Modified Stem Memory T Cells for Persistent Cancer Control
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
There is a long-felt need for a method to produce modified stem-cell memory T cells that can persist and effectively target cancer cells, preventing relapse by continuously recognizing antigens without causing T cell exhaustion.
Innovation Solution
The method involves introducing a transposon composition with an antigen receptor and a transposase into primary human T cells to produce modified stem memory T cells that express specific cell-surface markers, such as CD62L and CD45RA, enabling them to persist and expand, using transposons like piggyBac, Sleeping Beauty, or Tol2, and transposases like piggyBac or Sleeping Beauty, to achieve long-term engraftment and tumor eradication.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of stationary object
If traditional biologics and chemotherapeutics are used, then cancer treatment can be administered, but the need for repeat treatments arises and long-term cancer control is not achieved
Solution Approach 1:
The modified T cells are designed to self-renew and self-maintain as a stable population in the patient, continuously recognizing and targeting cancer cells without external intervention. This self-service capability eliminates the need for repeat treatments and achieves long-term cancer control.
Solution Approach 2:
The T cells are pre-modified ex vivo with antigen receptors (CARs, TCRs, or BCRs) and stem cell markers (CD335, CD127, CD45RA, CD62L) before administration. This preliminary modification enables the cells to immediately begin persistent cancer targeting upon infusion, establishing long-term control from the outset.
2Power
If modified-T cells are designed to rapidly reproduce upon antigen recognition, then tumor destruction capacity is enhanced, but T cell exhaustion through antigen-independent signaling occurs
Solution Approach 1:
The patent extracts and eliminates the problematic tonic signaling pathway by using transposon-based integration that places antigen receptors under T cell receptor (TCR) signaling control rather than constitutive expression. This removes the source of exhaustion while preserving tumor destruction capacity through antigen-driven activation only.
Solution Approach 2:
The T cell population is designed to be dynamic rather than static, with continuous self-renewal and differentiation capabilities. The stem cell memory phenotype (CD335+ CD127+ CD45RA+ CD62L+) enables the cells to adaptively respond to antigen challenges while maintaining a stable, non-exhausted population through regulated proliferation.
3Adaptability or versatility
If stem cell-like modified-T cells are used, then self-renewal capacity and multipotent capacity are enhanced, but manufacturing complexity increases
Solution Approach 1:
The manufacturing process is segmented into distinct modular steps: (1) isolation and activation of primary T cells, (2) transposon-based genetic modification with antigen receptor and stem cell marker genes, (3) expansion and selection of modified T cells with desired phenotype, and (4) quality control and infusion. This segmentation simplifies each step while achieving the complex goal of generating stem cell-like modified T cells.
Solution Approach 2:
The patent utilizes specific parameter changes in the transposon system (e.g., using Sleeping Beauty or piggyBac transposons with specific promoter constructs) to control the expression of stem cell markers (CD335, CD127, CD45RA, CD62L) and antigen receptors. By adjusting these molecular parameters, the desired stem cell-like phenotype is achieved with standardized manufacturing protocols.
4Duration of action of stationary object
If a stable population of modified T cells is maintained, then long-term engraftment and cancer control are achieved, but initial treatment effectiveness may be reduced
Solution Approach 1:
The patent merges multiple functional capabilities into a single cell population: (1) stem cell memory phenotype for long-term persistence and self-renewal, (2) antigen receptor (CAR, TCR, or BCR) for cancer recognition, and (3) effector T cell functions for tumor destruction. This combination enables both immediate tumor targeting and long-term engraftment within the same cell population, eliminating the trade-off between initial effectiveness and long-term control.
Data Source
AI summary
The disclosure provides a method of producing modified stem memory T cells (e.g. CAR-T cells) for administration to a subject as, for example an adoptive cell therapy.