سابِق|تال

نهج قائم على الهياكل الخلوية الهندسة الوراثية in situ لخلايا T المضيفة في العلاج المناعي للأورام الصلبة

  • role： First author第一作者
  • Affiliation：

    Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India

Hiren Y. Dandia1,  
  • Affiliation：

    Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India

Mamatha M. Pillai1,  
  • Affiliation：

    Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai 400085, India

Deepak Sharma2,  
  • Affiliation：

    Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India

Meghna Suvarna1,  
  • Affiliation：

    Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India

Neha Dalal1,  
  • Affiliation：

    Centre of Excellence in Epigenetics, Department of Biology, Indian Institute of Science Education and Research, Pune 411008, India

Ayush Madhok3,  
  • Affiliation：

    Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Mumbai 410210, India

Arvind Ingle4,  
  • Affiliation：

    Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Mumbai 410210, India

Shubhada V. Chiplunkar4,  
  • Affiliation：

    Centre of Excellence in Epigenetics, Department of Biology, Indian Institute of Science Education and Research, Pune 411008, India

Sanjeev Galande3,  
  • role： Corresponding author通信作者
  • Affiliation：

    Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India

  • Email：prakriti@iitb.ac.in
  • Introduction：*prakriti@iitb.ac.in
Prakriti Tayalia1*

ملخص

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 offers an off-the-shelf alternative that facilitates the use of host cells instead of allogeneic cells, thereby, overcoming a major hurdle.

مفهوم

Polyethylene glycol diacrylate;Poly-L-lysine;Lentiviruses;T-cell therapy;B16F10-OVA melanoma

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