Chimeric antigen receptor T (CAR-T) cell therapy achieved extraordinary achievements results in antitumor treatments, especially against hematological malignancies, where it leads to remarkable, long-term antineoplastic effects with higher target specificity. Nevertheless, some limitations persist in autologous CAR-T cell therapy, such as high costs, long manufacturing periods, and restricted cell sources. The development of a universal CAR-T (UCAR-T) cell therapy is an attractive breakthrough point that may overcome most of these drawbacks. Here, we review the progress and challenges in CAR-T cell therapy, especially focusing on comprehensive comparison in UCAR-T cell therapy to original CAR-T cell therapy. Furthermore, we summarize the developments and concerns about the safety and efficiency of UCAR-T cell therapy. Finally, we address other immune cells, which might be promising candidates as a complement for UCAR-T cells. Through a detailed overview, we describe the current landscape and explore the prospect of UCAR-T cell therapy.

Bispecific chimeric antigen receptor T-cell (CAR-T) therapies have shown promising results in clinical trials for advanced B-cell malignancies. However, it is challenging to broaden the success of bispecific CAR-T therapies to treat refractory/relapse (r/r) T-cell leukemia/lymphoma because targeting multiple T-cell-expressing antigens leads to exacerbated CAR-T cell fratricide and potential safety concerns. Fully human heavy chain variable (FHVH) antibodies that specifically target CD5 or CD7 were screened and constructed to CD5/CD7 bispecific CARs. A truncated Epidermal growth factor receptor were integrated into CAR constructs to address safety concerns. To tackle the fratricidal issue of CAR-T cells targeting T-cell-pan marker(s), CRISPR/Cas9-based CD5 and CD7 genes knockout were performed before lentiviral transduction of bispecific CARs. Functional comparison between different bispecific CAR structures: tandem CARs and dual CAR were performed in vitro and in vivo to determine the optimal construct suitable for addressing T-cell malignancy antigen escape in clinical setting. Knockout of CD5 and CD7 prevents fratricide of CD5/CD7 bispecific CAR-T cells, and FHVH-derived CD5/CD7 bispecific CAR-T cells demonstrate potent antitumor activity in vitro and in vivo. The fratricide-resistant FHVH-derived CD5/CD7 bispecific CAR-T cells have potent antitumor activity against T-cell malignancies, and tandem CARs are more effective than dual CAR in preventing tumor escape in heterogeneous leukemic cells. The meaningful clinical efficacy and safety of tandem CD5/CD7 CAR-T cells deserve to be explored urgently.

Background: Alternative splicing (AS) offers a main mechanism to form protein polymorphism. A growing body of evidence indicates the correlation between splicing disorders and carcinoma. Nevertheless, an overall analysis of AS signatures in stomach adenocarcinoma (STAD) is absent and urgently needed. Results: 2042 splicing events were confirmed as prognostic molecular events. Furthermore, the final prognostic signature constructed by 10 AS events gave good result with an area under the curve (AUC) of receiver operating characteristic (ROC) curve up to 0.902 for 5 years, showing high potency in predicting patient outcome. We built the splicing regulatory network to show the internal regulation mechanism of splicing events in STAD. QKI may play a significant part in the prognosis induced by splicing events. Conclusions: In our study, a high-efficiency prognostic prediction model was built for STAD patients, and the results showed that AS events could become potential prognostic biomarkers for STAD. Meanwhile, QKI may become an important target for drug design in the future.