NEχT: Nanobody Enabled CHImeric antigen receptor (CAR) T cells to treat glioblastoma

Chimeric antigen receptor (CAR) T cells have proven efficacy in hematological cancers but efficacy in
solid tumours is still limited. This is due to therapy shortcomings such as suboptimal CAR design and
resistance mechanisms, i.e., antigen loss and immune checkpoint (ICP) expression. My project will
tackle these issues, building on in-house clinical data, mRNA, lentiviral vector (LV) and nanobody
(Nb) technologies, and tumor spheroid and xenograft models. I will design CARs against multiple
antigens, using Nbs for antigen binding, as such improving CAR design and tackling antigen escape.
To that end, I will use a fast synthetic mRNA based screening platform to select Nbs optimal for CAR
design from available Nb collections. I will use high potential CARs and LVs to generate CAR T cells
for validation. I will armor these CAR T cells with available ICP blocking Nbs, studying the optimal
combination and constitutive versus inducible ICP blocking Nb expression. I chose glioblastoma as a
model to validate the screening platform and the Nb enabled CAR T cells or NEχT cells. CAR T cells
have gained traction for treatment of this lethal brain cancer, shown by >30 registered clinical trials
and industrial interest, with some reports of response. Thus, glioblastoma embodies the challenges
and opportunities for CAR T cells in solid tumors. My project will deliver a CAR screening platform
and effective NEχT T cells, which will be a gamechanger in the treatment of GBM and beyond.