CD19-targeted HSP90 inhibitor nanoparticle combined with TKIs reduces tumor burden and enhances T-cell immunity in murine B-cell malignancies.

Abstract

Rationale: Conventional chemotherapies for B-cell malignancies are often limited by drug resistance and significant side effects due to non-specific targeting. This research aimed to improve treatment efficacy by developing nano-delivery systems that specifically target tumor cells, thereby enhancing therapeutic precision and reducing off-target toxicity. Methods: The construction, biocompatibility, and targeting capability of CD19@NP/17-DMAG were evaluated using TEM, HPLC, FTIR spectroscopy, CCK-8 assay, flow cytometry (FC), and IVIS imaging. Therapeutic efficacy was assessed through Western blotting, RT-qPCR, flow cytometry, H&E staining, BrdU assay, and apoptosis assays. The mechanism of action of CD19@NP/17-DMAG in murine B-cell malignancies was investigated using RNA sequencing, in vivo T-cell depletion, and CRISPR/Cas9 technology. Results: CD19@NP/17-DMAG nanoparticles demonstrated enhanced efficacy in murine models of BCR-ABL1⁺ B-cell acute lymphoblastic leukemia (B-ALL) when combined with tyrosine kinase inhibitors (TKIs), including the BCR-ABL1-targeted imatinib and the broad-spectrum ponatinib. This combination significantly reduced tumor burden, prolonged survival, and induced a robust anti-tumor T-cell response. RNA-seq analysis indicated that the targeted treatment modulated genes related to cell proliferation, apoptosis, and antigen presentation. Notably, this treatment also increased MHC class I (MHC-I) expression, thereby strengthening antigen presentation in BCR-ABL1⁺ B-ALL cells. Ponatinib-based therapy achieved complete remission, eradicated minimal residual disease, and established long-term immune memory in BCR-ABL1⁺ B-ALL. In addition, CD19@NP/17-DMAG was effective in another B-cell malignancy model, A20 lymphoma, significantly slowing tumor growth and amplifying T-cell responses. Conclusions: These findings highlight the CD19@NP/17-DMAG system as a promising therapeutic approach that both augments T cell immune responses and minimizes side effects in B-cell malignancies.