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-10350302-B2
Publication Date
2019-07-16
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 disclosed approach provides a method for identifying a patient capable of benefitting from gene therapy treatment for tumor lesions and for treating a patient in need thereof by decreasing tumor burden. A gene therapy retroviral vector particle comprising an HSV-thymidine kinase (HSV-TK) polynucleotide is administered systemically to a target tissue, and cells are transduced so that HSV-TK is expressed. The HSV-TK polynucleotide encodes a mutated form of HSV-TK comprising a mutation at either amino acid residue 32 or 33, where each residue is independently mutated to an acidic amino acid or to cysteine, and the mutated form increases cell kill activity relative to a wild-type thymidine kinase.
A substrate of HSV-TK attached to a radioactive tracer is administered and the relative amount of radioactive tracer signal present in the target tissue is measured. The location of tumor lesions is determined to assess whether the tumor lesion co-localizes with the measured radioactive tracer signal, and whether the signal is above a certain threshold. This links a measurable tracer signal to lesion localization as part of patient selection and treatment decision-making.
If the measured radioactive tracer signal is above the certain threshold and co-localizes with tumor lesions, a second injection or infusion of the gene therapy retroviral vector particle comprising the HSV-TK polynucleotide and a substrate of HSV-TK that is not attached to a radioactive tracer is administered for treatment. The method treats the patient in need thereof.
Claims Coverage
One independent claim is reflected. The claim centers on HSV-TK retroviral gene therapy with a mutated HSV-TK, radioactive tracer signal measurement with a threshold, and tumor lesion co-localization before treatment continuation.
Mutated HSV-TK for increased cell kill activity
A gene therapy retroviral vector particle comprising an HSV-TK polynucleotide transduces cells to express an HSV-TK mutated at either amino acid residue 32 or 33, where each residue is independently mutated to an acidic amino acid or to cysteine, and the mutated form increases cell kill activity relative to a wild-type thymidine kinase.
Radioactive tracer substrate measurement with threshold-based patient selection
Administering a substrate of HSV-TK attached to a radioactive tracer; measuring the relative amount of radioactive tracer signal present in the target tissue; and identifying whether the signal is above a certain threshold.
Tumor lesion co-localization with measured radioactive tracer signal
Determining the location of tumor lesions to determine whether the tumor lesion co-localizes with the measured radioactive tracer signal, and administering a second injection or infusion of the gene therapy retroviral vector particle comprising the HSV-TK polynucleotide 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 certain threshold and the location co-localizes with tumor lesions.
Systemic administration for treating patients in need thereof
The gene therapy retroviral vector particle is administered systemically, and administering the treatment step treats the patient in need thereof.
The claim coverage combines a mutated HSV-TK retroviral gene therapy construct intended to increase cell kill activity with measurement of a radioactive HSV-TK substrate, a threshold criterion, and tumor lesion co-localization as conditions for administering treatment substrate without radioactive tracer.
Stated Advantages
Decreases tumor burden in the patient.
The mutated form of HSV-TK increases cell kill activity relative to a wild-type thymidine kinase.
Documented Applications
Identifying a patient capable of benefitting from gene therapy treatment for tumor lesions and treating the patient in need thereof by decreasing tumor burden.
Phase 1, open-label, dose-escalation clinical protocol for intravenous Reximmune-C2 including PET-CT pre-screening and treatment continuation decisions based on [18F]FHBG PET-CT results.
Use of immune-related response criteria (irRC) for extensive tumor assessment using CT/CT-PET imaging and confirmation intervals.
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