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- 조회87
J. Control. Release, Available online 27 February 2025 | https://doi.org/10.1016/j.jconrel.2025.02.075
Timely administration of drug combination improves chemoimmunotherapy of an immune-cold tumor
Fanfei Meng a,b,1, Yanying He a,1, Jiaqi Zhao a, Zhongyue Yuan a, Jianping Wang a, Karen Gutierrez Parra a, Melissa Fishel c, Timothy L. Ratliff d,e, Yoon Yeo a,d,f
aDepartment of Industrial and Molecular Pharmaceutics, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA
bDepartment of Biomedical and Nutritional Sciences, University of Massachusetts Lowell, 3 Solomont Way, Lowell, MA 01854, USA
cDepartments of Pediatrics and of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
dPurdue University Institute for Cancer Research, 201 South University Street, West Lafayette, IN 47907, USA
eDepartment of Comparative Pathobiology, Purdue University, 625 Harrison Street, West Lafayette, Indiana 47907, United States
fWeldon School of Biomedical Engineering, Purdue University, 206 S Martin Jischke Drive, West Lafayette, IN 47907, USA
1Authors contributed equally.
Corresponding author : Yoon Yeo
aDepartment of Industrial and Molecular Pharmaceutics, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA
bDepartment of Biomedical and Nutritional Sciences, University of Massachusetts Lowell, 3 Solomont Way, Lowell, MA 01854, USA
cDepartments of Pediatrics and of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
dPurdue University Institute for Cancer Research, 201 South University Street, West Lafayette, IN 47907, USA
eDepartment of Comparative Pathobiology, Purdue University, 625 Harrison Street, West Lafayette, Indiana 47907, United States
fWeldon School of Biomedical Engineering, Purdue University, 206 S Martin Jischke Drive, West Lafayette, IN 47907, USA
1Authors contributed equally.
Corresponding author : Yoon Yeo
Abstract
An immunoactive complex consisting of a polyethyleneimine derivative (2E’), paclitaxel (PTX), and cyclic dinucleotide (CDN) was developed for chemoimmunotherapy of solid tumors. Each component uniquely contributes to stimulating innate immune response to tumors: 2E’ carries PTX and CDN while stimulating antigen-presenting cells, PTX induces immunogenic cell death, and CDN activates the STING pathway. A single intratumoral injection of 2E’/PTX/CDN inhibited the growth of MOC1 oral squamous cell carcinoma and KPCY (2838c3) pancreatic tumors, achieving complete tumor regression in 80–100 % of mice. However, 2E’/PTX/CDN showed limited therapeutic efficacy with immune-cold B16F10 melanoma, accompanied by the increase of innate immune cells in the tumor draining lymph nodes peaking on day 5 post-administration. The addition of a complex of 2E’ and siRNA targeting PD-L1 (siPD-L1) at an optimal 5-d interval improved the response in B16F10 melanoma, resulting in tumor-free survival in 50 % of mice and rejection of live tumor rechallenge in 67 % of surviving animals. Consistent with the function of each component, the timed combination of 2E’/PTX/CDN and 2E’/siPD-L1 increased the fractions of mature dendritic cells and M1 macrophages, prevented the increase of regulatory T cells in tumor-draining lymph nodes, and increased melanoma antigen-specific CD8+ T cells in the spleen. These results demonstrate the effectiveness of the 2E’/PTX/CDN complex in the chemoimmunotherapy of solid tumors and highlight the significance of timely intervention to sustain the immunoactive phenotype in its application to immune-cold tumors.
논문정보
- Research article
- 2025년 02월 (BRIC 등록일 2025-03-03)
- 국외 연구진
- 바이오·의료융합 > 바이오센싱 및 나노바이오물질
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