Clinicopathological significance and immunotherapeutic outcome of claudin 18.2 expression in advanced gastric cancer:A retrospective study

Objective: Immunotherapeutic outcomes and clinical characteristics of claudin 18 isoform 2 positive(CLDN18.2-positive) gastric cancer(GC) vary in different clinical studies, making it difficult to optimize antiCLDN18.2 therapy. We conducted a retrospective analysis to explore the association of CLDN18.2 expression with clinicopathological characteristics and immunotherapeutic outcomes in GC.Methods: A total of 536 advanced GC patients from 2019 to 2021 in the CT041-CG4006 and CT041-ST-01clinical trials were included in the analysis. CLDN18.2 expression on ≥40% of tumor cells(2+, 40%) and CLDN18.2 expression on ≥70% of tumor cells(2+, 70%) were considered the two levels of positively expressed GC. The clinicopathological characteristics and immunotherapy outcomes of GC patients were analyzed according to CLDN18.2 expression status.Results: CLDN18.2 was expressed in 57.6%(cut-off: 2+, 40%) and 48.9%(cut-off: 2+, 70%) of patients.Programmed death-ligand 1(PD-L1) and CLDN18.2 were co-expressed in 19.8% [combined positive score(CPS)≥1, CLDN18.2(cut-off: 2+, 40%)] and 17.2% [CPS≥5, CLDN18.2(cut-off: 2+, 70%)] of patients.CLDN18.2 expression positively correlated with younger age, female sex, non-gastroesophageal junction(nonGEJ), and diffuse phenotype(P<0.001). HER2 and PD-L1 expression were significantly lower in CLDN18.2-positive GC(both P<0.05). Uterine adnexa metastasis(P<0.001) was more frequent and liver metastasis(P<0.001)was less common in CLDN18.2-positive GC. Overall survival and immunotherapy-related progression-free survival(ir PFS) were inferior in the CLDN18.2-positive group.Conclusions: CLDN18.2-positive GC is associated with poor prognosis and worse immunotherapeutic outcomes. The combination of anti-CLDN18.2 therapy, anti-PD-L1/PD-1 therapy, and chemotherapy for GC requires further investigation.

Combined local therapy and CAR-GPC3 T-cell therapy in advanced hepatocellular carcinoma:a proof-of-concept treatment strategy

Dear Editor,Available evidence regarding the most suitable treatment strategies for hepatocellular carcinoma(HCC)with inferior vena cava tumor thrombus(IVCTT)is extremely limited,and the median overall survival time for these patients after liver resection is only 17.76 months[1].Other local or systemic treatments for HCC with IVCTT result in a median overall survival time ranging from 5.88 to 15.36 months[1–3].Thus,new therapeutic strategies are urgently needed to improve the survival of HCC patients with IVCTT.Chimeric antigen receptor(CAR)T-cell therapy has seen success in treating B-cell neoplasms with impressive outcomes[4].However,this therapy alone has shown limited efficacy on solid tumors,such as HCC[5].

Genetically engineered T cells for cancer immunotherapy

T cells in the immune system protect the human body from infection by pathogens and clear mutant cells through specific recognition by T cell receptors(TCRs).Cancer immunotherapy,by relying on this basic recognition method,boosts the antitumor efficacy of T cells by unleashing the inhibition of immune checkpoints and expands adaptive immunity by facilitating the adoptive transfer of genetically engineered T cells.T cells genetically equipped with chimeric antigen receptors(CARs)or TCRs have shown remarkable effectiveness in treating some hematological malignancies,although the efficacy of engineered T cells in treating solid tumors is far from satisfactory.In this review,we summarize the development of genetically engineered T cells,outline the most recent studies investigating genetically engineered T cells for cancer immunotherapy,and discuss strategies for improving the performance of these T cells in fighting cancers.