Acellular scaffold‑based approach for in situ genetic engineering of host T‑cells in solid tumor immunotherapy  

作　　者：Hiren Y.Dandia Mamatha M.Pillai Deepak Sharma Meghna Suvarna Neha Dalal Ayush Madhok Arvind Ingle Shubhada V.Chiplunkar Sanjeev Galande Prakriti Tayalia 

机构地区：[1]Department of Biosciences and Bioengineering,Indian Institute of Technology Bombay,Powai,Mumbai 400076,India [2]Radiation Biology and Health Sciences Division,Bhabha Atomic Research Centre,Mumbai 400085,India [3]Centre of Excellence in Epigenetics,Department of Biology,Indian Institute of Science Education and Research,Pune 411008,India [4]Advanced Centre for Treatment,Research and Education in Cancer(ACTREC),Tata Memorial Centre,Kharghar,Mumbai 410210,India

出　　处：《Military Medical Research》2025年第1期16-35,共20页军事医学研究(英文版)

基　　金：Department of Biotechnology(DBT,Govt of India)(BT/PR31315/MED/32/667/2019);DBT along with Wadhwani Research Center for Bioengineering,IIT Bombay(BT/INF/22/SP23026/2017);Department of Biotechnology(DBT,Govt of India)(BT/INF/22/SP17358/2016).

摘　　要：Background:Targeted T-cell therapy has emerged as a promising strategy for the treatment of hematological malignancies.However,its application to solid tumors presents significant challenges due to the limited accessibility and heterogeneity.Localized delivery of tumor-specific T-cells using biomaterials has shown promise,however,procedures required for genetic modification and generation of a sufficient number of tumor-specific T-cells ex vivo remain major obstacles due to cost and time constraints.Methods:Polyethylene glycol(PEG)-based three-dimensional(3D)scaffolds were developed and conjugated with positively charged poly-L-lysine(PLL)using carbamide chemistry for efficient loading of lentiviruses(LVs)carrying tumor antigen-specific T-cell receptors(TCRs).The physical and biological properties of the scaffold were extensively characterized.Further,the scaffold loaded with OVA-TCR LVs was implanted in B16F10 cells expressing ovalbumin(B16-OVA)tumor model to evaluate the anti-tumor response and the presence of transduced T-cells.Results:Our findings demonstrate that the scaffolds do not induce any systemic inflammation upon subcutaneous implantation and effectively recruit T-cells to the site.In B16-OVA melanoma tumor-bearing mice,the scaffolds efficiently transduce host T-cells with OVA-specific TCRs.These genetically modified T-cells exhibit homing capability towards the tumor and secondary lymphoid organs,resulting in a significant reduction of tumor size and systemic increase in anti-tumor cytokines.Immune cell profiling revealed a significantly high percentage of transduced T-cells and a notable reduction in suppressor immune cells within the tumors of mice implanted with these scaffolds.Conclusions:Our scaffold-based T-cell therapy presents an innovative in situ localized approach for programming T-cells to target solid tumors.This approach offers a viable alternative to in vitro manipulation of T-cells,circumventing the need for large-scale in vitro generation and culture of tumor-specific T-cells.It off

关 键 词：Polyethylene glycol diacrylate POLY-L-LYSINE LENTIVIRUSES T-cell therapy B16F10-OVA melanoma 

分 类 号：R730.51[医药卫生—肿瘤]