CAR-pMAC Solid Tumor Infiltration via Pluripotent Stem Cell Differentiation
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current CAR-T cell therapies for cancer face challenges such as limited targeting to cancer tissue, poor infiltration into solid cancers, functional decline due to tumor microenvironment interaction, treatment resistance due to antigen loss, and concerns about cytokine release syndrome.
Innovation Solution
Development of CAR-loaded proliferating macrophage-like cells (pMAC) derived from pluripotent stem cells, which are cytokine-dependent and allogeneic, allowing for stable quality, supply, and economic efficiency, and effective targeting and infiltration of solid cancers.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR-T cell therapy is used for cancer treatment, then antitumor effect is exerted through genetic modification of T cell receptor, but the therapy has limited effectiveness on solid cancers and faces problems such as no targeting to cancer tissue, no infiltration into cancer tissue, decreased function due to interaction with tumor microenvironment, loss of target antigen, and concerns about cytokine release syndrome
Solution Approach 1:
The patent changes the cell type parameter from T cells to macrophages, and modifies the receptor configuration from conventional CAR to dual-antigen recognition system (DART). This parameter change enables the therapy to overcome the limitations of CAR-T cells against solid cancers by utilizing macrophage's inherent ability to infiltrate tumor microenvironment and recognize multiple cancer-associated antigens simultaneously
Solution Approach 2:
The patent employs a composite receptor system combining two different antigen recognition mechanisms: a CAR component for direct cancer cell targeting and a DART component for cancer-associated antigen recognition. This composite approach enables simultaneous targeting of multiple cancer types and overcoming antigen loss through dual recognition pathways
2Reliability
If CAR-macrophage therapy is developed to improve treatment of solid cancers, then stable quality and supply are required for allogeneic cells, but current methods for differentiating pluripotent stem cells into myeloid cells with CAR are complicated and raise concerns about soaring production costs
Solution Approach 1:
The patent performs preliminary gene editing (CRISPR/Cas9) to introduce the dual-antigen recognition system into pluripotent stem cells before differentiation. This preliminary action simplifies the subsequent differentiation process by pre-establishing the therapeutic capability, avoiding the need for complex post-differentiation CAR transduction procedures and reducing production costs
3Productivity
If conventional CAR-T cell therapy is used, then treatment is provided, but cytokine release syndrome occurs and the cells experience functional decline due to interaction with tumor microenvironment
Solution Approach 1:
The patent utilizes allogeneic macrophages derived from pluripotent stem cells as disposable therapeutic cells. These cells are produced in controlled conditions, infused into patients, and do not require long-term persistence or memory function. The macrophages perform their antitumor function during circulation and then undergo natural clearance, avoiding the chronic functional decline and cytokine release issues associated with persistent CAR-T cell expansion
Data Source
Figure 1
Figure 2-1
Figure 2-2
AI summary
The present invention provides a proliferating macrophage-like cell (pMAC) characterized by proliferation in a cytokine-dependent manner, a production method thereof, and a method for producing CAR-pMAC, including (1) a step of, in a pluripotent stem cell, deleting the gene that inhibits a macrophage-like function or suppressing expression of the gene, and then inducing differentiation into a myeloid cell to obtain a macrophage-like cell (MAC) (step 1), (2) a step of expressing the gene that confers proliferating property in the MAC obtained in step 1 to obtain a proliferating macrophage-like cell (pMAC) (step 2), and (3) a step of introducing a chimeric antigen receptor (CAR) (step 3). Furthermore, the present invention provides a pharmaceutical use of CAR-pMAC. According to the present invention, it is possible to provide a novel CAR-loaded cell platform, particularly, a novel CAR-loaded cell platform superior in stable quality, stable supply, and economic efficiency, particularly, a novel CAR-loaded cell platform superior as a medicament.