Breast cancer (BC) is the leading cause of cancer deaths in women. When diagnosed early, patients have a relatively good prognosis. However, once relapse or metastasis occurs, their survival rate declines tremendously. Harnessing the immune system, in particular T-cells, holds the promise of eradicating BC-cells with exquisite precision. Moreover, the immunological memory formed by T-cells ensures long-lasting response. Several T-cell centered immunotherapies are under construction for the treatment of BC, a.o. immune checkpoint blockade and immunization strategies. This project will contribute to these types of therapies, by developing and exploiting single domain antibodies (sdAbs), also known as nanobodies (Nbs) that bind human CD3 (huCD3). These Nbs will be evaluated for noninvasive SPECT/CT-imaging of T-cells within healthy and BC- bearing huCD3 knock-in (KI) mice, assessing the translocation of T-cells to tumors upon mRNA-based immunization, as currently performed in a clinical setting. Infiltration of tumors with CD3+ T-cells can be considered a sign of therapy response, irrespective of the T-cells’ subset and represents an anchoring point for therapies designed to increase the activity of helpful CD4+ T helper 1 (TH1) cells and CD8+ cytotoxic T- lymphocytes (CTLs), while decreasing the activity of non-helpful regulatory T-cells (Tregs). We propose to develop huCD3-targeted tumor-infiltrating T-cell activators with dual activity on cytokines. These will be encoded in mRNA to allow the body to produce its own drug upon systemic injection of mRNA packed lipid nanoparticles (NPs). Combining Nbs to predict therapy response and deliver proteins on-target, as such limiting potential side effects, has high potential to improve antitumor immunity in BC and beyond.
|Effective start/end date||1/11/21 → 31/10/22|
Flemish discipline codes
- Other medical and health sciences not elsewhere classified