HER2 bispecific CAR Natural Killer cells as advanced medicinal therapy to target HER2 positive solid tumors (N-KANCER²)

Fiche projet

Année

2026

Appel à projets

Appel à projets « Soutien à l'émergence de projets transfrontaliers » (Cancéropôle Est)

Acronyme

N-KANCER²

Resumé

HER2 is a receptor overexpressed in several aggressive cancers, including breast, gastric, ovarian and colorectal tumors. Although monoclonal antibodies targeting this antigen, such as Herceptin, have improved patient outcomes, resistance, limited tumor penetration and immune escape mechanisms—particularly via PD-L1 check point expression remain major challenges.

To overcome these limitations, we propose to generate primary NK cells expressing a bicistronic HER2/PDL1 chimeric antigen receptor (CAR) using a non-viral Sleeping Beauty transposon system.

The CAR construct incorporates single-domain antibodies (VHH) targeting both HER2 and PD-L1, allowing dual tumor targeting while counteracting immune checkpoint–mediated immunosuppression. This design aims to enhance tumor specificity, limit escape mechanisms, and improve efficacy within an immunosuppressive tumor microenvironment.

The project has three main objectives:
(1) demonstrate the feasibility of engineering primary NK cells using the Sleeping Beauty system;
(2) validate in vitro anti-tumor efficacy in 2D or 3D using different cell lines (HER2+/- , PDL-1+/-).
(3) compare functional profiles of CAR-NK and CAR-T cells under normal and immunosuppressive conditions.

Success criteria include ≥20% CAR expression before expansion, ≥50% cell viability post-transfection, and ≥50% specific cytotoxicity against HER2+/PDL1+ tumor cells.

This cross-border collaboration between Nancy (France) and the Luxembourg Institute of Health combines expertise in NK biology, molecular engineering, organoid modeling and ATMP production. If successful, the project will pave the way for GMP development and a regional Phase I clinical trial in HER2-positive solid tumors within the Grand Est region.

Avec Dr Carole DEVAUX (Luxembourg Institute of Health LIH)