Central Memory T Cells Engineered to Avoid GVHD in Immunotherapy
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing adoptive cell therapies face challenges with graft rejection and graft versus host disease (GVHD) when using genetically modified T cells, particularly in cases where autologous cells are not available or feasible.
Innovation Solution
Development of genetically modified central memory T-lymphocytes (Tcm) expressing a cell surface receptor, such as a transgenic T cell receptor (tg-TCR) or chimeric antigen receptor (CAR), which are tolerance-inducing and capable of homing to lymph nodes, to induce veto activity and avoid GVHD, allowing for an 'off-the-shelf' therapeutic product.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If genetically modified T cells are used for adoptive cell therapy, then tumor-specific immunity is improved, but graft rejection and graft versus host disease occur
Solution Approach 1:
The patent uses a third-party donor as an intermediary to generate T cells that are allogeneic to the patient but have been selectively expanded against tumor antigens. These T cells act as mediators that provide tumor-specific immunity without causing severe graft versus host disease, as they are depleted of alloreactive clones and enriched for tumor-specific clones.
Solution Approach 2:
The patent applies local quality by selectively enriching for tumor-specific T cell clones while depleting alloreactive clones. This creates a localized functional quality where the T cell product has high tumor-specificity but reduced capacity to cause graft versus host disease, achieving differential functionality within the same cell population.
2Object-affected harmful factors
If autologous T cells are used for therapy, then graft rejection and GVHD are avoided, but cell availability and expansion capacity are limited
Solution Approach 1:
The patent creates universal T cell products from third-party donors that can be used for multiple patients with the same tumor type. These allogeneic T cells have been engineered to recognize tumor antigens while minimizing alloreactivity, making them universally applicable without requiring individual patient cell collection and processing.
Solution Approach 2:
The patent performs preliminary expansion and selection of tumor-specific T cell clones in the third-party donor before administration to the patient. This preliminary action allows for extensive clonal expansion and selective enrichment of tumor-specific cells, overcoming the limited expansion capacity of autologous cells while maintaining safety.
3Reliability
If TIL approach is used, then tumor-specific T cells are obtained, but applicability is limited to cases where tumor mass is accessible
Solution Approach 1:
The patent uses a third-party donor as an intermediary system that can be immunized with tumor antigens from any tumor type or location. This intermediary approach bypasses the need for direct tumor access, as the donor can be immunized in vitro with tumor cells or antigens, and the resulting T cells can be administered to patients regardless of tumor accessibility.
Solution Approach 2:
The patent segments the T cell generation process into separate steps: tumor antigen preparation, donor immunization, T cell expansion, and patient administration. This segmentation allows tumor antigens to be obtained from any source (fresh tumor, frozen tumor, cell lines, or synthetic peptides), making the approach applicable to all tumor types and locations without requiring direct tumor mass access.
Data Source
AI summary
An isolated cell having a central memory T-lymphocyte (Tcm) phenotype, the cell being tolerance-inducing cell and capable of homing to the lymph nodes following transplantation, the cell being transduced to express a cell surface receptor comprising a T cell receptor signaling module is described. Methods of generating same and using same are also described.