells returned to normal 79 days after CAR-T cell infusion, which may be related to CAR-T cell depletion. IgG and IgM recovered on day 184 and 242 after CAR-T treatment, respectively. IgA recovered slowly and sustained longer at a low level compared with IgG and IgM, and did not return to normal 1 year after CAR-T cell treatment. A total of 9 infections occurred in 6 (28.57%) patients, including 6 cases with grade 2 infection and 3 cases with grade 3 infection. No patients died of severe infection. In patients with late relapse, IgG, IgA, and IgM were generally normal before CAR-T cell therapy, and were higher than those with early relapse, suggesting that patients with normal immunoglobulin levels before treatment may have longer remission time. Conclusion: Our results showed the kinetics of lymphocyte subsets and immunoglobulin reconstruction in R/R ALL patients after CD19 CAR-T cell therapy. The recovery of CD8+ cells was fast, whereas the recovery of the CD4+ cell was delayed. All patients developed B cell dysplasia, and it took about 3 months to recover. IgG recovered firstly, followed by IgM and IgA, the later would not recover at least 1 year. Disclosures No relevant conflicts of interest to declare.

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