Modified Immune Cells via DNMT3A Inhibition for Solid Tumor Therapy
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Solution Overview
Problem
Current CAR T cell therapies for cancer, especially for solid tumors and brain tumors, exhibit limited antitumor activity and long-term survival rates, necessitating the development of immune effector cells with preserved multipotency and enhanced antigen-specificity.
Innovation Solution
Modified immune effector cells with inhibited DNA (cytosine-5)-methyltransferase 3A (DNMT3A) activity and enhanced IL10 signaling pathway, achieved through DNMT3A inhibition or mutation, and exogenous IL10 administration or genetic modification, combined with chimeric antigen receptors (CARs) for targeted antigen binding.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR T cell therapy is used for cancer treatment, then antitumor activity is improved, but long-term survival rates and therapeutic effectiveness deteriorate
Solution Approach 1:
The patent applies parameter changes by modulating the epigenetic state of T cells through DNMT3A inhibition, which alters DNA methylation patterns. This changes the transcriptional profile of T cells to preserve multipotency and self-renewal capacity, thereby extending the duration of therapeutic action and improving long-term survival rates while maintaining antitumor activity.
Solution Approach 2:
The patent implements preliminary action by performing DNMT3A inhibition and IL-10 pathway enhancement during the ex vivo expansion phase of T cells before administration to patients. This preliminary modification of T cell epigenetic state ensures that the cells possess enhanced multipotency and persistence capabilities upon infusion, leading to improved long-term outcomes.
2Measurement precision
If T cells are differentiated for antigen-specificity, then antigen recognition is improved, but developmental potential and multipotency deteriorate
Solution Approach 1:
The patent uses parameter changes by manipulating DNA methylation levels through DNMT3A inhibition to alter the epigenetic landscape of T cells. This allows T cells to maintain a more open chromatin state that supports both antigen-specific receptor expression and multipotent differentiation capacity, resolving the contradiction between specialization and versatility.
Solution Approach 2:
The patent introduces IL-10 as an intermediary molecule that mediates between antigen-specific signaling and multipotency maintenance. IL-10 signaling acts as a bridge that allows T cells to retain stem-like properties while expressing antigen-specific receptors, thereby preserving both antigen recognition and developmental potential.
Data Source
AI summary
The application provides modified immune effector cells wherein the DNA (cytosine-5)-methyltransferase 3A (DNMT3A)-mediated de novo DNA methylation of the cell genome is inhibited, and IL10 signaling pathway is enhanced. The application also provides related pharmaceutical compositions and the methods for generating such modified immune effector cells. The application further provides uses of such modified immune effector cells for treating diseases such as cancers, infectious diseases and autoimmune diseases.