Switchable Dual CAR-T Cells Regulated by Exogenous Molecules
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Solution Overview
Problem
Current CAR-T cell therapy for tumors faces challenges such as cytokine storm and normal tissue toxicity due to non-specific targeting of tumor antigens like mesothelin, which are also expressed in normal tissues, leading to safety concerns and reduced efficacy.
Innovation Solution
Development of switchable dual-receptor CAR-T (sdCAR-T) cells equipped with dual chimeric antigen receptors for mesothelin and FITC, controlled by an exogenous bifunctional molecule, utilizing CD3ζ and 4/1BB signal domains, and transfected into T lymphocytes via electrotransfection, with a bifunctional small molecule drug enhancing tumor targeting and reducing normal tissue damage.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR-T cells are activated to kill tumor cells, then anti-tumor efficacy is improved, but cytokine storm and normal tissue damage occur
Solution Approach 1:
The patent divides the antigen recognition function into two separate receptors: one recognizing tumor antigen (MSLN) and another recognizing exogenous switching molecule (FITC). Both signals are required for full T cell activation, segmenting the activation pathway to prevent uncontrolled cytokine release while maintaining anti-tumor efficacy
Solution Approach 2:
An exogenous switching molecule (FITC-conjugated HM-3) is introduced as an intermediary that bridges tumor targeting and controlled activation. This mediator allows external control over CAR-T cell activation state and quantity, enabling precise regulation to avoid cytokine storm while maintaining tumor killing ability
2Reliability
If tumor antigens like mesothelin are targeted, then tumor cell specificity is improved, but normal tissue toxicity occurs due to expression in normal tissues
Solution Approach 1:
The patent segments the targeting mechanism by combining endogenous tumor antigen recognition (MSLN-specific CAR) with exogenous switching molecule recognition (FITC-specific CAR). This dual-recognition requirement ensures that even if MSLN is present on normal tissues, activation only occurs when both signals are present, reducing normal tissue toxicity while maintaining tumor specificity
Solution Approach 2:
The patent applies local quality by making the activation state and quantity of CAR-T cells controllable through exogenous switching molecules. Different concentrations and formulations of the switching molecule allow precise control over where and how strongly CAR-T cells are activated, enabling selective activation at tumor sites while sparing normal tissues
Data Source
AI summary
The present invention discloses a novel switchable dual chimeric antigen receptor-T (sdCAR-T) cell and a construction method and use thereof, which fall within the field of cellular immunotherapy for tumors. The dual chimeric antigen receptor consists of a first chimeric antigen receptor for MSLN and a second chimeric antigen receptor for FITC. A dual-targeted functional T cells regulated by specific exogenous bifunctional molecules is constructed, and the exogenous molecules are used to preliminarily discuss the in vivo and in vitro activity of the dual chimeric antigen receptor-T cell. By means of in vitro and in vivo tests, it is confirmed that the activation mode of the constructed CAR-T cell is controlled by the combination of endogenous tumor antigens and exogenous bifunctional molecules, and this combined regulation mode can significantly improve the safe application of CAR-T cell immunotherapy.