bims-adocet 2024-08-18 papers

Issue of 2024–08–18
two papers selected by
Shani Kassia Lyskov, Tel Aviv University

Br J Pharmacol. 2024 Aug 11.

Dual targeting chimeric antigen receptor cells enhance antitumour activity by overcoming T cell exhaustion in pancreatic cancer.

Sun Ruixin, Liu Yifan, Sun Yansha, Zhou Min, Dong Yiwei, Hu Xiaoli, Shi Bizhi, Jiang Hua, Li Zonghai.

BACKGROUND AND PURPOSE: Although our previous data indicated that claudin 18 isoform 2 (CLDN18.2)-targeted chimeric antigen receptor (CAR) T cells displayed remarkable clinical efficacy in CLDN18.2-positive gastric cancer, their efficacy is limited in pancreatic ductal adenocarcinoma (PDAC). The tumour microenvironment (TME) is one of the main obstacles to the efficacy of CAR-T and remodelling the TME may be a possible way to overcome this obstacle. The TME of PDAC is characterized by abundant cancer-related fibroblasts (CAFs), which hinder the infiltration and function of CLDN18.2-targeted CAR-T cells. The expression of fibroblast activation protein alpha (FAP) is an important feature of active CAFs, providing potential targets for eliminating CAFs.
EXPERIMENTAL APPROACH: In this study, we generated 10 FAP/CLDN 18.2 dual-targeted CAR-T cells and evaluated their anti-tumour ability in vitro and in vivo.
KEY RESULTS: Compared with conventional CAR-T cells, some dual-targeted CAR-T cells showed improved therapeutic effects in mouse pancreatic cancers. Further, dual-targeted CAR-T cells with better anti-tumour effect could suppress the recruitment of myeloid-derived suppressor cells (MDSCs) to improve the immunosuppressive TME, which contributes to the survival of CD8+ T cells. Moreover, dual-targeted CAR-T cells reduced the exhaustion of T cells in transforming TGF-β dependent manner.
CONCLUSION AND IMPLICATIONS: The dual-targeted CAR-T cells obtained enhancement of T effector function, inhibition of T cell exhaustion, and improvement of tumour microenvironment. Our findings provide a theoretical rationale for dual-targeted FAP/CLDN 18.2 CAR-T cells therapy in PDAC.

Keywords: T cell exhaustion; cancer‐associated fibroblasts; dual‐targeted CAR‐T; pancreatic cancer

DOI: https://doi.org/10.1111/bph.16505

Cell Mol Immunol. 2024 Aug 12.

CAR-T and CAR-NK as cellular cancer immunotherapy for solid tumors.

Lei Peng, Giacomo Sferruzza, Luojia Yang, Liqun Zhou, Sidi Chen.

In the past decade, chimeric antigen receptor (CAR)-T cell therapy has emerged as a promising immunotherapeutic approach for combating cancers, demonstrating remarkable efficacy in relapsed/refractory hematological malignancies in both pediatric and adult patients. CAR-natural killer (CAR-NK) cell complements CAR-T cell therapy by offering several distinct advantages. CAR-NK cells do not require HLA compatibility and exhibit low safety concerns. Moreover, CAR-NK cells are conducive to "off-the-shelf" therapeutics, providing significant logistic advantages over CAR-T cells. Both CAR-T and CAR-NK cells have shown consistent and promising results in hematological malignancies. However, their efficacy against solid tumors remains limited due to various obstacles including limited tumor trafficking and infiltration, as well as an immuno-suppressive tumor microenvironment. In this review, we discuss the recent advances and current challenges of CAR-T and CAR-NK cell immunotherapies, with a specific focus on the obstacles to their application in solid tumors. We also analyze in depth the advantages and drawbacks of CAR-NK cells compared to CAR-T cells and highlight CAR-NK CAR optimization. Finally, we explore future perspectives of these adoptive immunotherapies, highlighting the increasing contribution of cutting-edge biotechnological tools in shaping the next generation of cellular immunotherapy.

Keywords: CAR-NK; CAR-T; Cancer immunotherapy; Cell therapy; Solid tumor

DOI: https://doi.org/10.1038/s41423-024-01207-0