CANCER IMMUNOTHERAPY IN VETERINARY ONCOLOGY
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1 CANCER IMMUNOTHERAPY IN VETERINARY ONCOLOGY Matt Dowling, DVM, MS, Practice limited to Oncology Staff Oncologist VCA Northwest Veterinary Specialists
2 Overview Cancer and the immune system Introduction to immunotherapy Non-specific vs. specific Biologic response modifiers Recombinant cytokine therapy Cancer vaccines Melanoma Osteosarcoma Monoclonal antibodies Lymphoma Metronomic chemo Future directions
3 Cancer and the Immune System Spontaneous cancer remission Histiocytomas, TVT Immune infiltrate in solid tumors Canine MGTs Cancer in the immunosuppressed Diminished immune surveillance Immunomodulator-induced cancer remissions Infections, cancer, and improved survival Limb sparing procedures in dogs with OSA
4 Cancer and the Immune System Immune evasion by cancer Immunosuppressive cytokines IL-10 TGF-β Regulatory T cells Myeloid-derived suppressor cells Down regulation of MHC Class I Attenuation of B7
5 Cancer and the Immune System Immune evasion by cancer
6 Immunotherapy Definition: treatment of a disease by altering the host s immune response Non-specific immunotherapy TLR and NLR activation NK cells and macrophages/ monocytes Little memory Specific immunotherapy Vaccines, monoclonal antibodies Effector T cells Memory
7 Biologic response modifiers Non-specific immunotherapy Augmented immune response through antigen stimulation Coley s toxins Streptococcus pyogenes Serratia marcesens
8 Biologic response modifiers Bacillus Calmette-Guérin (BCG) Live, attenuated Mycobacterium bovis Intravesicular bladder instillation Canine cancer Mammary carcinomas Osteosarcoma Lymphoma LDI-100 (BCG + hcg) in canine mast cell tumors
9 Biologic response modifiers L-MTP-PE Liposomal-encapsulated muramyl tripeptide phosphatidylethanolamine Synthetic analog of peptidoglycan cell wall NLR-agonist Potent macrophage stimulator Veterinary medicine Osteosarcoma* Hemangiosarcoma Anti-metastatic properties
10 Biologic response modifiers Imiquimod Toll-like receptor 7 agonist Primary mechanism: Induction of IFNα and TH1 response Activation of macrophages/ monocytes Neutrophil chemotaxis B cell activation Bowen s disease in cats Actinic keratosis and solarinduced SCC in dogs
11 Recombinant cytokine therapy IL-2 Released by T cells Clonal expansion of T cells NK cell response Canine pulmonary carcinoma Aerosolization IL-2 vaccine Europe Feline fibrosarcomas In combo with surgery and RT Longer time to disease recurrence compared to historic control
12 Cancer Vaccines
13 Cancer Vaccines Malignant melanoma Oncept melanoma vaccine Xenogenic DNA vaccine Human tyrosinase* Transdermal administration 4 initial doses q 2 weeks, then q 6 months Immunogenicity Tyrosinase Ab production Demonstration of a specific T cell response
14 Cancer Vaccines DNA vaccines and the immune response
15 Cancer Vaccines Oncept melanoma vaccine Disputed efficacy Bergman et al. (2003) and Liao et al. (2006) à favorable response, MST = 389 d n=9, uncontrolled Grosenbaugh et al. (2011) à apparent survival benefit n=58, use of historical controls, high rate of patient censorship Ottnod et al. (2013) à no survival benefit n=22 vaccinees, n=23 control dogs Treggiari et al (2016) à no survival benefit No control group; other adjuvant therapy was not standardized
16 Cancer Vaccines Osteosarcoma Phase I clinical trial with DNA vaccine
17 Cancer Vaccines Osteosarcoma Attenuated, live Listeria monocytogenes expressing human HER2 Dose-escalation phase I clinical trial n=18 dogs Vaccinated with 3 doses q 3 weeks, then q 4-6 months Dogs received standard of care prior to vaccination Dogs had HER2+ tumors Minimal toxicity noted Reduced incidence of metastatic disease and improved overall survival *compared to historic controls
18 Cancer Vaccines Listeria vaccine technology
19 Cancer Vaccines Immune response to HER2 vaccine T cell response IFNγ release in response to exposure to HER2 Identified early and late responders within group No dose-dependent effect on immune response Dogs that developed IFNγ response to HER2 at > 6 months tended to have better long term survival
20 Monoclonal antibodies
21 Monoclonal antibodies Monoclonal antibody generation
22 Monoclonal antibodies Canine lymphoma B cell lymphoma CD20 mab Use in combo with CHOP à longer remission time and overall survival Use in combo with doxorubicin à improved progression free survival T cell lymphoma CD52 mab Preliminary results do not reveal survival benefit Reduced manufacturing
23 Metronomic chemotherapy Combination therapy Low-dose alkylating agent NSAID Anti-angiogenic Immunomodulatory Down regulation of regulatory T cells Soft tissue sarcomas Hemangiosarcoma Metastatic sarcomas and carcinomas
24 Future directions Modified T cell transfer CAR technology Checkpoint molecule inhibitors CTLA-4, PD-1 - mabs Results in significantly increased spontaneous T cell anti-tumor immunity No veterinary use to date T regulatory cell depletion mab technology? New vaccines! CSPG-4 vaccine for melanoma
25 References Regan D, Guth A, Coy J, Dow S. Cancer immunotherapy in veterinary medicine: Current options and new developments. The Veterinary Journal Jan;207:20 8. Mitchell L, Thamm DH, Biller BJ. Clinical and Immunomodulatory Effects of Toceranib Combined with Low-Dose Cyclophosphamide in Dogs with Cancer. Journal of Veterinary Internal Medicine Mar;26(2): Killick DR, Stell AJ, Catchpole B. Immunotherapy for canine cancer - Is it time to go back to the future? Journal of Small Animal Practice Apr;56(4): Bergman PJ. Immunotherapy in Veterinary Oncology. Veterinary Clinics of North America: Small Animal Practice Sep; 44(5): Mason NJ, Gnanandarajah JS, Engiles JB, Gray F, Laughlin D, Gaurnier-Hausser A, et al. Immunotherapy with a HER2- Targeting Listeria Induces HER2-Specific Immunity and Demonstrates Potential Therapeutic Effects in a Phase I Trial in Canine Osteosarcoma. Clinical Cancer Research Sep 1;22(17): Kwak Y, Kim H-E, Park SG. Insights into Myeloid-Derived Suppressor Cells in Inflammatory Diseases. Archivum Immunologiae et Therapiae Experimentalis Aug;63(4): Bergman PJ, McKnight J, Novosad A, Charney S, Farrelly J, Craft D, et al. Long-Term Survival of Dogs with Advanced Malignant Melanoma after DNA Vaccination with Xenogeneic Human Tyrosinase A Phase I Trial. Clinical Cancer Research. 2003;9(4): Burton JH, Mitchell L, Thamm DH, Dow SW, Biller BJ. Low-Dose Cyclophosphamide Selectively Decreases Regulatory T Cells and Inhibits Angiogenesis in Dogs with Soft Tissue Sarcoma: Metronomic Cyclophosphamide Decreases Treg and Angiogenesis. Journal of Veterinary Internal Medicine Jul;25(4): Wycislo KL, Fan TM. The Immunotherapy of Canine Osteosarcoma: A Historical and Systematic Review. Journal of Veterinary Internal Medicine May;29(3):
26 Questions?
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