Alloreactivity-Depleted CTLs for Off-the-Shelf Immunotherapy
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Solution Overview
Problem
Existing adoptive cell therapies face challenges with graft rejection and graft versus host disease due to alloreactivity in genetically modified T cells, limiting their therapeutic potential and requiring autologous cell sources and individualized manufacturing.
Innovation Solution
Development of genetically modified cytotoxic T-lymphocytes (CTLs) devoid of alloreactivity and central memory phenotype, expressing a cell surface receptor such as a transgenic T cell receptor (tg-TCR) or chimeric antigen receptor (CAR) to induce tolerance and target specific antigens, enabling off-the-shelf therapeutic applications.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If genetically modified T cells are used in adoptive cell therapy, then anti-tumor activity is improved, but graft versus host disease and graft rejection occur due to alloreactivity
Solution Approach 1:
The patent extracts and removes the alloreactive central memory T cell population from the donor T cells before generating the therapeutic product. This depletion step eliminates the harmful alloreactive cells that would cause graft versus host disease and graft rejection, while preserving the tumor-specific reactive T cells for therapeutic use.
Solution Approach 2:
The patent changes the phenotypic parameters of the donor T cells by selectively depleting central memory T cells (CD45RA- CD62L+ CD45RO+) and enriching for effector memory T cells (CD45RA+ CD62L- CD45RO+). This parameter change in cell population composition eliminates alloreactivity while maintaining anti-tumor activity.
2Object-affected harmful factors
If autologous cell sources are used to avoid alloreactivity, then graft versus host disease is prevented, but manufacturing complexity and cost increase due to individualized production
Solution Approach 1:
The patent creates a universal donor T cell product that can be used for multiple patients by depleting alloreactive central memory T cells. This single donor-derived product can be administered to different recipients without causing graft versus host disease, eliminating the need for individualized autologous manufacturing while maintaining safety.
Solution Approach 2:
The patent enables the use of allogeneic donor T cells that can be produced once and used multiple times (off-the-shelf product), rather than requiring expensive and complex individualized autologous cell manufacturing for each patient. The depleted alloreactive phenotype makes the product universally applicable.
3Duration of action of stationary object
If central memory T cells are present in the therapeutic product, then long-term persistence is improved, but alloreactivity and graft versus host disease occur
Solution Approach 1:
The patent extracts and removes the harmful central memory T cell population (CD45RA- CD62L+ CD45RO+) that would cause alloreactivity, while preserving the effector memory T cells that provide anti-tumor activity. This selective removal eliminates the source of graft versus host disease while maintaining therapeutic function.
Data Source
AI summary
An isolated cytotoxic T-lymphocyte (CTL), said CTL being a tolerance inducing cell and substantially depleted of alloreactivity, and wherein said CTL does not comprise a central memory T- lymphocyte (Tcm) phenotype, the CTL being transduced to express a cell surface receptor comprising a T cell receptor signaling module, is disclosed. Methods of generating same and using same are also disclosed.