CAR T Cells Targeting Immune Checkpoints for GVHD Treatment
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Solution Overview
Problem
Current methods for treating graft versus host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT) often result in unacceptable immunosuppression, leading to increased disease relapse or opportunistic infections, and existing prophylaxis strategies are inadequate in preventing or effectively managing GVHD.
Innovation Solution
Administration of chimeric antigen receptor (CAR) T cells or NK cells specifically directed against immune checkpoint molecules such as B7-H3, PD-1/PD-L1, TIM-3, or B7-H4, which are produced using immune cells from a donor or recipient, to selectively eliminate alloreactive T cells, thereby preventing or treating GVHD without broad immunosuppression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If high-dose systemic corticosteroids are used to treat acute GVHD, then GVHD symptoms are suppressed, but disease relapse and opportunistic infections increase due to broad immunosuppression
Solution Approach 1:
The invention segments the immune system by targeting only the pathogenic alloreactive T cells responsible for GVHD while preserving other immune functions. CAR T cells are engineered to specifically recognize and eliminate donor T cells expressing certain markers, thereby treating GVHD without causing broad immunosuppression that would compromise anti-tumor immunity and infection defense.
Solution Approach 2:
The treatment applies local quality by creating a targeted immunotherapeutic response rather than systemic immunosuppression. The CAR T cells are designed with specific chimeric antigen receptors that bind to markers on alloreactive T cells, enabling selective elimination of harmful cells while maintaining the functional integrity of the recipient's remaining immune system.
2Object-affected harmful factors
If broad immunosuppression is used to prevent GVHD, then GVHD incidence is reduced, but disease relapse rates increase due to compromised anti-tumor immunity
Solution Approach 1:
The approach segments the T cell population by selectively targeting and eliminating only the alloreactive subset that causes GVHD, while preserving non-alloreactive T cells that maintain anti-tumor immunity. This is achieved through CAR T cells engineered with specificity for markers expressed on donor alloreactive T cells but not on recipient anti-tumor T cells.
3Object-affected harmful factors
If conventional GVHD prophylaxis is used, then some protection is provided, but effectiveness is inadequate and side effects remain
Solution Approach 1:
The invention changes the fundamental parameter of GVHD prophylaxis from non-specific immunosuppression to specific targeted elimination. By engineering CAR T cells with defined antigen specificity, the treatment achieves superior effectiveness through precise targeting of alloreactive T cells, overcoming the limitations of conventional prophylaxis that provides inadequate protection with significant side effects.
Data Source
AI summary
The invention features a method for treating graft versus host disease in a human, including administering to said human a therapeutically effective amount of a cell including a chimeric antigen receptor (CAR) which is specifically directed against an immune checkpoint molecule.