Abstract
Chimeric antigen receptor (CAR) T cell therapy is a remarkably effective immunotherapy that relies on in vivo expansion of engineered CAR T cells, after lymphodepletion (LD) by chemotherapy. The quantitative laws underlying this expansion and subsequent tumour eradication remain unknown. We develop a mathematical model of T cell–tumour cell interactions and demonstrate that expansion can be explained by immune reconstitution dynamics after LD and competition among T cells. CAR T cells rapidly grow and engage tumour cells but experience an emerging growth rate disadvantage compared to normal T cells. Since tumour eradication is deterministically unstable in our model, we define cure as a stochastic event, which, even when likely, can occur at variable times. However, we show that variability in timing is largely determined by patient variability. While cure events impacted by these fluctuations occur early and are narrowly distributed, progression events occur late and are more widely distributed in time. We parameterized our model using population-level CAR T cell and tumour data over time and compare our predictions with progression-free survival rates. We find that therapy could be improved by optimizing the tumour-killing rate and the CAR T cells' ability to adapt, as quantified by their carrying capacity. Our tumour extinction model can be leveraged to examine why therapy works in some patients but not others, and to better understand the interplay of deterministic and stochastic effects on outcomes. For example, our model implies that LD before a second CAR T injection is necessary.
Highlights
In 2017, non-Hodgkin lymphoma was the most common haematologic malignancy in the US with 72 000 new cases (4.3% of all cancer) and 20 000 deaths (3.4% of all cancer deaths) [1]
These patients could benefit from autologous chimeric antigen receptor (CAR) T cell therapy that uses genetically engineered T cells re-targeted to CD19 [3]
We focus on normal T cells, CAR T cells and tumour cells and find that CAR expansion and decay can be explained via competitive growth in the context of immune reconstitution, which is a consequence of the lymphodepletion prior to therapy
Summary
In 2017, non-Hodgkin lymphoma was the most common haematologic malignancy in the US with 72 000 new cases (4.3% of all cancer) and 20 000 deaths (3.4% of all cancer deaths) [1]. Large B cell lymphoma (LBCL) is the most common subtype of non-Hodgkin lymphoma. LBCL patients that did not respond to chemotherapy have a median overall survival of under seven months [2]. These patients could benefit from autologous chimeric antigen receptor (CAR) T cell therapy that uses genetically engineered T cells re-targeted to CD19 [3]. A pivotal, multi-centre, phase 1–2 trial of the CAR T cell drug axicabtagene ciloleucel (axi-cel; n = 101 patients treated) was ZUMA-1 [4,5]. A complete understanding of why these patients progress is lacking
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
More From: Proceedings of the Royal Society B: Biological Sciences
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.