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International projects source: SICRIS

Generation of nanobodies against immunomodulating checkpoint receptors in glioblastoma tumor cells

Researchers (2)
no. Code Name and surname Research area Role Period No. of publicationsNo. of publications
1.  38279  PhD Ivana Jovchevska  Biochemistry and molecular biology  Head  2020 - 2022  87 
2.  23549  PhD Robert Roškar  Pharmacy  Researcher  2020 - 2022  304 
Organisations (2)
no. Code Research organisation City Registration number No. of publicationsNo. of publications
1.  0381  University of Ljubljana, Faculty of Medicine  Ljubljana  1627066  48,402 
2.  0787  University of Ljubljana, Faculty of Pharmacy  Ljubljana  1626973  17,216 
Abstract
Glioblastoma is the most aggressive intrinsic brain tumor in adults. In spite of maximal therapy consisting of surgery, radiotherapy and chemotherapy, glioblastoma remains largely incurable with a median overall survival of less than 15 months. Preclinical and early clinical research in immunotherapy for brain tumors has a track record of almost 20 years and indicated that an immune reaction against the tumor in the brain can be elicited and that several types of immunotherapy are feasible, safe and can result in anecdotical cases of long-term surviving patients in a good quality of life. Nevertheless, immunotherapy for brain cancer has not entered the arena of standard clinical practice unlike many other cancer types. One of the main reasons is that virtually all large immunotherapy trials for glioblastoma have ignored the brain specific constitution of the immune system and have focused on the same immune checkpoint targets as for peripheral tumors. However, current expression data suggest that other checkpoint regulators apart from PD-L1 are more abundantly expressed by GBM tumor cells, including members of the B7 family, and should therefore be considered as well. For these alternative targets, reagents to study their functional role are still largely missing however. In this project, we therefore aim to generate nanobodies against the 4 most abundantly expressed immunomodulating checkpoint receptors in glioblastoma tumor cells. This will be done by screening and expanding a pre-existing library of nanobodies that was generated following the immunization with a patient-derived glioblastoma cell line. Panning and selection will be done using the extracellular domains coupled to Fc-fragments, following binders will be selected using high and low expressing patientderived glioblastoma cell lines and negative controls (either other tumor cells or Crispr inactivated cells). Finally, using competition assays, we will select those nanobodies that are able to prevent the binding of the endogenous ligand to each receptor. This project will generate the foundation for novel reagents that can be used to assess the importance of the variety of checkpoint molecules in the modulation of the immune responses in the brain. Once nanobodies have been identified, they will be assessed in preclinical mouse models for their potential activities.
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