An elderly female patient with ROS1 rearrangement primary lung adenocarcinoma and breast carcinoma:a rare case report and review of the literature

We report the case of a 90-year-old female patient who was suffering from c-ros oncogene 1(ros-1)rearrangement adenocarcinoma and breast cancer.After about 14 months of a reduced dose of crizotinib treatment,she had a stable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1(RECIST 1.1).This patient’s case demonstrates that ros-1 rearrangements are not limited to patients of young age.In addition,this case indicates that crizotinib,as second-line,or even first-line,treatment may be effective and manageable in elderly patients.Furthermore,for elderly patients carrying a ros1 fusion,a reduced dose of crizotinib may be efficacious rather than a resistance factor.Based on our findings,we recommend that elderly patients with advanced lung adenocarcinoma should be considered for inclusion in molecular screening for ros-1 translocation,especially for never-smokers negative for epidermal growth factor receptor(egfr)mutation and the fusion between echinoderm microtubule associated protein-like 4(EML4)and anaplastic lymphoma kinase(ALK).This deserves attention because the population is aging,with increasing incidence and morbidity of multiple primary malignant tumors.Neglect of breast nodules at the onset is one of the limitations of our case,as combination of primary lung cancer with breast cancer is common.Above all,use of antiestrogens before and after the diagnosis of non-small-cell lung cancer is related to a reduced risk of lung cancer mortality.Therefore,careful attention should always be paid to these cases.

A PD-L1-targeting chimeric switch receptor enhances efficacy of CAR-T cell for pleural and peritoneal metastasis

Pleural and peritoneal metastasis accompanied by malignant pleural effusion(MPE)or malignant ascites(MA)is frequent in patients with advanced solid tumors that originate from the lung,breast,gastrointestinal tract and ovary.Regional delivery of CAR-T cells represents a new strategy to control tumor dissemination in serous cavities.However,malignant effusions constitute an immune-suppressive environment that potentially induces CAR-T cell dysfunction.Here,we demonstrated that the anti-tumor cytotoxicity of conventional 2nd-generation CAR-T cells was significantly inhibited by both the cellular and non-cellular components of MPE/MA,which was primarily attributed to impaired CAR-T cell proliferation and cytokine production in MPE/MA environment.Interestingly,we found that PD-L1 was widely expressed on freshly-isolated MPE/MA cells.Based on this feature,a novel PD-L1-targeting chimeric switch receptor(PD-L1.BB CSR)was designed,which can bind to PD-L1,switching the inhibitory signal into an additional 4-1BB signal.When co-expressed with a 2nd-generation CAR,PD-L1.BB CSR-modified CAR-T cells displayed superior fitness and enhanced functions in both culture medium and MPE/MA environment,causing rapid and durable eradication of pleural and peritoneal metastatic tumors in xenograft models.Further investigations revealed elevated expressions of T-cell activation,proliferation,and cytotoxicity-related genes,and we confirmed that PD-L1 scFv and 4-1BB intracellular domain,the two important components of PD-L1.BB CSR,were both necessary for the functional improvements of CAR-T cells.Overall,our study shed light on the clinical application of PD-L1.BB CSR-modified dual-targeting CAR-T cells.Based on this study,a phase I clinical trial was initiated in patients with pleural or peritoneal metastasis(NCT04684459).

Progression of malignant pleural effusion during the early stage of gefitinib treatment in advanced EGFR-mutant lung adenocarcinoma involving complex driver gene mutations

Dear Editor,Malignant pleural effusion(MPE)has been reported in~40%of advanced non-small cell lung cancer(NSCLC)patients,most frequently in those with lung adenocarcinoma(LUAD).Epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs)have brought a significant improvement in the clinical treatment of advanced EGFR-mutant NSCLC,however,during the early stage of EGFR-TKI administration,progression of MPE rather than lung lesions has been observed in a small group of patients.Although defined as a nontarget lesion by the Response Evaluation Criteria in Solid Tumors(RECIST)guidelines(version 1.1),MPE represents true neoplastic pleural dissemination and worse prognosis.In this situation,some clinicians tend to give up targeted therapy and switch to chemotherapy,since it seems that the patients do not benefit from EGFR-TKI treatment.Therefore,it is necessary to explore the underlying mechanism of early MPE progression for better clinical decision-making.