T-cell based approaches have been highly successful for the treatment of hematological malignancies, but so far they have failed to demonstrate effectiveness in the treatment of solid tumors. Macrophages could overcome this limitation: As a key determinant of the tumor microenvironment (TME) they can infiltrate solid tumors, kill tumor cells and confer tumoricidal activity upon adjacent immune cells within the TME. Furthermore, macrophage-based cell therapy was recently demonstrated to be safe in phase I trials.
Unfortunately, there are two serious roadblocks preventing application of this potential. First, unlike Tcells, human macrophages cannot be expanded in cell culture, limiting their utility for cell therapy due to insufficient cell numbers. Second, wildtype macrophages are commonly converted by tumor cell signals into a M2-like polarization state, which rather supports tumor growth and metastatic spread. We have explored how genetically engineered human macrophages can provide solutions to both of these problems. With ONCOMAC we worked on the translation of our encouraging results into a product fulfilling the European Medicines Agency (EMA)’s regulatory requirements for an ATIMP so that “First-in-human” studies with our genetically engineered human macrophages can be initiated.
The objectives were
A. Development of in vitro assays for the oncolytic activity of genetically engineered macrophages
B. Development of a simple in vitro assay for the detection of undifferentiated iPS cells
C. Development of a FACS assay for the characterization of the process intermediate and end product
D. Assaying the pharmacokinetics and pharmacodynamics of genetically engineered human macrophages in vivo
E. Preparing the proof-of-concept study in humanized mice
F. IP generation
