León-Triana Odelaisy, Pérez-Martínez Antonio, Ramírez-Orellana Manuel, Pérez-García Víctor M
Mathematical Oncology Laboratory (MOLAB), Department of Mathematics, Instituto de Matemática Aplicada a la Ciencia y la Ingeniería, Universidad de Castilla-La Mancha, Avda. Camilo José Cela, 3, 13071 Ciudad Real, Spain.
Paediatric Haemato-Oncology Department, Hospital Universitario La Paz, 28046 Madrid, Spain.
Cancers (Basel). 2021 Feb 9;13(4):703. doi: 10.3390/cancers13040703.
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.
嵌合抗原受体（CAR）-T细胞疗法在治疗B细胞恶性肿瘤方面取得了巨大成功，这引发了科学界和临床界越来越浓厚的兴趣，想要将其应用扩展到实体癌治疗中。然而，到目前为止，实体瘤的治疗效果有限，部分原因是免疫抑制性肿瘤微环境能够使CAR-T细胞克隆失活。在本文中，我们提出了一个数学模型，该模型描述了CAR-T细胞与肿瘤细胞之间的竞争，并考虑了它们的免疫抑制能力。利用这个数学模型，我们表明，使用大量靶向实体瘤抗原的CAR-T细胞可以克服癌症的免疫抑制潜力。为了达到如此高数量的CAR-T细胞，我们提出并通过计算研究了靶向两种抗原（CD19和一种肿瘤相关抗原）的CAR-T细胞的制造和注射。我们在计算机模拟中研究了注射该产品后疾病的动态变化，发现血液和淋巴造血器官中CAR-T细胞群体的扩增可能会导致大量靶向实体瘤的CAR-T细胞产生，并有可能克服其免疫抑制能力。这种策略可能会受益于与PD-1抑制剂的联合使用以及低肿瘤负荷。我们的计算结果为在完成经典的细胞减灭治疗后，使用具有肿瘤内外活性的双CAR与抗PD-1药物联合治疗工程化的T细胞治疗不同类型的实体瘤提供了理论支持。
