Central Memory T Cells for Anti-Leukemia Treatment Without GVHD
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Solution Overview
Problem
Current treatments for hematological malignancies like non-Hodgkin lymphoma often lead to complete remission but result in residual tumor cells, and donor lymphocyte infusion (DLI) with graft-versus-leukemia/lymphoma (GVL) reactivity can kill these cells, but is offset by graft-versus-host disease (GVHD), which increases transplant-related mortality.
Innovation Solution
Administering isolated populations of non-graft versus host (GVHD) inducing anti-third party cells with a central memory T-lymphocyte phenotype, capable of homing to lymph nodes, either non-syngeneic with both the subject and the graft or non-syngeneic with the graft and syngeneic with the subject, to treat diseases like leukemia and lymphoma without causing GVHD.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If donor lymphocyte infusion (DLI) with graft-versus-leukemia/lymphoma reactivity is administered, then malignant cells are killed, but graft-versus-host disease occurs increasing transplant-related mortality
Solution Approach 1:
The patent segments the T cell population into specific subsets (central memory CD8+ T cells with Tcm phenotype) that possess GVL reactivity while lacking GVHD-inducing capacity. This segmentation allows selective administration of beneficial cells while excluding harmful ones, resolving the contradiction between anti-malignant effect and GVHD prevention
Solution Approach 2:
The patent applies local quality by endowing the administered T cells with specific phenotypic characteristics (central memory phenotype, CD62L expression, L-selectin expression) that confer both GVL reactivity and tolerance to host tissues. These localized quality modifications enable the cells to exert anti-malignant effects while avoiding GVHD
2Productivity
If CD8+ T cells are used for graft-versus-leukemia effect, then residual malignant cells are killed, but transplant-related mortality increases due to GVHD
Solution Approach 1:
The patent utilizes the dynamic properties of central memory T cells, which possess high proliferative capacity and can expand in vivo after administration. This dynamic characteristic allows a small initial number of GVL-reactive cells to generate sufficient anti-malignant activity while maintaining tolerance to host tissues, thus improving productivity without compromising safety
Solution Approach 2:
The patent performs preliminary selection and characterization of T cells to identify those with central memory phenotype and GVL reactivity before administration. This preliminary action ensures that only cells with the desired dual properties (GVL effect and GVHD tolerance) are administered, resolving the contradiction between productivity and reliability
Data Source
AI summary
A method of treating a disease in a subject in need thereof is disclosed. The method comprising: (a) transplanting a non-syngeneic cell or tissue graft to the subject; and (b) administering to the subject a therapeutically effective amount of an isolated population of cells comprising non-graft versus host (GVHD) inducing anti-third party cells having a central memory T-lymphocyte (Tcm) phenotype, the cells being tolerance-inducing cells and capable of homing to the lymph nodes following transplantation, and further wherein the cells are either: (i) non-syngeneic with both the subject and the graft; or (ii) non-syngeneic with the graft and syngeneic with the subject, thereby treating the subject.