Immunologic Effects of Stereotactic Body Radiotherapy in Dogs with Spontaneous Tumors and the Impact of Intratumoral OX40/TLR Agonist Immunotherapy
Abstract
:1. Introduction
2. Results
2.1. Combination Radiation Therapy and Immunotherapy Study Design and Animal Enrollment
2.2. Immune Infiltrates and Impact of SBRT and Immunotherapy
2.3. Immune Gene Expression in Tumor Tissues and Impact of SBRT and Immunotherapy
2.4. Serum Cytokine Responses Following Treatment with SBRT or SBRT and Immunotherapy
2.5. Impact of SBRT or SBRT and Immunotherapy on Tissue Vascularity and Oxygenation
2.6. Treatment Responses to SBRT and SBRT and Immunotherapy
3. Discussion
4. Materials and Methods
4.1. Study Design
4.2. Tissue Sampling
4.3. Histological and Immunohistochemical Evaluation and Quantitative Image Analysis
4.4. Gene Expression Analysis
4.5. Serum Cytokine Analysis
4.6. Tumor Oxygenation
4.7. Determination of Tumor Responses, Progression Free Survival and Overall Survival Times
4.8. Toxicity Grading Criteria
4.9. Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Signalment | Tumor Type and Location | Tumor Volume | Injection Type and Volume | Stage of Disease at Time of Treatment | SBRT Protocol |
---|---|---|---|---|---|
12y MC Australian Terrier | Melanoma (mandible) | 5.5 cm3 | Vehicle control (PBS) (2 mL injections) | Primary tumor | 10 Gy × 3 |
13y FS Mixed Breed | Carcinoma (salivary gland) | 66 cm3 | Vehicle control (PBS) (3 mL injections) | Primary tumor, Distant (pulmonary) metastasis | 10 Gy × 3 |
10y MC Labrador Retriever | Melanoma (maxilla) | 51.9 cm3 | Vehicle control (PBS) (3 mL injections) | Primary tumor | 10 Gy × 3 |
3y MC German Shepherd | Soft tissue sarcoma (mandible) | 8.6 cm3 | Vehicle control (PBS) (2 mL injections) | Primary tumor | 6 Gy × 5 |
9y FS Maltese | Melanoma (maxilla) | 17.9 cm3 | Vehicle control (PBS) (3 mL injections) | Primary tumor | 10 Gy × 3 |
15y MC Mixed Breed | Carcinoma (maxilla) | 9.8 cm3 | Vehicle control (PBS) (2 mL injections) | Primary tumor | 10 Gy × 3 |
13y FS Miniature Dachshund | Carcinoma (salivary gland) | 30.1 cm3 | OX40/TLR agonists (200 mg OX40 in 3 mL; 10 mg polyIC/10 mg pDNA in 3 mL) | Primary tumor, Regional (nodal) metastasis | 8 Gy × 5 |
8y MC Mixed Breed | Soft tissue sarcoma (maxilla) | 112.7 cm3 | OX40/TLR agonists (200 mg OX40 in 3 mL; 10 mg polyIC/10mg pDNA in 3 mL) | Primary tumor | 8 Gy × 5 |
10y MC Labrador Retriever | Melanoma (maxilla) | 2.3 cm3 | OX40/TLR agonists (100 mg OX40 in 1 mL; 5 mg polyIC/5 mg pDNA in 1 mL) | Primary tumor | 10 Gy × 3 |
10y MC Mixed Breed | Melanoma (maxilla) | 33.8 cm3 | OX40/TLR agonists (200 mg OX40 in 3 mL; 10 mg polyIC/10 mg pDNA in 3 mL) | Primary tumor | 10 Gy × 3 |
10y FS Labrador Retriever | Carcinoma (mandible) | 35.5 cm3 | OX40/TLR agonists (200 mg OX40 in 3 mL; 10 mg polyIC/10 mg pDNA in 3 mL) | Primary tumor | 10 Gy × 3 |
9y FS Miniature Poodle | Soft tissue sarcoma (axilla) | 69.9 cm3 | OX40/TLR agonists (200 mg OX40 in 3 mL; 10 mg polyIC/10 mg pDNA in 3 mL) | Primary tumor | 8 Gy × 5 |
Signalment 1 | Tumor Type and Location | Treatment Response | Progression Free Survival (Days) | Pattern of Failure | Overall Survival Time (Days) | Cause of Death |
---|---|---|---|---|---|---|
12y MC Australian Terrier | Melanoma (mandible) | Progressive disease | 75 | Local, Regional, Distant | 452 | Local, Regional, Distant |
13y FS Mixed Breed | Carcinoma (salivary gland) | Stable disease | 115 | Distant | 477 | Local, Regional, Distant |
10y MC Labrador Retriever | Melanoma (maxilla) | Complete response | 147 | Local | 147 | Local |
3y MC German Shepherd | Soft tissue sarcoma (mandible) | Partial response | 127 | Local | 262 | Local |
9y FS Maltese | Melanoma (maxilla) | Complete response | 260 | Local | 371 (alive at the time of analysis) | Alive at the time of analysis |
15y MC Mixed Breed | Carcinoma (maxilla) | Complete response | 154 | Local | 162 | Local |
13y FS Miniature Dachshund | Carcinoma (salivary gland) | Progressive disease | 19 | Regional (out-of-field) | 52 | Regional (out-of-field) |
8y MC Mixed Breed | Soft tissue sarcoma (maxilla) | Stable disease | 114 | Distant | 224 | Distant |
10y MC Labrador Retriever | Melanoma (maxilla) | Partial response | 260 | Local, regional (nodal), distant | 635 | Local, Regional, Distant |
10y MC Mixed Breed | Melanoma (maxilla) | Partial response | 82 | No evidence of progression at time of death | 82 | Other (Acute collapse) |
10y FS Labrador Retriever | Carcinoma (mandible) | Progressive disease | 79 | Regional (out-of-field) | 192 | Other (Acute kidney injury) |
9y FS Miniature Poodle | Soft tissue sarcoma (axilla) | Stable disease | 433 (no progression) | No evidence of progression at time of analysis | 433 | Alive at the time of analysis |
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Boss, M.-K.; Watts, R.; Harrison, L.G.; Hopkins, S.; Chow, L.; Trageser, E.; Easton, C.; LaRue, S.M.; Regan, D.; Dewhirst, M.W.; et al. Immunologic Effects of Stereotactic Body Radiotherapy in Dogs with Spontaneous Tumors and the Impact of Intratumoral OX40/TLR Agonist Immunotherapy. Int. J. Mol. Sci. 2022, 23, 826. https://doi.org/10.3390/ijms23020826
Boss M-K, Watts R, Harrison LG, Hopkins S, Chow L, Trageser E, Easton C, LaRue SM, Regan D, Dewhirst MW, et al. Immunologic Effects of Stereotactic Body Radiotherapy in Dogs with Spontaneous Tumors and the Impact of Intratumoral OX40/TLR Agonist Immunotherapy. International Journal of Molecular Sciences. 2022; 23(2):826. https://doi.org/10.3390/ijms23020826
Chicago/Turabian StyleBoss, Mary-Keara, Remy Watts, Lauren G. Harrison, Sophie Hopkins, Lyndah Chow, Erin Trageser, Carina Easton, Susan M. LaRue, Daniel Regan, Mark W. Dewhirst, and et al. 2022. "Immunologic Effects of Stereotactic Body Radiotherapy in Dogs with Spontaneous Tumors and the Impact of Intratumoral OX40/TLR Agonist Immunotherapy" International Journal of Molecular Sciences 23, no. 2: 826. https://doi.org/10.3390/ijms23020826