Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Dual-Target Car-Ts With on- and off-Tumour Activity May Override Immune Suppression in Solid Cancers: A Mathematical Proof of Concept

Version 1 : Received: 4 December 2020 / Approved: 7 December 2020 / Online: 7 December 2020 (15:06:37 CET)

How to cite: León-Triana, O.; Pérez-Martínez, A.; Ramírez-Orellana, M.; Pérez-García, V.M. Dual-Target Car-Ts With on- and off-Tumour Activity May Override Immune Suppression in Solid Cancers: A Mathematical Proof of Concept. Preprints 2020, 2020120166 (doi: 10.20944/preprints202012.0166.v1). León-Triana, O.; Pérez-Martínez, A.; Ramírez-Orellana, M.; Pérez-García, V.M. Dual-Target Car-Ts With on- and off-Tumour Activity May Override Immune Suppression in Solid Cancers: A Mathematical Proof of Concept. Preprints 2020, 2020120166 (doi: 10.20944/preprints202012.0166.v1).

Abstract

Chimeric antigen receptor (CAR)-T cell-based therapies have achieved substantial successes against B-cell malignancies, what has led to a growing scientific and clinical interest on extending their use to solid cancers. However, results for solid tumours have been limited up to now, in part due to the immuno-suppressive tumour microenvironment, that 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, accounting for their immunosuppressive capabilities. Using the mathematical model, we show that the use of large numbers of CAR-T cells targeting the solid tumour antigens could overcome the cancer immunosuppressive potential. To achieve such high levels of CAR-T cells we propose and study computationaly, the manufacture and injection of CAR-T cells targeting 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 generation of an army of CAR-T cells targetting the solid tumour, and potentially overcoming its inmune suppression capabilities. That strategy could benefit from the combination with PD-1 inhibitors and of low tumour loads. Our computational results provide a 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-PD1 drugs after completion of classical cytoreductive treatments.

Subject Areas

Mathematical oncology; CAR-T cells; mathematical immunology; mathematical modelling; immunotherapy of solid tumours; glioblastoma

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