HSPC-Engineered iNKT Cells for Sustained Immune Function
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Solution Overview
Problem
Existing clinical trials for iNKT cell-based therapies face limitations due to low frequency, high variability, and rapid depletion of endogenous iNKT cells, leading to unsatisfactory results, particularly in cancer treatments, and the use of induced pluripotent stem cells introduces risks of oncogenesis from exogenous nuclear reprogramming factors.
Innovation Solution
Engineering hematopoietic stem and progenitor cells with exogenous invariant natural killer T cell receptor (iNKT TCR) nucleic acid molecules, avoiding oncogenes like Oct4, Sox2, and c-Myc, and generating functional iNKT cells through transduction and engraftment, which follow a developmental path similar to endogenous iNKT cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If endogenous iNKT cells are directly stimulated or expanded ex vivo, then short-term immune response is achieved, but the cells rapidly deplete and provide only limited long-term benefits
Solution Approach 1:
The patent applies preliminary action by genetically modifying hematopoietic stem and progenitor cells (HSPCs) with iNKT cell receptor genes before transplantation. This pre-engineering ensures that the regenerated iNKT cells will be present in sufficient quantities and maintain functionality long-term, rather than attempting to expand the already scarce endogenous cells after transplantation.
Solution Approach 2:
The patent segments the approach into two distinct components: (1) genetic modification of HSPCs with specific iNKT cell receptor nucleic acid sequences, and (2) transplantation of these modified cells to regenerate the iNKT cell population. This segmentation allows for controlled generation of functional iNKT cells without relying on the variable endogenous population.
2Ease of manufacture
If induced pluripotent stem cells are used to engineer iNKT cells, then cell production is achieved, but oncogenesis risk increases due to exogenous nuclear reprogramming factors
Solution Approach 1:
The patent extracts and eliminates the harmful exogenous reprogramming factors (Oct4, Sox2, Klf4, c-Myc) from the iPS cell generation process. Instead of using full iPS cell reprogramming, the invention selectively introduces only the necessary iNKT cell receptor nucleic acid sequences into HSPCs, thereby achieving iNKT cell engineering without the oncogenic risk of complete pluripotent reprogramming.
Solution Approach 2:
The patent uses a simplified, safer alternative to full iPS cell reprogramming by directly transducing HSPCs with iNKT receptor genes. This approach uses transient, targeted genetic modification rather than permanent introduction of oncogenic reprogramming factors, effectively replacing a high-risk method with a lower-risk approach that achieves the same functional outcome.
3Quantity of substance
If high numbers of iNKT cells are required for therapy, then cell expansion is attempted, but the variability and low frequency of endogenous cells limit success
Solution Approach 1:
The patent enables the engineered HSPCs to self-generate and self-renew into functional iNKT cells within the host organism. The modified stem cells serve themselves by differentiating into the desired cell type without requiring external continuous supply or expansion, ensuring consistent and reliable production of therapeutic iNKT cells.
Data Source
AI summary
Disclosed herein are invariant natural killer T (iNKT) cells engineered using hematopoietic stem and progenitor cells (HSPCs) and methods of making and using thereof.