CAR-T Cells Secreting VHH Proteins for Solid Tumor Therapy
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Solution Overview
Problem
Current cancer immunotherapy using CAR-T cells faces challenges with solid tumors due to limited tumor-specific antigens and a highly immunosuppressive microenvironment, as well as the need for frequent dosing of systemic immune-modulating molecules.
Innovation Solution
Engineered cells expressing chimeric antigen receptors (CARs) that secrete immune-modulating VHHs or VHH-fusion proteins, which are produced locally, targeting specific antigens and providing a self-renewing source of therapeutics, thereby enhancing tumor killing and reducing toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If systemic immune-modulating molecules are injected, then immune modulation effect is achieved, but toxicity increases and frequent dosing is required
Solution Approach 1:
The patent applies local quality by enabling CAR-T cells to locally produce immune-modulating VHHs at the tumor site through integrated expression cassettes. This localized production achieves immune modulation effects while minimizing systemic toxicity, as the therapeutic molecules are generated precisely where needed rather than being distributed throughout the body via systemic injection
Solution Approach 2:
The patent implements self-service by designing CAR-T cells with self-renewing capability to continuously produce immune-modulating VHHs. The integrated expression cassette allows the engineered cells to autonomously generate therapeutic molecules at the target site, eliminating the need for repeated external dosing and providing sustained immune modulation through the persistent presence of the engineered cells
2Measurement precision
If CAR-T cells are used for solid tumors, then tumor targeting is achieved, but limited tumor-specific antigens and immunosuppressive microenvironment reduce efficacy
Solution Approach 1:
The patent applies universality by equipping CAR-T cells with dual functionality: (1) tumor targeting through the CAR receptor and (2) immune modulation through secreted VHHs. The integrated expression cassette enables single cells to perform both functions simultaneously, allowing the therapy to overcome the immunosuppressive microenvironment while maintaining precise tumor targeting
Solution Approach 2:
The patent implements composite materials by creating a hybrid therapeutic entity that combines CAR-T cell targeting capabilities with VHH-based immune modulation. The integrated expression cassette produces a composite system where the CAR-T cell serves as both the delivery vehicle and the source of immune-modulating molecules, enhancing overall therapeutic efficacy against solid tumors
3Duration of action of stationary object
If VHHs are secreted by engineered cells, then constant therapeutic source is provided, but metabolic strain on cells increases
Solution Approach 1:
The patent applies self-service by designing the CAR-T cells to autonomously produce and secrete immune-modulating VHHs through integrated expression cassettes. The engineered cells serve themselves by generating their own therapeutic payload locally, providing a self-renewing source of treatment that persists as long as the cells remain viable at the target site, thereby extending therapeutic duration without requiring external intervention
Data Source
AI summary
Provided herein are engineered cells that comprising a chimeric antigen receptor comprising an extracellular target-binding moiety and an intracellular signaling domain; and secrets a heavy-chain antibody (VHH) or a VHH fusion protein. Methods of using the engineered cell to treat a disease (e.g., cancer or autoimmune disease) are also provided.