Tumor-Antigen-Specific Memory CD8 T Cell Expansion for PD-1 Blockade
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Solution Overview
Problem
Current immunotherapy strategies, such as PD-1 immune checkpoint blockade, face challenges with low response rates and drug resistance due to the limited proliferative potential and steady epigenetic characteristics of exhausted CD8 T cell subsets in tumors, necessitating the identification of new key CD8 T cell subsets that can effectively respond to therapy.
Innovation Solution
Identification and amplification of non-exhausted tumor antigen-specific memory CD8 T cells in draining lymph nodes, characterized by specific surface markers and transcription factors, which are essential for replenishing exhausted subsets and responding to PD-1/PD-L1 immune checkpoint blockade therapy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If PD-1 immune checkpoint blockade therapy is used, then anti-tumor immune response is enhanced, but response rate remains low due to limited proliferative potential of exhausted CD8 T cells
Solution Approach 1:
The patent identifies and isolates progenitor exhausted T cells (TPEX) from tumor tissues before therapy, then performs in vitro expansion to generate large numbers of activated memory T cells. These pre-expanded cells are subsequently reinfused into patients, providing a preliminary action that overcomes the limited proliferative potential of endogenous exhausted T cells and enables higher response rates to PD-1 blockade therapy
Solution Approach 2:
The patent creates artificial copies of functional T cells by isolating TPEX, expanding them in vitro to generate activated memory T cells, and reinfusing these copied cells back into patients. This copying process bypasses the limitations of natural T cell proliferation in the tumor microenvironment and provides sufficient numbers of functional T cells to achieve therapeutic efficacy
2Adaptability or versatility
If exhausted CD8 T cell subsets in tumors are targeted, then immune checkpoint blockade can be administered, but steady epigenetic characteristics limit therapeutic response
Solution Approach 1:
The patent performs preliminary isolation and in vitro expansion of TPEX cells before reinfusion, allowing these cells to undergo epigenetic reprogramming in the controlled in vitro environment. This preliminary action enables the cells to escape from the steady epigenetic state that characterizes exhausted T cells in tumors, making them more responsive to immune checkpoint blockade therapy upon reinfusion
Solution Approach 2:
The patent changes the epigenetic parameters of exhausted T cells by culturing them in vitro with specific cytokines and activation signals. This parameter change transforms the steady epigenetic characteristics of tumor-infiltrating exhausted T cells into a more plastic, responsive state that can effectively respond to PD-1 blockade therapy
Data Source
AI summary
The present application provides identification, in vitro amplification, and application method of memory CD8 T cells specific for an antigen in a solid tumor-draining lymph node.