Dual TCR-CAR Stem Cells for Sustained Multi-Antigen Tumor Targeting
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Solution Overview
Problem
Current cancer treatments, including CAR-T therapy, face challenges such as cytokine storms, limited supply of CAR-T cells, and incomplete tumor destruction, particularly in metastatic cancers, necessitating improved systemic therapies.
Innovation Solution
Genetically modified stem cells, such as iPSCs, are engineered to express both a T cell receptor (TCR) and a chimeric antigen receptor (CAR) directed to multiple tumor antigens, ensuring a stable and sustained supply of T cells with dual specificity, addressing the limitations of existing CAR-T technology.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR-T therapy is used to treat cancer, then tumor destruction is achieved, but cytokine storms and limited supply of CAR-T cells occur
Solution Approach 1:
The patent segments the immune response by using two distinct receptors: TCR for recognizing tumor antigens presented by MHC molecules and CAR for direct antigen binding. This segmentation allows controlled activation and reduces uncontrolled cytokine release while maintaining effective tumor destruction
Solution Approach 2:
The patent creates dual-specific T cells that express both TCR and CAR, making these cells multi-functional. The TCR provides MHC-restricted antigen recognition while the CAR provides MHC-independent binding, giving the immune cells universal capability to respond to multiple tumor antigens and reduce cytokine storm risk
2Reliability
If CAR-T cells are produced to treat cancer, then tumor targeting is achieved, but limited supply and incomplete tumor destruction occur
Solution Approach 1:
The patent uses stem cells that can self-renew and differentiate into T cells. These stem cells are genetically modified to express both TCR and CAR, allowing them to continuously produce dual-specific T cells in vivo, thereby providing a sustained supply without repeated external infusions
Solution Approach 2:
The patent performs preliminary genetic modification of stem cells ex vivo to establish dual TCR/CAR expression before transplantation. This preliminary action ensures that the stem cells are pre-programmed to continuously generate functional dual-specific T cells upon transplantation, addressing the supply limitation
3Ease of manufacture
If single-specific T cells are used, then treatment simplicity is maintained, but incomplete tumor destruction occurs
Solution Approach 1:
The patent merges two antigen recognition systems (TCR and CAR) into a single T cell population. This combination allows the cells to recognize multiple tumor antigens through different mechanisms, improving tumor destruction completeness while maintaining a relatively straightforward genetic modification process
Data Source
AI summary
The present invention relates generally to a population of stem cells (e.g., iPSCs or HSCs) that comprise nucleic acids encoding a T cell receptor and a chimeric antigen receptor directed to multiple distinct antigenic determinants, for example two distinct tumour antigenic determinants. The present invention is also directed to a population of T cells that co-express a T cell receptor and a chimeric antigen receptor directed to multiple distinct antigenic determinants, such as two distinct tumour antigenic determinants. The cells of the present invention can be derived from chosen donors whose HLA type is compatible with significant sectors of the populations, and are useful in a wide variety of applications, in particular in the context of the therapeutic treatment of neoplastic conditions.