IL-10 CAR CD4+ T Cells for Scalable Immune Tolerization
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Solution Overview
Problem
The production of donor-derived or autologous Tr1 cells for large-scale therapy in patients with high unmet medical needs is cumbersome and does not allow for the generation of large quantities, limiting their effectiveness in conditions like Crohn's disease and graft-versus-host disease.
Innovation Solution
Engineering CD4+ T cells to express both interleukin-10 (IL-10) and a chimeric antigen receptor (CAR), redirecting their cytotoxic properties to therapeutically useful targets other than myeloid cells while preserving immune-regulatory functions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If donor-derived or autologous Tr1 cells are produced through conventional methods, then immune-regulatory function is maintained, but production is cumbersome and large quantities cannot be generated
Solution Approach 1:
The patent combines two separate genetic modifications into a single engineered T cell: expression of IL-10 (to provide immune-regulatory function) and expression of CAR (to provide targeted cytotoxicity). This merging allows simultaneous achievement of large-scale production capability, immune regulation, and targeted therapy, resolving the contradiction between maintaining regulatory function and achieving scalable production.
Solution Approach 2:
The engineered CD4IL-10/CAR cell exhibits multi-functionality: it can suppress immune responses through IL-10 secretion, kill target cells through CAR-mediated cytotoxicity, and be produced at large scales. This universal design resolves the contradiction by making a single cell type capable of multiple therapeutic functions that were previously requiring separate cell populations.
2Adaptability or versatility
If CD4IL-10 cells are used for immune suppression, then immune-regulatory activity is achieved, but cytotoxic capability is directed only at myeloid cells limiting therapeutic versatility
Solution Approach 1:
The patent segments the cytotoxic function from the regulatory function by using two separate molecular mechanisms: IL-10 provides constitutive immune suppression, while CAR provides antigen-specific cytotoxicity. This segmentation allows the cell to maintain reliable immune-regulatory activity through IL-10 while gaining adaptability to target different antigens through various CAR designs.
Solution Approach 2:
The CAR acts as an intermediary that redirects the cytotoxic capability of the T cell toward specific antigens while IL-10 serves as an intermediary maintaining immune suppression. This dual-intermediary approach allows the cell to expand its therapeutic versatility without compromising its immune-regulatory reliability.
3Adaptability or versatility
If engineered CD4+ T cells express both IL-10 and CAR, then cytotoxic properties are redirected to useful targets, but device complexity increases
Solution Approach 1:
The patent merges two genetic modification protocols into a unified engineering approach: introducing both IL-10 expression and CAR expression into the same T cell population. This merging simplifies the overall process compared to using separate cell populations, and the dual-function cell can be produced through coordinated transduction or transgenesis followed by selection and expansion.
Data Source
AI summary
The present disclosure provides a population of CD4IL-10/CAR cells (autologous or allogeneic single-donor and allogeneic polydonor) generated by genetically modifying CD4+ T cells to express IL-10 and a chimeric antigen receptor. Further provided are methods of generating the CD4IL-10/CAR cells and methods of using the CD4IL-10/CAR cells for immune tolerization, treating GvHD, cell and organ transplantation, cancer, and other autoimmune and inflammatory disorders.