Engineered T Cells with CAR Ligand Binding Domain for PET Imaging
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Solution Overview
Problem
Current methods for imaging engineered cells, particularly immune cells used in cell-based therapies, face challenges such as immunogenicity and background uptake, limiting their clinical application and the ability to track engineered cells effectively.
Innovation Solution
The use of engineered T cells with a chimeric antigen receptor (CAR) and a nucleic acid molecule comprising a ligand binding domain, combined with radiolabeled tracers for PET imaging, allows for the detection and assessment of engineered T cells in subjects through positron emission tomography (PET) or computed tomography (CT) imaging.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If reporter genes (HSV-tk, hNET, PSMA) are added to host cells for imaging, then cell tracking capability is improved, but cell viability and efficacy are reduced
Solution Approach 1:
The patent introduces a small molecule substrate (e.g., 1,4-dihydroxy-2,3-naphthoquinone or 5-fluorouracil) as an intermediary between the engineered cell and the imaging system. The cell expresses only a minimal enzyme (HSV-tk or hNET) that metabolizes the small molecule substrate into a detectable signal, rather than expressing large reporter proteins that burden the cell. This intermediary approach enables imaging while preserving cell function.
Solution Approach 2:
The patent changes the imaging parameter from direct protein expression detection to metabolic product detection. By having the cell metabolize a small molecule substrate into a detectable compound (e.g., converting 5-fluorouracil to fluorouracil monophosphate), the system achieves imaging capability with minimal impact on cell physiology, as the substrate and its metabolites are naturally compatible with cell metabolism.
2Measurement precision
If HSV-tk reporter gene is used for imaging, then cell detection is enabled, but background uptake at tumor site increases
Solution Approach 1:
The patent applies local quality by making the imaging capability specific to the engineered cell population through selective enzyme expression. Only cells that have been engineered with the HSV-tk or hNET enzyme can metabolize the small molecule substrate and produce the imaging signal. This creates a localized imaging signal at the site of engineered cell accumulation, distinguishing it from background tumor uptake that lacks the enzymatic conversion capability.
3Measurement precision
If nuclear molecular imaging technologies are implemented, then treatment response assessment is improved, but barrier to entry and clinical implementation difficulty increase
Solution Approach 1:
The patent employs small molecule substrates that are chemically simple, inexpensive to synthesize, and can be administered systemically. Examples include 1,4-dihydroxy-2,3-naphthoquinone and 5-fluorouracil, which are small molecules rather than complex radiolabeled proteins or antibodies. This reduces the barrier to entry compared to traditional nuclear imaging tracers while maintaining the ability to assess treatment response through PET or other imaging modalities.
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
This approach enables precise tracking and assessment of engineered T cells, improving the monitoring and efficacy of adoptive cell therapies by providing a non-invasive method to detect cell distribution and toxicity, thereby enhancing the management of cell-based therapies.
Implementation Method 1
radiolabeled tracers for PET imaging
Implementation Method 2
positron emission tomography (PET) imaging
Data Source
AI summary
The present disclosure provides immunes cells comprising a radiolabeled tracer useful in imaging tests such as positron emission topography (PET)/computed tomography (CT) scans. The present disclosure further includes engineered cells comprising a chimeric antigen receptor (CAR) further comprising a nucleic acid molecule comprising a ligand binding domain capable of binding to radiolabeled tracer. This disclosure also includes methods for assessing the efficacy or toxicity of an adoptive cell therapy in a subject, methods for detecting the quantity of engineered T cells in a subject, methods for monitoring an immunotherapy treatment in a subject and methods of imaging engineered T cells in a subject. In some embodiments, the radiolabeled tracer is [18F]fluoropropyl-trimethoprim ([18F]FPTMP).