Phase I/II Trial of Urokinase Plasminogen Activator-Targeted Oncolytic Newcastle Disease Virus for Canine Intracranial Tumors
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. rLAS-uPA Viral Formulation and In Vitro Viral and Immunological Analytical Methods
2.1.1. Formulation of rLAS-uPA Recombinant NDV
2.1.2. Cell Lines
2.1.3. Virus Neutralization Test
2.1.4. Cell Viability Assays and Syncytia Formation
2.1.5. Infectious Viral Recovery
2.1.6. rLAS-uPA qRT-PCR in Brain Tumor Samples
2.1.7. Serum Cytokine Analyses
2.2. In Vivo Canine Clinical Trial Protocol and Clinical Endpoints
2.3. Canine Tissue Collection and Preservation for In Vitro Viral and Immunologic Analyses
2.4. Statistical Analyses
3. Results
3.1. Canine Study Subjects and Tumor Characteristics
3.2. rLAS-uPA Viral Treatment, Safety and Neuroimaging Assessments, and Secondary Clinical Endpoints in Canine Subjects
3.2.1. Adverse Events in Canine Subjects
3.2.2. Neuroimaging Evaluation of Anti-Tumor Effects in Canine Subjects
3.2.3. Secondary Clinical Endpoints in Canine Subjects
3.3. rLAS-uPA Viral and Immunologic Assays
3.3.1. Infectious Viral Recovery and Viral Neutralizing Antibodies
3.3.2. rLAS-uPA qRT-PCR in Brain Tumors
3.3.3. Serum Cytokine Analysis
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Monitoring Parameter | Methods | Time Point (Trial Day) | ||||||
---|---|---|---|---|---|---|---|---|
−14 to 0 | 1 | 14 | 28 | 42 | 84 | 180 | ||
Owner | Observation | ✓ Daily Days 1–42 | X Daily Days 43–180 | |||||
Rectal temperature | ||||||||
Adverse events | ||||||||
−14 to 0 | 1 | 14 | 28 | 42 | 84 | 180 | ||
Clinical | Physical/Neurological Exams | ✓ | ✓ | ✓ | ✓ | ✓ | X | X |
Karnofsky Performance Score | ✓ | ✓ | ✓ | ✓ | ✓ | X | X | |
Adverse events | ✓ | ✓ | ✓ | ✓ | ✓ | X | X | |
Laboratory | CBC, Chemistry, Urinalysis | ✓ | ✓ | ✓ | ✓ | ✓ | X | X |
Cerebrospinal fluid | ✓ | ✓ | X | X | ||||
Viral Shedding | Blood and urine infectious viral recovery | † | † | † | † | |||
Cerebrospinal fluid infectious viral recovery | † | |||||||
Viral Immune Response | Anti-NDV antibodies; plaque neutralization assay | ✓ | ✓ | ✓ | ✓ | ✓ | X | X |
Serum TNF-α, IFN-α, TRAIL; ELISA | † | † | † | † | ||||
Tumor Response | Brain MRI | ✓ | ✓ | X | X | |||
Quality of Life Assessment | CanBrain-24 QOL Caregiver Survey | X | X | X | X | |||
Intervention | rLAS-uPA NDV IV Infusion | ✓ | ✓ | ✓ |
Adverse Events Attributable to rLAS-uPA Treatment | |||
---|---|---|---|
Adverse Event | Category | Grade | Canine Subject (n, Dog Identification) |
Fever | Constitutional | 3/DLT | n = 2, Dog 10 ^, Dog 11 ◊ |
Anorexia | Gastrointestinal | 3/DLT | n = 2, Dog 10 ^, Dog 11 ◊ |
Thrombocytopenia | Blood/Bone Marrow | 4/DLT | n = 1, Dog 10 ^ |
Cerebral edema | Neurology | 3/DLT | n = 1, Dog 11 ◊ |
Shivering/tremor | Administration Reaction | 1 | n = 14, Dogs 1 •, 2 •, 3 •, 4 •, 5 *, 7 •, 9 *, 10 *, 11 ◊, 12 *, 13 •, 15 •, 17 •, 18 *, 20 • |
Diarrhea | Gastrointestinal | 1 | n = 6, Dogs 1 *, 2 ^, 7 *, 15 *, 18 *, 20 • |
Diarrhea | Gastrointestinal | 2 | n = 2, Dogs 12 ^, 14 * |
Fever | Constitutional | 1 | n = 4, Dogs 7 *, 9 *, 17 *, 19 * |
Fever | Constitutional | 2 | n = 1, Dog 1 * |
Appetite, altered | Gastrointestinal | 1 | n = 3, Dogs 10 *, 14 •, 17 * |
Conjunctivitis | Ocular | 2 | n = 1, Dog 14 * |
Adverse Events Attributable to Concomitant Medication | |||
High alanine aminotransferase | Metabolic | 1 | n = 4, Dogs 1, 2, 15, 20 (prednisone, phenobarbital) |
High alkaline phosphatase | Metabolic | 1 | n = 6, Dogs 1, 2, 3, 5, 13, 20 (prednisone, phenobarbital) |
High alkaline phosphatase | Metabolic | 2 | n = 1, Dog 15 (prednisone, phenobarbital) |
Adverse Events Attributable to Non-Investigational Protocol Procedures | |||
Cystitis/hematuria | Genitourinary | 2 | n = 1, Dog 15 (cystocentesis) |
Hematoma | Hemorrhage/Bleeding | 1 | n = 1, Dog 7 (jugular venipuncture) |
Adverse Events Attributable to Pre-existing Disease | |||
Seizures | Neurology | 2 | n = 8, Dogs 2, 3, 7, 8, 13, 14, 15, 19 (structural epilepsy) |
Seizures | Neurology | 4 | n = 1, Dog 1 (structural epilepsy) |
Depressed level of consciousness | Neurology | 4 | n = 1, Dog 18 (tumor progression) |
Hydrocephalus | Neurology | 3 | n = 1, Dog 18 (tumor progression) |
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Rossmeisl, J.H.; King, J.N.; Robertson, J.L.; Weger-Lucarelli, J.; Elankumaran, S. Phase I/II Trial of Urokinase Plasminogen Activator-Targeted Oncolytic Newcastle Disease Virus for Canine Intracranial Tumors. Cancers 2024, 16, 564. https://doi.org/10.3390/cancers16030564
Rossmeisl JH, King JN, Robertson JL, Weger-Lucarelli J, Elankumaran S. Phase I/II Trial of Urokinase Plasminogen Activator-Targeted Oncolytic Newcastle Disease Virus for Canine Intracranial Tumors. Cancers. 2024; 16(3):564. https://doi.org/10.3390/cancers16030564
Chicago/Turabian StyleRossmeisl, John H., Jamie N. King, John L. Robertson, James Weger-Lucarelli, and Subbiah Elankumaran. 2024. "Phase I/II Trial of Urokinase Plasminogen Activator-Targeted Oncolytic Newcastle Disease Virus for Canine Intracranial Tumors" Cancers 16, no. 3: 564. https://doi.org/10.3390/cancers16030564