Immunotherapy and imaging diagnosis of canine cancers
Date Issued
2011
Date
2011
Author(s)
Chuang, Tien-Fu
Abstract
Cancer is the most common disease-associated cause of death or euthanasia in older canines. Among canine cancers, mammary gland tumor (MGT) is the most common tumor in female canines accounting for near 50% of all tumors and around 50% of those MGT is malignant. The oral melanoma accounted for 20% to 50% of oral malignancies and has been routinely considered an extremely aggressive tumor. So far, surgical excision is the most widely accepted treatment for MGT and oral melanoma, however, it offers poorly on long term prognostic or preventing metastasis in malignant cases. Other adjunctive therapies, such as chemotherapy, radiation or hormone therapy, cannot effectively promote the therapeutic effect of surgical removal. In this thesis, we looked for new approaches to therapy malignant MGT and oral melanoma and to achieve a good quality of life in canine patients.
First, according to recent achievement in targeted therapy and immunotherapy, we applied a recombinant rat Her2 xenogeneic DNA vaccine, pING-rHer2, to treat canine malignant MGTs following surgical removal of the tumor masses. Twenty-nine canines with MGT were enrolled in this program and were divided into two groups, control (surgical removal only) and Her2 (combined treatment, surgery plus vaccination). The DNA vaccine was delivered by two transdermal injections followed by an intramuscular electroporation. The antigen-specific ELIspot IFN-γ response elicited by pIGN-rHer2 DNA vaccinations was a clear demonstration that this vaccine was able to overcome tolerance to the Her2 self antigen under clinically relevant conditions. Furthermore, the results demonstrated that surgery combined with pING-rHer2 DNA vaccination significantly restrained the tumor growth and distant mestastasis, and substantially postponed post-surgical recurrence in canine spontaneous malignant MGT. The vaccine significantly prolonged the patients overall survival time in the Her2 group. In addition, there was no detectable side effect. In conclusion, this xenogeneic DNA vaccine should be further considered as a potential immunotherapy of canine malignant MGT.
Second, because the use of an allogeneic bone marrow-derived dendritic cell (BMDC)/tumor cell fusion vaccine to treat canine oral malignant melanoma has not been documented and the efficacy of the BMDC/syngeneic melanoma cell fusion vaccine was evaluated in canine oral melanoma patients. We also compared the clinical benefits for patients between single treatments and a combination protocol of surgery/fusion vaccine. Thirty-one canines with stage III oral melanoma were enrolled in this program and were divided into three groups, SR (surgical removal only), VO (vaccination only) and CT (combined treatment, surgery plus vaccination). The vaccine significantly improved the overall survival time in the CT group (259 days; 90–350 days) in comparison with the VO (124 days; 43–231days) and SR groups (82 days; 50–140 days). Moreover, the CT protocol dramatically decreased the metastatic rate and delayed in situ recurrence; it also stimulated potent tumor cell-specific cytotoxic T lymphocytes (CTL). In addition, the population of Treg cells in peripheral blood decreased significantly in the CT canines in comparison with the other groups. Besides, there was no clinically-detectable toxicity. These results indicate that surgical removal combined with the allogeneic BMDC/syngeneic tumor cell fusion vaccine was the effective treatment protocol for late-stage canine oral melanoma and resulted in an improvement in quality of life. It is suggested that this combined protocol can be considered one of the treatments of choice for canine oral melanoma and has the potential to be used in other mammals.
Furthermore, we have developed new image technique to indicate immunotherapy response sooner than anatomic changes depicted by traditional modalities, and less invasively than histological sampling. Regarding immunotherapy of cancer, PET/CT has been used in mice models to evaluate antitumor response. There are few researches in monitoring the efficacy of cancer immunotherapy in larger animal models such as canines using PET/CT. Canine transmissible venereal tumor (CTVT) can be experimentally transplanted to allogeneic canines. CTVT is an ideal model for cancer study. Previously, we have publisded that intratumoral electroporation of pIL-12 resulted in successful tumor regression and attracted significantly more lymphocytes infiltrating to the tumors in the canine CTVT model. CTVT metabolism can be measured by serial FDG-PET scansand the change of tumor in the early phase can be detected. At 60 min after FDG delivery, there was a stable trend of FDG uptake ratio in CTVT. The pIL-12 immunotherapy resulted inhigher FDG uptake ratios per volume of CTVT, which can be detected as early as 19 days after CTVT inoculation. Delivery of pIL-12 and FDG did not result in any detectable toxicity in the canines. The FDG PET/CT early detect the tumor growth pattern. The ability of FDG PET/CT to measure tumor growth directly after the commencement of treatment may provide an early indicator of the success of therapy. Immediately, the strategies of treatment will be managed. The FDG PET/CT will improve the diagnosis of the efficacy and successful rate of future immunotherapy clinical trials in cancer patients. Therefore, these protocols have the potential to be used in other canine cancers.
Canine cancers may serve as an important bridge between preclinical studies in mouse model systems and clinical trials in humans with cancer and support the synergy of collaborations between veterinary and human cancer centers. Such collaboration will result in the development of therapy in canines cancers and has shown promising results in humans.
Subjects
Canine
Mammary gland tumor
Oral melanoma
Immunotherapy
Her2 DNA vaccine
Fusion vaccine
FDG PET/CT
SDGs
Type
thesis
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