Replacement of microglia and tumor-associated macrophages as a novel cell therapy for pediatric high-grade gliomas

Projektbeschreibung

Die Tumormikroumgebung bei pädiatrischen Gliomen umprogrammieren

Tumorassoziierte Makrophagen (TAMs) sind Immunzellen, die in Tumore eindringen und oftmals das Krebswachstum fördern, indem sie eine immunsuppressive Umgebung schaffen. Bei aggressiven Hirntumoren mit schlechter Prognose wie etwa hochgradig malignen Gliomen im Kindesalter, sind TAMs besonders zahlreich vorhanden, so dass sie ein vielversprechendes therapeutisches Ziel darstellen. Das ERC-finanzierte Projekt REPLACE-TAM hat das Ziel, eine neuartige adoptive Zelltherapie zu entwickeln, bei der native TAMs und Mikroglia mittels hämatopoetischer Transplantation durch myeloide gespendete Stammzellen ersetzt werden. Die Idee besteht darin, die Tumormikroumgebung mit gentechnisch veränderten gespendeten Zellen so umzuprogrammieren, dass die Immunsuppression gestört oder Tumorantigene direkt erkannt werden, und hierdurch eine stark krebshemmende Wirkung zu erzielen.

Ziel

Pediatric high-grade gliomas are aggressive central nervous system (CNS) tumors with poor prognosis and no curative treatment options. Tumor-associated macrophages (TAM) represent one of the most abundant cell types of the tumor microenvironment (TME), and directly contribute to tumor-promoting and immunosuppressive mechanisms. Novel methods of CNS myeloid cell replacement provide a unique opportunity to effectively modify this critical tumor component. This project aims to overcome current treatment limitations through the preclinical development of adoptive cell therapeutic strategies targeting TAM in high-grade gliomas to reprogram the TME immune state:

Through the depletion of TAM and microglia, combined with the transplantation of hematopoietic donor cells, the TME will be repopulated with graft-derived myeloid cells. We will investigate the resulting immunological and clinical impact in different models of high-grade glioma. To further increase the effectiveness of this approach, we will perturb dysfunctional immune pathways in donor cells. Transplanted gene-edited cells will permanently disrupt the immunosuppressive state of the TME and empower an enduring anti-cancer response by the host’s adaptive immune system. In an orthogonal approach, we will engineer donor cells that – after myeloid differentiation in the CNS – are able to specifically recognize tumor antigens and actively eliminate cancer cells.

Collectively, my group will pioneer a novel treatment modality against brain cancer by replacing the CNS myeloid niche population with hematopoietic cells that can be engineered to withstand mechanisms of tumor resistance and attack malignant targets. The applicability of this approach in different models of pediatric high-grade glioma will emphasize its translational relevance.