1. Academic Validation
  2. Autologous patient-derived exhausted nano T-cells exploit tumor immune evasion to engage an effective cancer therapy

Autologous patient-derived exhausted nano T-cells exploit tumor immune evasion to engage an effective cancer therapy

  • Mol Cancer. 2024 May 9;23(1):83. doi: 10.1186/s12943-024-01997-x.
José L Blaya-Cánovas # 1 2 3 Carmen Griñán-Lisón # 2 3 4 5 Isabel Blancas 2 6 7 Juan A Marchal 2 5 8 9 César Ramírez-Tortosa 2 10 Araceli López-Tejada 2 3 4 Karim Benabdellah 3 Marina Cortijo-Gutiérrez 3 M Victoria Cano-Cortés 2 3 11 Pablo Graván 2 5 12 Saúl A Navarro-Marchal 2 5 8 12 Jaime Gómez-Morales 13 Violeta Delgado-Almenta 3 Jesús Calahorra 1 2 3 María Agudo-Lera 3 Amaia Sagarzazu 3 Carlos J Rodríguez-González 6 Tania Gallart-Aragón 7 14 Christina Eich 15 Rosario M Sánchez-Martín 2 3 11 Sergio Granados-Principal 16 17 18
Affiliations

Affiliations

  • 1 UGC de Oncología Médica, Hospital Universitario de Jaén, Jaén, 23007, Spain.
  • 2 Instituto de Investigación Biosanitaria ibs.GRANADA, University Hospitals of Granada- University of Granada, Granada, 18100, Spain.
  • 3 Centre for Genomics and Oncological Research, GENYO, Pfizer/University of Granada/Andalusian Regional Government, Granada, 18016, Spain.
  • 4 Department of Biochemistry and Molecular Biology 2, Faculty of Pharmacy, University of Granada, Campus de Cartuja s/n, Granada, 18071, Spain.
  • 5 Excellence Research Unit "Modeling Nature" (MNat), University of Granada, Granada, 18100, Spain.
  • 6 UGC de Oncología, Hospital Universitario San Cecilio, Granada, 18016, Spain.
  • 7 Department of Medicine, University of Granada, Granada, 18016, Spain.
  • 8 Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research, (CIBM), University of Granada, Granada, 18100, Spain.
  • 9 Department of Human Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada, 18016, Spain.
  • 10 UGC de Anatomía Patológica, Hospital San Cecilio, Granada, 18016, Spain.
  • 11 Department of Medicinal & Organic Chemistry and Excellence Research Unit of "Chemistry Applied to Biomedicine and the Environment", Faculty of Pharmacy, University of Granada, Campus de Cartuja s/n, Granada, 18071, Spain.
  • 12 Department of Applied Physics, Faculty of Science, University of Granada, Granada, 18071, Spain.
  • 13 Laboratorio de Estudios Cristalográficos IACT-CSIC-UGR, Armilla, 18100, Spain.
  • 14 UGC de Cirugía General y del Aparato Digestivo, Hospital Universitario San Cecilio, Granada, 18016, Spain.
  • 15 Translational Nanobiomaterials and Imaging, Department of Radiology, Leiden University Medical Center, Leiden, 2333, The Netherlands.
  • 16 Instituto de Investigación Biosanitaria ibs.GRANADA, University Hospitals of Granada- University of Granada, Granada, 18100, Spain. [email protected].
  • 17 Centre for Genomics and Oncological Research, GENYO, Pfizer/University of Granada/Andalusian Regional Government, Granada, 18016, Spain. [email protected].
  • 18 Department of Biochemistry and Molecular Biology 2, Faculty of Pharmacy, University of Granada, Campus de Cartuja s/n, Granada, 18071, Spain. [email protected].
  • # Contributed equally.
Abstract

Background: Active targeting by surface-modified nanoplatforms enables a more precise and elevated accumulation of nanoparticles within the tumor, thereby enhancing drug delivery and efficacy for a successful Cancer treatment. However, surface functionalization involves complex procedures that increase costs and timelines, presenting challenges for clinical implementation. Biomimetic nanoparticles (BNPs) have emerged as unique drug delivery platforms that overcome the limitations of actively targeted nanoparticles. Nevertheless, BNPs coated with unmodified cells show reduced functionalities such as specific tumor targeting, decreasing the therapeutic efficacy. Those challenges can be overcome by engineering non-patient-derived cells for BNP coating, but these are complex and cost-effective approaches that hinder their wider clinical application. Here we present an immune-driven strategy to improve nanotherapeutic delivery to tumors. Our unique perspective harnesses T-cell exhaustion and tumor immune evasion to develop a groundbreaking new class of BNPs crafted from exhausted T-cells (NExT) of triple-negative breast Cancer (TNBC) patients by specific culture methods without sophisticated engineering.

Methods: NExT were generated by coating PLGA (poly(lactic-co-glycolic acid)) nanoparticles with TNBC-derived T-cells exhausted in vitro by acute activation. Physicochemical characterization of NExT was made by dynamic LIGHT scattering, electrophoretic LIGHT scattering and transmission electron microscopy, and preservation and orientation of immune checkpoint receptors by flow cytometry. The efficacy of chemotherapy-loaded NExT was assessed in TNBC cell lines in vitro. In vivo toxicity was made in CD1 mice. Biodistribution and therapeutic activity of NExT were determined in cell-line- and autologous patient-derived xenografts in immunodeficient mice.

Results: We report a cost-effective approach with a good performance that provides NExT naturally endowed with immune checkpoint receptors (PD1, LAG3, Tim3), augmenting specific tumor targeting by engaging cognate ligands, enhancing the therapeutic efficacy of chemotherapy, and disrupting the PD1/PDL1 axis in an immunotherapy-like way. Autologous patient-derived NExT revealed exceptional intratumor accumulation, heightened chemotherapeutic index and efficiency, and targeted the tumor stroma in a PDL1+ patient-derived xenograft model of triple-negative breast Cancer.

Conclusions: These advantages underline the potential of autologous patient-derived NExT to revolutionize tailored adoptive Cancer nanotherapy and chemoimmunotherapy, which endorses their widespread clinical application of autologous patient-derived NExT.

Keywords

Biomimetic nanoparticles; Immune checkpoint; Immune evasion; Immunotherapy; PD1; PDL1; Patient-derived xenograft; T-cell exhaustion; Triple-negative breast cancer.

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