Genetically Programmable Vesicles for Enhancing CAR‐T Therapy against Solid Tumors

Abstract

Chimeric antigen receptor‐T (CAR‐T) cell therapy has shown remarkable success in eradicating hematologic malignancies; however, its efficacy in treating solid tumors has always been limited due to the presence of an immune‐suppressive tumor microenvironment (TME). Here, genetically programmable cellular vesicles expressing high‐affinity anti‐programmed death‐ligand 1 single chain variable fragment (anti‐PD‐L1 scFv) loaded with glutamine antagonist (D@aPD‐L1 NVs) are developed to metabolically dismantle the immunosuppressive TME and enhance the efficiency of anti‐mesothelin CAR‐T cells in orthotopic lung cancer. As anti‐PD‐L1 scFv can specifically bind to the programmed death‐ligand 1 (PD‐L1) on tumor cells, D@aPD‐L1 NVs enable the targeted delivery of glutamine antagonists to the tumor site and address the upregulation of PD‐L1 on tumor cells, which prevents the premature exhaustion of CAR‐T cells. More importantly, D@aPD‐L1 NVs effectively reduce the number of immunosuppressive cells and promote the recruitment of inflammatory cells and the secretion of inflammatory cytokines in tumor tissues. These unique features of D@aPD‐L1 NVs improve the infiltration and effector functions of CAR‐T cells, which ultimately enhance the anti‐tumor ability and long‐term memory immunity of CAR‐T cells. The findings support that D@aPD‐L1 NVs act as a promising drug to strengthen the effectiveness of CAR‐T cells against solid tumors.

Platelet-Derived Apoptotic Vesicles Promote Bone Regeneration via Golgi Phosphoprotein 2 (GOLPH2)-AKT Signaling Axis

“…ApoVs, as nanoparticles derived from apoptotic cells, are considered to have biocompatibility and reduced immunogenicity compared with other synthetic nanoparticles. , However, due to the unwanted off-target activities and potential “dilution effects” during systemic administration, which may affect their ability to reach the target tissue, the use of apoVs in therapeutic applications may be limited. , Increasing evidence have shown that EVs could be engineered or modified to improve their efficiency, specificity, and safety in treatment. − Likewise, to fully exploit the apoV therapeutic potential in bone regeneration, engineering treatment should be considered.…”

Engineering high‐affinity dual targeting cellular nanovesicles for optimised cancer immunotherapy

“…Therefore, we used HEK293 cells (human embryonic kidney cells) to produce NVs in our study, which were easy to expand in vitro, perform engineering and could function on different types of tumour cells with high biological safety (Zhang et al., 2018). Additionally, there are significant differences in the expression levels of PD‐L1 and CD47 on tumour cells with different malignancy and NVs internalised into cells after anchoring to ligands on the surface of target high malignance cells by high‐affinity PD‐1 and SIRPα proteins, suggesting that these fusion HAC NVs were potential for targeted drug delivery application (Bian et al., 2022; Li et al., 2023; Zhang et al., 2018).…”

Genetically engineered cell-derived nanovesicles for cancer immunotherapy

“…Based on the similar principle of immune checkpoint blockade, Li et al generated a stable HEK 293T cell line expressing anti-PD-L1 scFv to produce aPD-L1 nanovesicles for remodeling the anti-inflammatory TME into a pro-inflammatory state. 100 Further loading glutamine antagonists with the aPD-L1 nanovesicles via electroporation facilitated the upregulation of oxidative metabolism in effector T cells to promote their differentiation into a highly activated phenotype, ultimately enhancing the efficacy of CAR-T therapy against solid tumors in immunocompetent mouse models.…”