Thymidine kinase diagnostic assay for gene therapy applications
Inventors
Levy, John P. • Reed, Rebecca A. • MCNULTY, Joseph • Johnson, Jr., Robert G.
Assignees
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Publication Number
US-11253611-B2
Publication Date
2022-02-22
Expiration Date
Abstract
Nucleic acid sequences encoding improved Herpes Simplex Virus Thymidine Kinases are provided, including their use in diagnostic and therapeutic applications. The thymidine kinases may be mutated using conservative mutations, non-conservative mutations, or both. Also provided are gene therapeutic systems, including viral and retroviral particles.
Core Innovation
The invention describes a method for identifying a patient capable of benefitting from gene therapy treatment for tumor lesions and for treating the patient in need thereof by decreasing tumor burden. A first injection or infusion of a gene therapy retroviral vector particle is administered systemically to a target tissue, and cells from the target tissue are transduced to express HSV-thymidine kinase (HSV-TK) from an HSV-TK polynucleotide. The HSV-TK polynucleotide encodes a mutated form of HSV-TK having a mutation at amino acid residue 32 or 33, where each mutated residue is independently mutated to a cysteine, glycine, serine, aspartic acid, or glutamic acid.
After expression of the mutated HSV-TK, a substrate of HSV-TK attached to a radioactive tracer is administered and a radioactive tracer signal present in the target tissue generated by expression of the mutated form of HSV-TK is measured. The measured radioactive tracer signal is evaluated to identify whether it is above a threshold level after a time delay. A location of tumor lesions is determined to determine whether tumor lesions co-localize with the measured radioactive tracer signal.
Treatment is administered only when the measured radioactive tracer signal is above the threshold level and the location of the measured radioactive tracer signal co-localizes with tumor lesions. The method includes administering a second injection or infusion of the gene therapy retroviral vector particle comprising the HSV-TK polynucleotide and a HSV-TK substrate that is not attached to a radioactive tracer for treatment. The described approach links patient selection and treatment decision-making to radioactive tracer signal detection and co-localization with tumor lesions.
Claims Coverage
One independent claim is reflected in the provided content, centered on systemic gene therapy delivery, radioactive-tracer signal measurement, and conditional treatment based on co-localization with tumor lesions. The main inventive features are extracted below from the independent claim text provided.
Systemic retroviral vector encoding mutated HSV-TK for transduction
Administering a first injection or infusion of a gene therapy retroviral vector particle comprising an HSV-thymidine kinase polynucleotide to a target tissue in the patient, thereby expressing mutated HSV-TK in transduced cells, where the HSV-TK polynucleotide encodes a mutated form of HSV-TK comprising a mutation at amino acid residue 32 or 33, with each mutated residue independently mutated to a cysteine, glycine, serine, aspartic acid, or glutamic acid.
Radioactive-tracer substrate imaging of HSV-TK expression
Administering a substrate of HSV-TK attached to a radioactive tracer, measuring a radioactive tracer signal present in the target tissue generated by expression of the mutated form of HSV-TK, and identifying whether the radioactive tracer signal is above a threshold level in the target tissue after a time delay.
Co-localization of radioactive tracer signal with tumor lesion location
Determining a location of tumor lesions to determine whether the tumor lesions co-localize with the measured radioactive tracer signal.
Conditional second treatment with non-radioactive HSV-TK substrate
Administering a second injection or infusion of the gene therapy retroviral vector particle and a substrate of HSV-TK that is not attached to a radioactive tracer for treatment if the measured radioactive tracer signal is above the threshold level and the location of the measured radioactive tracer signal co-localizes with tumor lesions.
The claim coverage centers on a systemic retroviral vector expressing mutated HSV-TK, radioactive-tracer signal measurement above a threshold after a time delay, and co-localization with tumor lesions before administering a second gene therapy administration with a non-radioactive HSV-TK substrate.
Stated Advantages
Enables identifying patients capable of benefitting from gene therapy treatment for tumor lesions.
Treats the patient in need thereof by decreasing tumor burden.
Supports patient selection by administering treatment only when radioactive tracer signal is above a threshold and co-localizes with tumor lesions.
Documented Applications
Patient identification and eligibility assessment for gene therapy treatment of tumor lesions using radioactive-tracer HSV-TK substrate imaging and tracer-signal thresholding, with treatment administered when tracer signal and lesion co-localization criteria are met.
Monitoring/surrogate assessment for HSV-TK-based gene therapy in a clinical trial framework for Reximmune-C2 using PET-based measurement of tracer signal and eligibility criteria.
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