Allogeneic iPSC-Derived CAR-T Cells for Solid Tumor Therapy
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Solution Overview
Problem
Current CAR-T therapy for cancer is limited by high production costs, inefficient anti-tumor response in solid tumors, limited penetration of CAR T cells into the tumor microenvironment, poor persistence of CAR-T cells, and adverse events such as cytokine release syndrome and graft-versus-host disease.
Innovation Solution
Genetically engineered induced pluripotent stem cells (iPSCs) and their derivative cells are developed to express a chimeric antigen receptor (CAR) for allogenic cell therapy. These cells include a polynucleotide encoding an inactivated cell surface receptor linked with interleukin 15 (IL-15) via an autoprotease peptide, enhancing therapeutic efficacy and reducing side effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If autologous CAR-T therapy is used to achieve patient-specific anti-tumor activity, then therapeutic efficacy is improved, but production costs increase and manufacturing complexity increases
Solution Approach 1:
The patent uses allogeneic CAR-T cells derived from iPSCs as a 'copy' or substitute for autologous CAR-T cells. Instead of custom-making CAR-T cells for each patient from their own T cells (autologous), the invention creates universal donor-derived CAR-T cells that can be manufactured once and used for multiple patients, significantly reducing production costs while maintaining therapeutic efficacy through the same CAR mechanism
Solution Approach 2:
The patent changes the source parameter of CAR-T cells from patient-specific (autologous) to donor-derived (allogeneic) through iPSC differentiation. This parameter change enables standardized manufacturing processes and reduces per-patient production costs while the CAR structure and function remain unchanged to preserve therapeutic efficacy
2Reliability
If CAR-T cells are engineered to enhance anti-tumor activity, then tumor killing capability is improved, but susceptibility to immunosuppressive tumor microenvironment increases
Solution Approach 1:
The patent performs preliminary engineering of CAR-T cells during manufacturing to include enhanced survival and resistance capabilities before infusion. The cells are pre-equipped with modifications that enable them to resist the immunosuppressive tumor microenvironment beforehand, rather than attempting to overcome it after infiltration
Solution Approach 2:
The patent creates composite CAR-T cells that combine multiple functional elements: the antigen recognition domain for tumor targeting, plus additional engineered components that provide resistance to immunosuppressive microenvironment factors. This composite structure integrates both tumor-killing capability and microenvironment resistance in a single cell type
3Reliability
If CAR-T cells are engineered for high anti-tumor activity, then tumor cell killing is improved, but adverse events such as cytokine release syndrome increase
Solution Approach 1:
The patent applies controlled modulation of CAR signaling intensity or duration to achieve partial activation that is sufficient for tumor killing but insufficient to trigger excessive cytokine release. By tuning the activation level to an optimal range rather than maximum, the invention achieves therapeutic efficacy while minimizing adverse events
Solution Approach 2:
The patent introduces intermediary control mechanisms in the CAR structure or signaling pathway that act as buffers or regulators between antigen recognition and full T cell activation. This intermediary layer prevents direct, uncontrolled activation that leads to cytokine release syndrome while still allowing effective tumor cell killing
4Duration of action of stationary object
If CAR-T cells are engineered to improve persistence in vivo, then long-term anti-tumor activity is improved, but manufacturing complexity increases
Solution Approach 1:
The patent performs preliminary engineering during the manufacturing phase to incorporate persistence-enhancing modifications into CAR-T cells before infusion. By pre-installing the necessary genetic or epigenetic modifications that enable long-term survival and persistence, the invention avoids the need for complex post-infusion support or repeated administrations, thereby managing manufacturing complexity at the production stage
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The use of genetically engineered iPSCs and derivative cells improves the therapeutic efficacy of CAR-T therapy by enhancing anti-tumor activity, reducing production costs, minimizing adverse events, and improving the persistence and penetration of immune cells within the tumor microenvironment.
Implementation Method 1
an inactivated cell surface receptor and an interleukin 15 (IL-15), wherein the inactivated cell surface receptor and the IL-15 are operably linked by an autoprotease peptide
Data Source
AI summary
Provided are polynucleotides encoding inactivated cell surface receptors. Also provided are genetically engineered induced pluripotent stem cells (iPSCs) and derivative cells thereof expressing a chimeric antigen receptor (CAR) and methods of using the same. Also provided are compositions, polypeptides, vectors, and methods of manufacturing.