4.6 Article

Dual-Target CAR-Ts with On- and Off-Tumour Activity May Override Immune Suppression in Solid Cancers: A Mathematical Proof of Concept

期刊

CANCERS
卷 13, 期 4, 页码 -

出版社

MDPI
DOI: 10.3390/cancers13040703

关键词

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

类别

资金

  1. James S. Mc. Donnell Foundation (USA) 21st Century Science Initiative in Mathematical and Complex Systems Approaches for Brain Cancer [220020450]
  2. Ministerio de Ciencia e Innovacion, Spain [PID2019-110895RB-I00]
  3. Junta de Comunidades de Castilla-La Mancha [SBPLY/17/180501/000154]
  4. University of Castilla-La Mancha research plan

向作者/读者索取更多资源

CAR-T cell-based therapies have shown success in hematological malignancies but have been limited in solid tumors due to the immunosuppressive tumor microenvironment. A mathematical model in this paper suggests that targeting solid tumor antigens with large numbers of CAR-T cells could overcome this immunosuppression, potentially leading to successful treatments. Computer simulations indicate that the strategy of utilizing CAR-T cells targeting multiple antigens may lead to the expansion of a strong army of CAR-T cells in solid tumors. This proposed approach could provide a promising avenue for overcoming the immune suppression and achieving successful CAR-T cell therapies against solid tumors.
Simple Summary (CAR)-T cell-based therapies have achieved substantial success against different haematological malignancies. However, results for solid tumours have been limited up to now, in part due to the fact that the immunosuppressive tumour microenvironment inactivates CAR-T cell clones. In this paper we study mathematically the competition of CAR-T and tumour cells, taking into account their immunosuppressive capacity. Using computer simulations, 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 in silico, the manufacture and injection of CAR-T cells targetting two antigens: CD19 and a tumour-associated antigen. This strategy lead in our simulations to the expansion of the CAR-T cells injected and the production of a massive army of CAR-T cells targetting the solid tumour, and potentially overcoming its immune suppression capabilities. Thus, our proposed strategy could provide a way to develop successful CAR-T cell therapies against solid tumours. 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.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.6
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据