CAR-T Cell Co-Expression of Transcription Factors
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Solution Overview
Problem
The expansion and persistence of CAR-modified T cells in vivo are hampered by the lack of costimulatory signals after engagement with target antigens, as many tumor cells down-regulate their expression of costimulatory molecules required for optimal T-cell function, proliferation, and persistence.
Innovation Solution
Engineering CAR-T cells to express at least one transcription factor, such as T-bet, STAT-1, or STAT-4, which can enhance CAR expression, promote TH1 cell development, increase cytokine production, and suppress the development of non-TH1 cells, thereby overcoming the limitations of costimulatory signal deficiency.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR-T cells are engineered to express transcription factors (T-bet, STAT-1, or STAT-4), then cytotoxic activity, cytokine secretion, and persistence are enhanced, but the complexity of the nucleic acid construct and cell engineering process increases
Solution Approach 1:
The patent combines multiple functional elements (CAR signaling domain, costimulatory domain, and transcription factor coding sequences) into a single integrated nucleic acid construct. This merging approach delivers multiple therapeutic functions (antigen recognition, costimulation, and transcriptional regulation) through one construct, thereby enhancing persistence while managing complexity through unified design rather than separate components
Solution Approach 2:
The nucleic acid construct is designed to perform multiple functions simultaneously: it encodes the CAR receptor for antigen recognition, includes costimulatory domains for enhanced signaling, and expresses transcription factors (T-bet, STAT-1, or STAT-4) that regulate cytokine production and cell persistence. This multi-functionality in a single construct addresses the technical contradiction by providing comprehensive therapeutic effects without requiring multiple separate engineering steps
2Productivity
If transcription factors are overexpressed to enhance cytokine production and TH1 cell development, then antitumor activity increases, but the risk of unwanted immune responses and off-target effects increases
Solution Approach 1:
The transcription factors (T-bet, STAT-1, STAT-4) are expressed specifically in CAR-T cells that have been engineered to recognize and bind tumor antigens. This localized expression ensures that enhanced cytokine production and TH1 cell development occur primarily in the context of tumor-targeted immune responses, minimizing off-target effects while maintaining high productivity against tumor cells
Solution Approach 2:
The patent utilizes specific transcription factors (T-bet, STAT-1, STAT-4) that are known to regulate TH1 differentiation and cytokine production. By selecting and expressing these particular transcription factors with defined functions, the invention optimizes cytokine production parameters while controlling potential harmful effects through the specific biological properties and regulatory networks of these transcription factors
Data Source
AI summary
Nucleic acid constructs, vectors, and recombinant cells harboring the nucleic acid constructs or vectors are disclosed. The nucleic acid constructs include genes encoding a chimeric antigen receptor (CAR) and/or one or more transcription factors, optionally mutated. The transcription factors include those that mediate proinflammatory cytokine expression, e.g., T-bet, STAT1, or STAT4. Methods are disclosed of co-expression of the CAR and the transcription factor in a human or non-human immune cell, preferably human T cells. Also disclosed are methods for using these cells for immunotherapy, e.g., in treating cancer, infection, autoimmunity, allergy or inflammation diseases by the administration of a prophylactically or therapeutically effective amount of one or more of the nucleic acid constructs, vectors, and/or immune cells, e.g., human CAR-T cells, described herein.