Safety of an Oncolytic Myxoma Virus in Dogs with Soft Tissue Sarcoma
Abstract
:1. Introduction
2. Materials and Methods
2.1. Recombinant MYXVΔserp2
2.2. Treatment with MYXVΔserp2
2.2.1. Patient Enrollment
2.2.2. Intratumoral Injection of MYXVΔserp2
2.2.3. Post-Operative Injection of MYXVΔserp2
2.3. Patient Monitoring
2.4. Detection of Viral DNA
2.5. Evaluation of the Immune Response to MYXVΔserp2
2.5.1. Tumor Histopathology
2.5.2. Flow Cytometry of Peripheral Blood Leukocytes
2.5.3. Anti-MYXV Antibody Response
3. Results
3.1. Patient Demographics
3.2. Clinical Data
3.3. Virus Distribution
3.4. Tumor Histopathology
3.5. Peripheral Blood Leukocyte Subsets
3.6. Neutralizing Antibody
4. Discussion
5. Conclusions
Author Contributions
Acknowledgments
Conflicts of Interest
Appendix A
Patient | Treatment | Decreased Hematocrit | Decreased Automated Platelet Count | Increased Urea Nitrogen | Increased Creatinine | Increased Phosphorus | Increased Potassium | Increased Calcium | Increased Alkaline Phosphatase | Increased Creatinine Kinase |
---|---|---|---|---|---|---|---|---|---|---|
Dog 1 | 106 pfu MYXVΔserp2 Day 0 | Grade 2 Days 0, 2 | ||||||||
Dog 2 | 106 pfu MYXVΔserp2 Day 0 | Grade 2 Days 2, 6, 14, 21, 28 | Grade 2 Day 21 | Grade 2 Day 21 | Grade 2 Days 0–7, 14, 21 Grade 3 Day 28 | Grade 2 Days 21, 28 | ||||
Dog 3 | 106 pfu MYXVΔserp2 Day 0 | Grade 2 Day 7 | ||||||||
Dog 4 | 106 pfu MYXVΔserp2 Day 0 | Grade 2 Day 1 | ||||||||
Dog 5 | 106 pfu MYXVΔserp2 Day 0 | Grade 2 Day 28 | ||||||||
Dog 6 | 107 pfu MYXVΔserp2 Days 0 and 28 | Grade 2 Days −2, 14, 28 | ||||||||
Dog 7 * | 5 × 106 pfu MYXVΔserp2 Days 0 and 14 | |||||||||
Dog 8 * | 107 pfu MYXVΔserp2 Days 0 and 18 | |||||||||
Dog 9 | 8 × 106 pfu MYXVΔserp2 Days 0 and 14 | Grade 3 Days 0, 14, 28 | ||||||||
Dog 10 * | 107 pfu MYXVΔserp2 Days 0 and 14 |
Date: | Largest Tumor Diameter (cm): | Weight (pounds): | |||
Circle a Score for each Clinical Sign | 0 = did not occur. 1 = mild, slightly > normal, occurred once, and no treatment needed. 2 = moderate, 2× > normal, occurred more than once, call 970-297-5000 to discuss signs with a veterinarian. 3 = severe, 3× > normal, treatment needed, call 970-297-5000 to make an appointment to see a veterinarian. | ||||
Discharge from tumor site | 0 | 1 | 2 | 3 | |
Pain or licking at tumor site * | 0 | 1 | 2 | 3 | |
New masses or wounds detected | 0 | 1 | 2 | 3 | |
Excessive panting | 0 | 1 | 2 | 3 | |
Vomiting | 0 | 1 | 2 | 3 | |
Diarrhea | 0 | 1 | 2 | 3 | |
Water intake > 200 mL per pound | 0 | 1 | 2 | 3 | |
Increased urination | 0 | 1 | 2 | 3 | |
Decreased urination | 0 | 1 | 2 | 3 | |
Decreased interest in food | 0 | 1 | 2 | 3 | |
Lethargy/Malaise | 0 | 1 | 2 | 3 | |
Anxiousness/Anxiety | 0 | 1 | 2 | 3 | |
Increased vocalization | 0 | 1 | 2 | 3 | |
Other observations: |
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Target Gene Sequence | Technique | Forward Primer Sequence | Reverse Primer Sequence | Template Length (Base Pairs) | Annealing Temperature (°C) |
---|---|---|---|---|---|
Myxoma virus M135R-M136R | Standard PCR | 5′-CGA GAA TTC CAC CTG TGT ATG TT-3′ | 5′-CCA TGT ACA ATA ACA CAC AGT TCG G-3′ | 1164 | 52 |
Myxoma virus M033R-M034L | Standard PCR | 5′-CAC CCT CTT TAG TAA AGT ATA CAC C-3′ | 5′-GAA ATG TTG TCG GAC GGG-3′ | 818 | 52 |
Myxoma virus M033R | Droplet Digital PCR | 5′-CGC CAT CCT TTA CCT AAC GA-3′ | 5′-CGA CAA AAA TAA CAC CGG GT-3′ | 94 | 60 |
Canine GAPDH | Droplet Digital PCR | 5′-GCC CTC AAT GAC CAC TTT GT-3′ | 5′-TCA GCT ACA GCA ACC AGG TG-3′ | 69 | 60 |
Patient | Age (Years) | Breed | Sex | Pertinent Medical History Prior to Study Enrollment | Study Arm | Largest Tumor Diameter on Day 0 (cm) | Largest Tumor Diameter Median (Range) Day 0 to Day 28 (cm) | Tumor Location | Pre-Treatment Biopsy Diagnosis |
---|---|---|---|---|---|---|---|---|---|
Dog 1 | 10 | Mixed | Castrated male | Tumor excisions 1 and 2 years prior Regrowth~1 month | Intra-tumoral | 2.9 | 2.9 (2.6–3.5) | Right elbow | Grade 2 STS, PNST |
Dog 2 | 12 | Miniature schnauzer | Castrated male | Chronic renal failure Tumor present~3 months | Intra-tumoral | 11.0 | 10.8 (10.2–11.3) | Left inguinal and perianal areas | Grade 1 STS, myxo-sarcoma |
Dog 3 | 8 | Mixed | Castrated male | Tumor excision 1 year prior Regrowth~1 month | Intra-tumoral | 4.8 | 4.6 (4.0–5.0) | Left elbow | Grade 3 Undiffer-entiated sarcoma |
Dog 4 | 11 | Italian grey-hound | Castrated male | Tumor present~1 month | Intra-tumoral | 7.5 | 7.6 (7.2–7.8) | Tail base | Grade 1 STS, PNST |
Dog 5 | 10 | Shetland sheepdog | Castrated male | Tumor present~1 year | Intra-tumoral | 14.1 | 12.1 (10.0–15.3) | Right caudal brachium | Grade 2 STS, PNST |
Dog 6 | 12 | Mixed | Spayed female | Tumor excision~4 months prior Regrowth~5 months | Post-operative | 5 (per lobule) | TE | Multi-lobulated mass dorsal thorax | Grade 3 Undiffer-entiated sarcoma |
Dog 7 | 11 | Greyhound | Castrated male | Tumor excision 2 & 6 years prior Regrowth~1 month | Post-operative | 3.5 | TE | Left lateral meta-tarsus | Grade 2 STS, PNST |
Dog 8 | 15 | Labrador retriever | Castrated male | Tumor present 2–3 years | Post-operative | 22 | TE | Ventral abdomen | Grade 2 STS, myxoid fibro-sarcoma |
Dog 9 | 12 | Labrador retriever | Spayed female | Tumor excision 2 years prior Regrowth~1 month | Post-operative | 3.5 | TE | Right caudo-lateral thorax | Grade 2 STS, PNST |
Dog 10 | 11 | Mixed | Spayed female | Tumor present~1 month | Post-operative | 6.5 | TE | Left flank | Grade 2 STS, PNST |
Patient | Sample | Diagnosis and Comments | Mitotic Index Per 40× Field | Percent Necrosis | Inflammatory Infiltrate |
---|---|---|---|---|---|
Dog 1 | Pre-treatment biopsy | Grade 2 STS, PNST | 1 | 0 | Rare |
Day 4 biopsy | No tumor | N/A | N/A | N/A | |
Day 14 biopsy | Grade 2 STS, PNST | 1 | 0 | None | |
Resected tumor | Grade 2 STS, PNST Slight edema | 1 | 0 | Rare | |
Dog 2 | Pre-treatment biopsy | Grade 1 STS, myxosarcoma Edema | 1 | 0 | Rare |
Day 4 biopsy | No tumor | N/A | N/A | N/A | |
Day 14 biopsy | No tumor Granulation tissue | N/A | N/A | N/A | |
Dog 3 | Pre-treatment biopsy | No tumor | N/A | N/A | N/A |
Day 4 biopsy | Grade 3 undifferentiated sarcoma | 6 | 0 | Rare | |
Day 14 biopsy | No tumor | N/A | N/A | N/A | |
Resected tumor | Grade 3 undifferentiated sarcoma Slight apoptosis | 2 | 10 | Rare | |
Dog 4 | Pre-treatment biopsy | Grade 1 STS, PNST | < 1 | 0 | Occasional |
Day 4 biopsy | Grade 1 STS, PNST Fibrosis and hemorrhage | <1 | 0 | Mild | |
Day 14 biopsy | Grade 1 STS, PNST | <1 | 35% | Occasional | |
Resected tumor | Grade 1 STS, PNST | <1 | 10% | Occasional | |
Dog 5 | Pre-treatment biopsy | Grade 2 STS, PNST | 1 | 5% | Mild |
Day 4 biopsy | Grade 2 STS, PNST | 1 | 10% | Occasional | |
Day 14 biopsy | Grade 2 STS, PNST | 1 | 5% | Mild | |
Resected tumor | Grade 2 STS, PNST | 1 | 50% | Moderate |
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MacNeill, A.L.; Weishaar, K.M.; Séguin, B.; Powers, B.E. Safety of an Oncolytic Myxoma Virus in Dogs with Soft Tissue Sarcoma. Viruses 2018, 10, 398. https://doi.org/10.3390/v10080398
MacNeill AL, Weishaar KM, Séguin B, Powers BE. Safety of an Oncolytic Myxoma Virus in Dogs with Soft Tissue Sarcoma. Viruses. 2018; 10(8):398. https://doi.org/10.3390/v10080398
Chicago/Turabian StyleMacNeill, Amy L., Kristen M. Weishaar, Bernard Séguin, and Barbara E. Powers. 2018. "Safety of an Oncolytic Myxoma Virus in Dogs with Soft Tissue Sarcoma" Viruses 10, no. 8: 398. https://doi.org/10.3390/v10080398
APA StyleMacNeill, A. L., Weishaar, K. M., Séguin, B., & Powers, B. E. (2018). Safety of an Oncolytic Myxoma Virus in Dogs with Soft Tissue Sarcoma. Viruses, 10(8), 398. https://doi.org/10.3390/v10080398