Allogeneic CAR-MAIT Cells for Off-the-Shelf Immunotherapy
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Solution Overview
Problem
Current CAR-T cell therapies using autologous T cells are patient-specific, leading to variability in potency and safety, and the use of allogeneic cells is limited by host versus graft rejection and graft versus host disease, making them costly, time-consuming, and unsuitable for widespread use.
Innovation Solution
Development of mucosal-associated invariant T (MAIT) cells expressing chimeric antigen receptors (CAR-MAIT) that are allogeneic, non-proliferative, and non-inductive of graft versus host disease, allowing for pre-manufactured, universal, and cost-effective immunotherapy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Loss of time
If allogeneic cells are used for CAR-T therapy, then production time is reduced and pre-manufacture is enabled, but host versus graft rejection and graft versus host disease occur
Solution Approach 1:
The patent extracts and removes the endogenous T cell receptor (TCR) from allogeneic T cells through genetic inactivation. This eliminates the harmful alloreactive TCR while preserving the cell's effector functions and CAR expression capability, thereby enabling safe allogeneic CAR-T therapy without GVHD
Solution Approach 2:
The patent uses an intermediary approach by selecting NKT cells or MAIT cells as intermediate cell types. These cells naturally have limited TCR repertoire and lower alloreactivity compared to conventional T cells, serving as a bridge between autologous and fully allogeneic approaches while reducing rejection risks
2Manufacturing precision
If allogeneic cells are used for CAR-T therapy, then patient-specific variability is eliminated, but graft versus host disease is triggered
Solution Approach 1:
The patent removes the harmful endogenous TCR from allogeneic T cells through genetic inactivation, eliminating the source of GVHD while maintaining consistent allogeneic cell product manufacturing with uniform potency and safety across patients
Solution Approach 2:
The patent creates universal CAR-T cell products using allogeneic cells with inactivated TCR. These universal cells can be manufactured once and used for multiple patients without triggering GVHD, achieving both product consistency and broad applicability
3Object-affected harmful factors
If NKT cells or MAIT cells are used instead of conventional T cells, then alloreactivity is reduced, but cell frequency in blood is very low
Solution Approach 1:
The patent applies preliminary enrichment and expansion steps to increase the quantity of NKT or MAIT cells before CAR transduction. This preliminary action ensures sufficient cell numbers are available for therapy while maintaining their low-alloreactive characteristics
Solution Approach 2:
The patent changes the concentration and purity parameters of NKT/MAIT cell populations through enrichment processes, increasing their frequency from trace amounts in whole blood to therapeutic levels while preserving their favorable alloreactivity profile
Data Source
Figure 1A~1B
Figure 2
Figure 3A~3B
AI summary
The present invention relates generally to immunotherapy, in particular immunotherapy for treating cancer, infectious diseases or autoimmune diseases. More specifically, the invention relates to Mucosal-Associated Invariant T (MAIT) cells expressing Chimeric Antigen Receptors (CARs), wherein the MAlT cell is allogenic with respect to the subject to be treated.