Allogeneic EV-Loaded Dendritic Cells for MSS CRC T-Cell Infiltration
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Solution Overview
Problem
Existing immune checkpoint inhibitor (ICI) therapies for colorectal cancer (CRC) are ineffective in the majority of patients with microsatellite stable (MSS) phenotype, highlighting the need to understand intrinsic resistance mechanisms and enhance tumor T cell infiltration.
Innovation Solution
Development of dendritic cells (DCs) contacted ex-vivo with allogeneic extracellular vesicles (EVs) lacking microRNA-424 expression to stimulate an anti-tumor immune response, increasing CD8+ T cell activation and tumor infiltration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If immune checkpoint inhibitor (ICI) therapies are used for colorectal cancer treatment, then therapeutic avenues are broadened for MSI-H subtype patients, but the therapies remain ineffective for the majority of MSS phenotype patients
Solution Approach 1:
The patent uses dendritic cells as intermediary carriers to deliver modified extracellular vesicles to the tumor microenvironment. These DCs act as mediators that bridge the gap between the immune system and tumor cells, enabling T cell activation specifically in MSS CRC tumors without affecting the broad applicability of ICI therapies for other subtypes.
Solution Approach 2:
The invention modifies the immune response locally at the tumor site by using tumor-derived EVs that are specifically engineered to overcome resistance mechanisms in MSS CRC. The localized delivery of modified EVs through DCs creates a targeted immunotherapeutic effect that addresses MSS-specific resistance without compromising the effectiveness of ICIs for MSI-H patients.
2Ease of operation
If standard ICI therapies are administered, then treatment is simplified and broadly applicable, but tumor T cell infiltration remains insufficient in MSS-CRC cases
Solution Approach 1:
The patent employs dendritic cells that are pre-loaded with modified extracellular vesicles ex vivo before administration. This preliminary preparation ensures that the DCs are primed and ready to deliver the therapeutic cargo immediately upon contact with tumor antigens, thereby accelerating T cell infiltration without complicating the overall treatment protocol.
Solution Approach 2:
The modified EVs carry cargo that enables them to autonomously overcome resistance mechanisms and activate T cells within the tumor microenvironment. The EVs self-regulate their immunomodulatory function by targeting specific molecular pathways that inhibit T cell infiltration in MSS CRC, thereby increasing infiltration without requiring complex external intervention.
3Stability of the object's composition
If extracellular vesicles with miR-424 are used, then tumor cell communication is maintained, but immune suppression is enhanced and T cell response is inhibited
Solution Approach 1:
The patent extracts and removes miR-424 from the extracellular vesicles through genetic modification of the donor tumor cells. By eliminating this specific microRNA from the EV cargo, the invention removes the immune-suppressive component while preserving other beneficial signaling molecules that maintain tumor cell communication and identity.
Solution Approach 2:
The invention changes the molecular composition parameter of the EVs by modifying the expression levels of miR-424 in the donor cells. This parameter change transforms the EVs from immune-suppressive to immune-stimulatory, allowing them to enhance T cell response while maintaining other critical functions through controlled modification of specific molecular parameters.
Data Source
AI summary
The present invention provides compositions of dendritic cells contacted with extracellular vesicles and methods of use thereof. The extracellular vesicles lack or contain a reduce amount of microRNA-424. The dendritic cells may be administered to a subject diagnosed with cancer to treat the cancer or stimulate an anti-tumor response in the subject.