Macrophages Resistant to Tumor-Induced Repolarization
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Solution Overview
Problem
Current approaches to reprogramming tumor-associated macrophages to an M1 phenotype for cancer treatment are unstable and face challenges with tumor-induced re-polarization, and the use of viral vectors raises safety and regulatory concerns.
Innovation Solution
Development of human macrophages with specific mutations, such as deletions in MAF and MAFB genes, that are resistant to tumor-induced re-polarization, maintaining an M1 phenotype even in environments promoting M2 polarization, thereby enhancing anti-tumor activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If macrophages are polarized towards M1-phenotype prior to administration for cancer treatment, then anti-tumor activity is improved, but the M1-phenotype becomes unstable and macrophages get re-polarized to M2-like phenotype by the tumor microenvironment
Solution Approach 1:
The patent applies preliminary anti-action by pre-modifying macrophages with chimeric antigen receptors (CARs) that specifically recognize tumor-associated antigens. This preliminary genetic engineering equips macrophages with targeted anti-tumor capabilities before they encounter the tumor microenvironment, enabling them to resist re-polarization to M2 phenotype and maintain their anti-tumor M1-like phenotype throughout therapy
Solution Approach 2:
The patent employs parameter changes by modifying the genetic composition of macrophages through CAR introduction. This genetic parameter change fundamentally alters the macrophage phenotype stability, enabling them to maintain M1-like characteristics (including MHC class II expression and pro-inflammatory cytokine production) even in the presence of M2-polarizing cytokines in the tumor microenvironment
2Reliability
If adenoviral vectors are used to genetically engineer macrophages with CARs, then anti-tumor activity is improved, but safety and regulatory issues arise due to viral vector sequences in transduced cells
Solution Approach 1:
The patent utilizes the characteristic that adenoviral DNA does not integrate into the genome and is not replicated during cell division. The viral vector serves as a temporary delivery vehicle that provides CAR expression during the therapeutic window but is naturally eliminated over time, reducing long-term safety concerns associated with persistent viral sequences in transduced cells
Solution Approach 2:
The patent addresses safety concerns beforehand by carefully selecting adenoviral vectors and controlling transduction conditions to minimize potential adverse effects. The transient nature of adenoviral persistence acts as a built-in safety mechanism, limiting the duration of viral sequence presence in therapeutic cells
Data Source
AI summary
The present invention relates to a human macrophage for use in cancer therapy, said human macrophage comprising at least one mutation in both alleles of a chromosomal gene, wherein said macrophage is resistant to tumor-induced reprogramming and/or shows anti-tumor activity. The human macrophage of the invention demonstrates typical markers of an M1 macrophage, such as the presence of MHC class II proteins, even after having been cultured in an environment which promotes M2-polarization, such as in the presence of M-CSF and/or IL4 and/or IL13. The invention also relates to a collection of human macrophages of the invention, to their use in medicine, and in particular to their use in cancer therapy such as the treatment of solid tumors as a preferred example.