Genetically Engineered Macrophages Neutralize Immunosuppressive Tumor Microenvironment
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Solution Overview
Problem
Current immunotherapies for solid tumors, such as glioblastoma, are ineffective due to the immunosuppressive tumor microenvironment that prevents immune cells from targeting and eliminating cancer cells, despite successes in hematological neoplasms and some solid tumors.
Innovation Solution
Genetically engineered macrophages are introduced into the brain to neutralize the tumor microenvironment by promoting a pro-inflammatory response and enhancing immune activity, using a lentiviral expression system to stabilize transgene expression and avoid immune suppression, and CRISPR to knock out immunosuppressive genes like IL-10 and PD-L1.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If immunotherapies are administered to treat solid tumors, then immune response is activated, but the immunosuppressive tumor microenvironment prevents effective immune cell function
Solution Approach 1:
The patent uses genetically engineered macrophages as intermediary cells that are introduced into the tumor microenvironment to mediate between the immune system and tumor cells. These engineered macrophages express chimeric antigen receptors (CARs) that enable them to recognize and respond to tumor-associated antigens while modulating the immunosuppressive microenvironment, thereby facilitating effective immune cell function against solid tumors
Solution Approach 2:
The patent alters the functional parameters of macrophages through genetic engineering, transforming them from immunosuppressive cells into immunostimulatory cells. By introducing CARs and modifying gene expression profiles, the macrophages change their phenotype to produce pro-inflammatory cytokines and enhance antigen presentation, thereby reversing the immunosuppressive characteristics of the tumor microenvironment
2Reliability
If genetically engineered macrophages are introduced to transform the tumor microenvironment, then anti-tumor immunity is enhanced, but there is risk of causing morbidity or accelerating tumor growth
Solution Approach 1:
The patent incorporates feedback mechanisms where the genetically engineered macrophages respond to tumor-associated signals and adjust their immune-modulating functions accordingly. The CAR-expressing macrophages detect tumor antigens and activate immune responses only in the presence of tumor cells, while also sensing the tumor microenvironment conditions to regulate cytokine production and cell recruitment, thereby preventing inappropriate immune activation that could cause morbidity or tumor progression
Solution Approach 2:
The patent extracts and removes the harmful immunosuppressive functions from the tumor microenvironment by engineering macrophages to specifically target and counteract suppressive mechanisms. The engineered macrophages are designed to eliminate or neutralize immunosuppressive cells and molecules while preserving normal tissue function, thereby enhancing anti-tumor immunity without causing harmful side effects
Data Source
AI summary
Disclosed are methods of making a genetically modified immune cell for modifying a tumor microenvironment (TME) and methods of modifying a tumor microenvironment (TME). In some embodiments, the method can include delivering a first vector to an immune cell, wherein the first vector comprises a nucleic acid encoding a protein that induces T-cell proliferation, promotes persistence and activation of endogenous or adoptively transferred NK or T cells and/or induces production of an interleukin, an interferon, a PD-1 checkpoint binding protein, HMGB1, MyD88, a cytokine or a chemokine. Methods of modulating the suppression of the immune response in a tumor microenvironment, minimizing the proliferation of tumor and suppressive cells, and increasing the efficiency of an anti-cancer therapy, anti-infection therapy, antibacterial therapy, anti-viral therapy, or anti-tumoral therapy are also provided.