Abstract 474P
Background
Immune checkpoint inhibitors have revolutionized cancer treatment but only a fraction of patients actually benefitted since the development of resistance. Simultaneously targeting PD-1 and TGFβ is prompted to be a favorable strategy to reverse the phenomenon but the hydrophobicity of TGFβ inhibitors and latent drug-related adverse events restrained the utility. To circumvent this hindrance, we construct an enzymatically responsive nanoscale drug delivery system on the basis of our previous work and loaded it with αPD-1 antibody and TGFβ inhibitor, referring to as GPNPs. Upon systemic administration, the loading would be particularly released at gelatinase-rich tumor environment with enhanced permeability and retention ability, followed by alterations in tumor heterogeneity.
Methods
The GPNPs were synthesized by double-emulsion method and characterized. Subcutaneous LLC and A549 murine models were established for evaluation of GPNPs' therapeutic efficacy and side effects.The underlying mechanism was explored by cyTOF, FCM, scRNAseq and fate mapping.
Results
The GPNPs were successfully established with enhanced accumulation in tumors. The tumor growth of GPNP-treated group was inhibited (p<0.05) with prolonged survival and no obvious side effects. The growing speed of GPNP-treated group dropped in reseeding assay and CIK combinative therapy. More infiltration of Treg, CTL and Tmem as well as less M1 and M2 were observed in GPNP-treated tumors, especially when expressed with early-activated marker CD38 or CD69, inhibitory marker PD-1 or PD-L1 (p<0.05). scRNAseq displayed significant collagen-related signatures in fibroblast subpopulation. Fate mapping showed co-expressions of αSMA and PDGFRα in saline and αPD-1-treated group but not in GPNP-treated group.
Conclusions
Above, we developed a biocompatible gelatinase-responsive nanocarrier loaded with αPD-1 antibody and TGF-β inhibitor that was able to target tumor without apparent systemic loss. Robust antitumor efficacy, long term memory and safety profile were demonstrated in vivo. Further, applying GPNPs aroused specific immunity and created an immune-permissive environment as shown by multi-modal single-cell analysis of TME.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
National Natural Science Foundation of China (81972192); The Key Research and Development Project of Jiangsu Province (BE2020619).
Disclosure
All authors have declared no conflicts of interest.