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

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-ß 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.

Expressing IL-15/IL-18 and CXCR2 improve infiltration and survival of EGFRvIII-targeting CAR-T cells in breast cancer.

Previously, we have generated EGFRvIII-targeting CAR-T cells and brought hope for treating advanced breast cancer. However, EGFRvIII-targeting CAR-T cells were defined limited anti-tumor efficacy, which might be due to reduced accumulation, persistence of therapeutic T cells in tumor site of breast cancer. CXCLs were highly expressed in tumor environment of breast cancer and CXCR2 is the main receptor for CXCLs. Here, CXCR2 could significantly improve the trafficking and tumor specific accumulation of CAR-T cells both in vivo and in vitro. However, the anti-tumor effect of CXCR2 CAR-T cells were weaken which might be results of the apoptosis of T cells. Cytokines could stimulate Tcell proliferation, such as interleukin (IL)-15 and IL-18. Then, we generated CXCR2 CAR with synthetic IL-15 or IL-18 production. Co-expressing IL-15 or IL-18 could significantly suppress the exhaustion and apoptosis of T cells and enhanced the anti-tumor activity of CXCR2 CAR-T cells in vivo. Further, coexpression IL-15 or IL-18 in CXCR2 CAR-T cells did not cause toxicity. These findings provide a potential therapy strategy of co-expression IL-15 or IL-18 in CXCR2 CAR-T cells for the treatment of advancing breast cancer in the future.

Growth suppression of colorectal cancer expressing S492R EGFR by monoclonal antibody CH12 / 医学前沿

Colorectal cancer (CRC) is a common malignant tumor in the digestive tract, and 30%-85% of CRCs express epidermal growth factor receptors (EGFRs). Recently, treatments using cetuximab, also named C225, an anti-EGFR monoclonal antibody, for CRC have been demonstrated to cause an S492R mutation in EGFR. However, little is known about the biological function of S492R EGFR. Therefore, we attempted to elucidate its biological function in CRC cells and explore new treatment strategies for this mutant form. Our study indicated that EGFR and S492R EGFR accelerate the growth of CRC cells in vitro and in vivo and monoclonal antibody CH12, which specifically recognizes an EGFR tumor-specific epitope, can bind efficiently to S492R EGFR. Furthermore, mAb CH12 showed significantly stronger growth suppression activities and induced a more potent antibody-dependent cellular cytotoxicity effect on CRC cells bearing S492R EGFR than mAb C225. mAb CH12 obviously suppressed the growth of CRC xenografts with S492R EGFR mutations in vivo. Thus, mAb CH12 may be a promising therapeutic agent in treating patients with CRC bearing an S492R EGFR mutation.