- Supervisors: Prof. Dr. Michael Bachmann and Dr. Anja Feldmann
- Institution: Dresden University of Technology - TU Dresden (PhD carried out at Helmholtz-Zentrum Dresden-Rossendorf (HZDR))
- Defended: 17 June 2026
- Download the PhD thesis
​Asbtract: Despite remarkable efficacy in hematologic malignancies, chimeric antigen receptor (CAR) T-cell therapy remains associated with significant toxicities, and its translation to solid tumors is limited by tumor heterogeneity and the immunosuppressive tumor microenvironment. To circumvent these limitations, several adaptor CAR platforms such as the UniCAR system have been developed. UniCAR T-cell activation relies on target modules (TM), which mediate cross-linking of CAR T-cells to target cells, subsequently leading to target cell elimination. This modular approach allows the control of effector cell activity, flexible targeting of multiple antigens, and combination of CAR-based immunotherapy with nuclear medicine applications. In the context of solid tumor, fibroblast activation protein (FAP) has emerged as a promising target for immunotheranostic approaches due to its selective overexpression in the tumor stroma. The primary aim of this thesis was therefore to design novel FAP inhibitor (FAPI)-based TMs targeting FAP for both UniCAR T-cell immunotherapy and targeted radioligand delivery. We first developed monomeric FAPI TMs combining the UAMC-1110 FAPI moiety, the NODA-GA chelator, the E5B9 UniCAR epitope, and polyethylene glycol (PEG) spacers of varying length (PEG4/12/24). Although all three constructs selectively accumulated in FAP-positive tumors in xenograft mice, only the TMs with extended spacers (PEG12 and PEG24) successfully redirected UniCAR T-cells to FAP-positive cells in vitro and in vivo. In line with computational analyses, the E5B9 epitope was inaccessible for UniCAR binding when the PEG4-based TM was bound to FAP, demonstrating that spacer length is a critical determinant of effective T-cell redirection. Building on these findings, we developed homodimeric FAPI TMs incorporating two UAMC-1110 moieties, the E5B9 epitope, an optimized PEG spacer, and an additional functional group enabling further chemical modification for diagnostic and radiotherapeutic applications. The dimeric TMs efficiently redirected UniCAR T-cells and mediated potent lysis of FAP-positive cells both in vitro and in immunodeficient mouse models. To better recapitulate the complexity of solid tumors, we further established a 3D heterospheroid model comprising prostate stem cell antigen (PSCA)-positive tumor cells and FAP-positive stromal fibroblasts. We demonstrate that the simultaneous targeting of both compartments markedly enhanced UniCAR-mediated cytotoxicity. Collectively, this work establishes monomeric and homodimeric FAPI-based adapter molecules as highly promising immunotheranostic tools for personalized diagnostic imaging and immunotherapy.
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