Pulmonary Delivery of <scp>TCR</scp> Bispecific Proteins via Mesenchymal Stem Cells Facilitates Efficient Clearance of Lung Cancers

T-cell receptor (TCR) bispecific proteins represent a pioneering therapeutic modality that harnesses the diverse target recognition capabilities inherent to TCRs while preserving the beneficial characteristics associated with protein therapeutics. However, investigations into TCR bispecific proteins, particularly within the context of lung diseases, remain limited. This study aims to elucidate their potential for the treatment of lung cancer. We employed a humanized murine model to evaluate the efficacy of TCR bispecific proteins in eradicating lung tumors in vivo. Cytotoxic activity was assessed against various lung cancer cell lines, and statistical tests were used to analyze the data. To address concerns regarding toxic side effects from systemic administration, mesenchymal stem cells (MSCs) were explored as vehicles for the targeted delivery of TCR bispecific proteins. Our findings demonstrate that TCR bispecific proteins exhibit substantial cytotoxic activity against a variety of lung cancer cell lines. MSCs, with optimal pulmonary targeting properties, were shown to persist within the lungs for over 7 days. By employing MSCs to locally secrete TCR bispecific proteins, we achieved therapeutic effects comparable to systemic administration without manifestations of immune overactivation in murine subjects. Additionally, we evaluated various cytokine combinations and discovered that the combination of IL-7, IL-21, and TCR bispecific proteins significantly augmented their capacity to eliminate antigen-negative cells in a heterogeneous tumor model. Collectively, our findings suggest that the combinatorial therapy of TCR bispecific proteins and MSCs holds considerable promise for clinical application in the treatment of lung cancer, potentially enhancing therapeutic efficacy while minimizing adverse effects.