TSP Cell Mobilization via CXCR4 Antagonists for Solid Tumor Therapy
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Solution Overview
Problem
Current therapeutic approaches using adoptive transfer of genetically modified T cells are limited in targeting solid tumors due to poor mobilization and persistence of T cells in non-lymphoid tissues.
Innovation Solution
The development of a novel subtype of tissue-resident memory T cells, known as side population T (TSP) cells, which display a quiescent phenotype, are mobilized using CXCR4 antagonists like plerixafor, isolated, and modified ex vivo for enhanced tissue infiltration and persistence.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If adoptive transfer of genetically modified T cells is used to target solid tumors, then therapeutic potential is improved, but T cell mobilization and persistence in non-lymphoid tissues deteriorates
Solution Approach 1:
The patent applies preliminary action by pre-conditioning T cells with specific transcription factors (such as NF-κB, STAT3, or STAT5) before adoptive transfer. This pre-programming ensures that T cells are primed to express homing receptors and survive in non-lymphoid tissues, thereby improving both therapeutic efficacy and T cell persistence simultaneously
Solution Approach 2:
The patent utilizes parameter changes by modifying the transcriptional state of T cells through exposure to specific cytokines (IL-2, IL-15, IL-21) and transcription factors. These parameter changes in gene expression profiles enable T cells to acquire tissue-resident memory characteristics, enhancing their ability to infiltrate and persist in solid tumor microenvironments
2Speed
If T cells are activated for rapid effector function, then immediate anti-tumor activity is improved, but long-term persistence and memory formation deteriorates
Solution Approach 1:
The patent applies dynamics by creating a dynamic transcriptional program in T cells that allows sequential activation of different gene sets. Initially, effector genes are activated for rapid tumor killing, then memory and persistence genes (such as those regulated by TCF-1 and NF-κB) are upregulated to ensure long-term survival and tissue residency, achieving both rapid response and sustained persistence
Solution Approach 2:
The patent ensures continuity of useful action by maintaining T cells in a state of controlled activation through sustained cytokine exposure (particularly IL-15 and IL-21) and transcription factor expression. This continuous molecular stimulation prevents T cell exhaustion while promoting memory formation and long-term persistence without sacrificing effector function
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
TSP cells demonstrate increased tissue infiltration and persistence, potentially improving the efficacy of adoptive T cell therapy for solid tumors by leveraging their quiescent and slow-cycling properties.
Implementation Method 1
The CXCR4 antagonist induces mobilization of the TSP cell from the subject's tissue or bone marrow into the subject's circulation
Data Source
AI summary
The present disclosure includes compositions, methods, and uses for a subset of T cells, SP T (TSP) cells, which display a quiescent (G0) phenotype. Aspects of the disclosure include methods for obtaining and mobilizing TSP cells in a subject. Other aspects include methods of adoptive cell transfer in a subject utilizing TSP cells.