Chimeric antigen receptor (CAR)-T cell-based therapies have achieved substantial success against B-cell malignancies, which has led to a growing scientific and clinical interest in extending their use to solid cancers. However, results for solid tumours have been limited up to now, in part due to the immunosuppressive tumour microenvironment, which is able to inactivate CAR-T cell clones. In this paper we put forward a mathematical model describing the competition of CAR-T and tumour cells, taking into account their immunosuppressive capacity. Using the mathematical model, we show that the use of large numbers of CAR-T cells targetting the solid tumour antigens could overcome the immunosuppressive potential of cancer. To achieve such high levels of CAR-T cells we propose, and study computationally, the manufacture and injection of CAR-T cells targetting two antigens: CD19 and a tumour-associated antigen. We study in silico the resulting dynamics of the disease after the injection of this product and find that the expansion of the CAR-T cell population in the blood and lymphopoietic organs could lead to the massive production of an army of CAR-T cells targetting the solid tumour, and potentially overcoming its immune suppression capabilities. This strategy could benefit from the combination with PD-1 inhibitors and low tumour loads. Our computational results provide theoretical support for the treatment of different types of solid tumours using T cells engineered with combination treatments of dual CARs with on- and off-tumour activity and anti-PD-1 drugs after completion of classical cytoreductive treatments.
Tumor growth is the result of the interplay of complex biological processes in a huge number of individual cells in a changing environment. Effective simple mathematical laws have been shown to describe tumor growth in vitro, or in animal models with bounded-growth dynamics accurately. However, results for human cancers in patients are scarce. The study mined a dataset of 1133 brain metastases (BMs) with longitudinal imaging follow-up, treated with radiosurgery (SRS) to find growth laws for untreated BMs, relapsing treated BMs, and radiation necrosis (RN). Untreated BMs showed sustained growth acceleration, most likely related to the underlying evolutionary dynam- ics. Relapsing BM growth was slower, most probably due to a reduction in tumor heterogeneity after SRS, which may limit the evolutionary possibilities of the tumor. RN lesions had significantly larger growth exponents than relapsing BMs, providing a way to differentiate them from true pro- gression. This may help in solving a problem of clinical relevance, since the first condition may resolve spontaneously, and not require further work-up, while the second requires therapeutic action.
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