Journal Article Epublish
PubMed: 40713180 DOI: 10.1136/jitc-2025-011783
hCCL19-expressing recombinant Newcastle disease virus boosts CAR T cell infiltration and efficacy in solid tumor.
J Immunother Cancer 13(7)
Authors: Man Liu, Can Li, Lan-Ting Feng, Ren-Yu Zhang, Wen-Liang Li, Ling Wang, Hai-Jiao Yang, Qian Li, Ze-Kun Liu, Yu-Le Yong, Xiang-Min Yang, Hong-Yong Cui, Ling-Min Kong, Wen Yin, Zhi-Nan Chen, Huijie Bian, Ding Wei
Affiliations
- Department of Cell Biology and National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an, China. State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Xi'an, China.
- Department of Health Statistics, Fourth Military Medical University, Xi'an, China.
- Department of Cell Biology and National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an, China.
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Xi'an, China.
- Department of Transfusion Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
- Department of Cell Biology and National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an, China. State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Xi'an, China.
Abstract
BACKGROUND
Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of hematological malignancies; however, it faces significant challenges in treating solid tumors, including limited immune infiltration into tumor tissues and immunosuppressive tumor microenvironment. Oncolytic viruses (OVs), which selectively destroy cancer cells and trigger antitumor immune responses, offer a compelling solution to these challenges. Newcastle disease virus (NDV) is a natural OV that exhibits antitumor activity with minimal side effects in clinical studies. We hypothesized that combining NDV, engineered to express a chemokine, with tetracycline-inducible CAR T cells could synergistically enhance CAR T cell therapy efficacy against solid tumors.
METHODS
We constructed a recombinant NDV expressing human CCL19 (rNDV19) and evaluated its therapeutic efficacy alongside doxycycline-inducible CAR T cells in an orthotopic lung cancer mouse model. Tumor burden, immune cell infiltration, and mouse survival were analyzed.
RESULTS
rNDV19 retained potent oncolytic activity, significantly reducing tumor cell viability while achieving stable expression of human CCL19. rNDV19 triggered significant recruitment of CAR T cells into tumors and promoted their activity. Mechanistic analysis revealed that rNDV19 and CAR T cell combination therapy remodeled the tumor microenvironment. Transcriptomic profiling highlighted activation of critical immune pathways-including leukocyte chemotaxis, T cell differentiation, cytokine production, and immune response-activating signaling in combination therapy. These findings were further corroborated by upregulated expression of T cell activation markers like IL-2, TNF-α, IFN-γ, and cytotoxic effector molecules such as granzyme A and perforin. Therapeutically, the combination synergistically extended median survival time from 22 to 36 days, outperforming monotherapies.
CONCLUSIONS
The combination of rNDV19 and CAR T cells represents a promising strategy for overcoming the limitations of CAR T cell therapy for solid tumors. This approach enhances immune cell infiltration and activation, potentially converting "cold" tumors into "hot" tumors to improve therapeutic outcomes and offering a robust translational framework for solid tumor immunotherapy.
MeSH
Cells, Newcastle Disease, Neoplasms, Immunotherapy, Viruses, Immunity, Therapeutics, T-Lymphocytes, Tumor Microenvironment, Newcastle Disease Virus, Virus Diseases, Car-T Cell