CD40 CAR-Engineered Myeloid Cells for Solid Tumor Infiltration
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Solution Overview
Problem
Current CAR T cell therapies fail to effectively treat solid tumors due to challenges in antigen specificity, physical barriers, metabolic resource limitations, and exhaustion, leading to inefficiencies in infiltrating and activating anti-tumor responses within the tumor microenvironment (TME).
Innovation Solution
Development of myeloid cells, such as macrophages, engineered with a chimeric antigen receptor (CAR) containing an extracellular antigen-binding domain for tumor antigens, a transmembrane domain, and an intracellular signaling domain comprising the CD40 cytoplasmic tail, which enhances antigen-dependent immune responses and pro-inflammatory cytokine secretion.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR T cells are used to treat solid tumors, then anti-tumor response is activated, but the therapy fails due to physical barriers and metabolic resource limitations in the tumor microenvironment
Solution Approach 1:
The patent merges the CAR construct with myeloid cells (macrophages, dendritic cells, monocytes) instead of using T cells, creating CAR-myeloid cell therapies that combine the antigen-specific killing capability of CARs with the invasive and immunomodulatory properties of myeloid cells, thereby overcoming the physical and metabolic barriers that limit CAR T cell efficacy in solid tumors
Solution Approach 2:
The patent introduces myeloid cells as intermediary carriers that express CARs, allowing the therapy to leverage the natural infiltrative and immunomodulatory capabilities of myeloid cells while maintaining CAR-mediated antigen-specific tumor targeting, thus mediating effective tumor penetration and immune activation
2Productivity
If CAR T cells infiltrate the tumor microenvironment, then tumor cells are targeted, but the cells become exhausted and lose effector function due to persistent antigen stimulation
Solution Approach 1:
The patent changes the cell type parameter from T cells to myeloid cells, which have different activation and exhaustion dynamics. Myeloid cells can maintain effector functions longer and induce more sustained anti-tumor responses, thereby changing the temporal profile of anti-tumor activity to prevent exhaustion-related functional loss
3Productivity
If myeloid cells are engineered with CAR constructs, then phagocytosis of tumor cells is enhanced, but the complexity of genetic engineering and cellular modification increases
Solution Approach 1:
The patent employs self-transducing viral vectors that automatically insert the CAR construct into myeloid cells without requiring external genetic manipulation or complex laboratory procedures. This self-service approach simplifies the engineering process while maintaining high-level CAR expression and tumor cell phagocytosis capability
Data Source
AI summary
A modified myeloid cell comprises a chimeric antigen receptor (CAR), or a modified induced pluripotent stem cell (iPS) or hematopoietic stem cell (HSC) comprising a CAR, wherein said CAR comprises an extracellular antigen-binding domain which binds to a tumor antigen or a tumor microenvironment (TME) antigen; a transmembrane domain; and an intracellular signaling domain comprising the CD40 cytotail. Therapeutic uses of the modified myeloid cell are disclosed.