CD8-Depleted Allogeneic Lymphocyte Infusion for Tumor Immunity
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Cancer treatment is hindered by functional defects in patient's CD4+ T cells, leading to unresponsiveness of CD8+ T cells, and existing allogeneic T cell therapies risk sustained engraftment and graft-versus-host disease.
Innovation Solution
Infusion of allogeneic lymphocytes with CD4+ T cells, depleted of CD8+ T cells and regulatory T cells, to provide exogenous CD4+ T cell help for tumor-reactive CD8+ T cells, combined with chemotherapy to promote homeostatic expansion and minimize engraftment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If allogeneic T cell therapy is administered to treat cancer, then anti-tumor immunity is enhanced, but graft-versus-host disease and sustained engraftment occur
Solution Approach 1:
The patent extracts and removes CD8+ T cells from the allogeneic lymphocyte infusion, retaining only CD4+ T cells. This selective removal prevents graft-versus-host disease while preserving the ability to provide exogenous CD4+ help for anti-tumor immunity through homeostatic expansion in the recipient.
Solution Approach 2:
The patent employs transiently engrafting donor CD4+ T cells that are intentionally designed to be short-lived in the recipient. These cells provide temporary exogenous help to expand recipient CD8+ T cells and activate anti-tumor immunity, then are rejected by the recipient's immune system, avoiding sustained engraftment and graft-versus-host disease.
2Object-generated harmful factors
If CD8+ T cells are depleted from donor lymphocytes, then graft-versus-host disease is reduced, but anti-tumor effector cells are lost
Solution Approach 1:
The patent enables the recipient's own CD8+ T cells to serve as the anti-tumor effector population. By providing exogenous CD4+ help through transient donor cells, the recipient's endogenous CD8+ T cells are activated and expanded to perform the anti-tumor function, eliminating the need for donor CD8+ T cells while maintaining therapeutic efficacy.
3Productivity
If chemotherapy is administered prior to lymphocyte infusion, then homeostatic expansion of transferred lymphocytes is promoted, but myeloid-derived suppressor cells and regulatory T cells increase
Solution Approach 1:
The patent administers chemotherapy prior to lymphocyte infusion to pre-condition the recipient's immune system. This preliminary treatment induces transient lymphopenia that promotes homeostatic expansion of the transferred CD4+ T cells while the timing and dosing are optimized to minimize the generation of suppressive cell populations.
Data Source
AI summary
The invention provides methods and compositions for administration of allogeneic lymphocytes as an exogenous source of CD4+ T cell help for endogenous, tumor-reactive CD8+ T cells. Depletion of CD8+ T cells from the donor lymphocyte infusion reduces the risk of sustained engraftment and graft-versus-host disease. Removal of regulatory T cells from the infused population may augment the ability of non-regulatory T cells to provide help for endogenous effectors of anti-tumor immunity. Allogeneic T cell therapy is typically given in the context of allogeneic stem cell transplantation, in which the patient receives highly immunosuppressive conditioning followed by an infusion of a stem cell graft containing unselected populations of mature T cells. In the treatment described here, the graft is engineered to minimize the possibility of sustained donor cell engraftment, and the anti-tumor effector T cells derive from the host.