Periodic Reporting for period 1 - ONCOMAC (Allogeneic Macrophages for Cancer Therapy)
Período documentado: 2022-05-01 hasta 2023-10-31
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
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
A. We have established an in vitro tumor cell killing assay for macrophages. The results are confidential at this point and the details are described in the confidential scientific report.
The tumor cell killing assay can form the basis for a potency assay for regulatory purposes.
B. We have investigated possible QC processes for demonstrating that our macrophage cell product is not contaminated with iPSCs. The results are confidential at this point and the details are described in the confidential scientific report.
C. We have obtained scRNAseq data for the intermediate and fully differentiated macrophages (final product). The results are confidential at this point and the details are described in the confidential scientific report.
D. This objective proved to be unrealistic and has been modified. The reasoning behind this is confidential at this point and the details are described in the confidential scientific report.
E. We have prepared, filed and obtained the permit for testing the antitumor activity of genetically engineered macrophages in humanized and non-humanized immunotolerant NSG mice. The results are confidential at this point and the details are described in the confidential scientific report.
F. Two patent applications have been filed as PCT applications. Additionally we have filed a new invention disclosure, a priority application based thereon was filed in 2022 and the corresponding PCT-application was filed in 2023.
The tumor cell killing assay can form the basis for a potency assay for regulatory purposes.
B. We have investigated possible QC processes for demonstrating that our macrophage cell product is not contaminated with iPSCs. The results are confidential at this point and the details are described in the confidential scientific report.
C. We have obtained scRNAseq data for the intermediate and fully differentiated macrophages (final product). The results are confidential at this point and the details are described in the confidential scientific report.
D. This objective proved to be unrealistic and has been modified. The reasoning behind this is confidential at this point and the details are described in the confidential scientific report.
E. We have prepared, filed and obtained the permit for testing the antitumor activity of genetically engineered macrophages in humanized and non-humanized immunotolerant NSG mice. The results are confidential at this point and the details are described in the confidential scientific report.
F. Two patent applications have been filed as PCT applications. Additionally we have filed a new invention disclosure, a priority application based thereon was filed in 2022 and the corresponding PCT-application was filed in 2023.
The results are confidential at this point and the details are described in the confidential scientific report.
Summary of the most important results:
• Anti-tumor activity assays established for genetically engineered macrophages;
• scRNAseq data obtained for process intermediate and final cell product
• Purity assays established
• IP-position strengthened with a new invention
Summary of the most important results:
• Anti-tumor activity assays established for genetically engineered macrophages;
• scRNAseq data obtained for process intermediate and final cell product
• Purity assays established
• IP-position strengthened with a new invention