Evaluation of an autologous cancer vaccine for the treatment of metastatic canine hemangiosarcoma: a preliminary study.

BACKGROUND: Canine hemangiosarcoma (HSA) is an aggressive cancer arising from multipotential bone marrow-derived stem cells. Anthracycline chemotherapy drugs have been the mainstay adjuvant chemotherapy following surgery with only modest improvement in survival and an attendant risk for adverse events. Immunotherapy, using a whole cell autologous cancer vaccine adjuvanted with MIM-SIS, may improve outcomes for dogs with HSA with a lower risk for adverse events compared with chemotherapy. RESULTS: In cultured DH82 canine monocyte-like cells, autologous cancer vaccines prepared from 13 dogs with HSA increased MHC-II surface expression ranging from 20.0-60.4% on single-stained cells, CD80 surface expression ranging from 23.7-45.9% on single-stained cells, and MHC-II/CD80 surface expression ranging from 7.2-20.1% on double-stained cells. Autologous cancer vaccines were able to, on average, stimulate an up-regulation of MHC-II and CD80 by 48-fold as compared to media only (MHC-II + CD80 + cells: 12.19 ± 3.70% vs. 0.25 ± 0.06%; p < 0.001). The overall median survival time for dogs treated with the autologous cancer vaccine was 142 days (range, 61 to 373 days). Dogs treated with the autologous cancer vaccine or maximum tolerated dose (MTD) chemotherapy had significantly (P < 0.001) longer survival than dogs treated with surgery alone. The 1-year survival rate was 12.5% for dogs treated with the autologous cancer vaccine, and 0% for dogs treated with surgery alone or MTD chemotherapy. No adverse events were observed in the dogs treated with the autologous cancer vaccine. CONCLUSIONS: The adjuvanted autologous cancer vaccine is capable of up-regulating MHC-II and CD80 in cultured canine monocyte-derived cells, which are important stimulatory molecules in generating an immune response and improves survival time in dogs with metastatic (stage III) HSA when compared to surgical treatment alone. Autologous cancer vaccine-treated dogs had survival similar to those dogs treated with MTD chemotherapy without any observed adverse events. This autologous cancer vaccine represents an effective form of individualized immunotherapy that is an appealing option for dog owners not wanting to pursue adjuvant chemotherapy for HSA.

Field Safety Experience With an Autologous Cancer Vaccine in 41 Horses: A Retrospective Study (2019-2021).

Autologous cancer vaccines (ACV) are an emerging option for adjuvant cancer treatment in veterinary medicine. With this form of active immunotherapy, the patient's tumor cells are processed ex vivo and returned to the patient with the goal of stimulating an immune response to unique, patient-specific antigens. The case accession database at Torigen was queried to identify horses that underwent biopsy or surgical resection of their primary tumor and received at least one subcutaneous dose of an adjuvanted whole-cell autologous cancer vaccine. The records were then reviewed for any reported adverse events (AE). Forty-one horses met the inclusion criteria and received 252 doses of Torigen's ACV (ACV-T). There were seven AEs reported in four horses, which were associated with 1.6% of the administered doses of the ACV-T. Of the reported AE, all were characterized as mild. The ACV-T appears to be well tolerated by horses, and may be useful as a treatment option for owners who are concerned about AEs that can occur with other types of adjuvant cancer therapy. Additional studies are warranted to evaluate the efficacy of this ACV in horses with solid tumors.

Field safety experience with an autologous cancer vaccine in tumor-bearing cats: a retrospective study of 117 cases (2015-2020).

OBJECTIVES: The aim of this study was to determine the frequency and severity of adverse events (AEs) reported from use of an adjuvanted whole-cell autologous cancer vaccine in cats with solid tumors under field conditions. METHODS: The case accession database at Torigen Pharmaceuticals was searched to identify client-owned cats that underwent biopsy or surgical resection of their primary tumor, had histologic confirmation of neoplasia and received at least one subcutaneous dose of an adjuvanted whole-cell autologous cancer vaccine. Records were reviewed for any reported AEs. RESULTS: In total, 117 cats met the inclusion criteria and received 422 doses of autologous cancer vaccine. Six (5.1%) cats had seven reported AEs, with the majority of these (85.7%) being characterized as grade 1 or 2 (mild) and resolving without medical intervention. CONCLUSIONS AND RELEVANCE: AEs were infrequent in cats treated with an adjuvanted whole-cell autologous cancer vaccine under typical field use conditions. This form of active cancer immunotherapy appears to be well tolerated by cats and may represent a treatment option for owners who are concerned about AEs associated with chemotherapy or radiotherapy. Additional studies are warranted to determine the efficacy of this form of individualized immunotherapy in cats with solid tumors.

Predictive modeling for cancer drug discovery using canine models.

INTRODUCTION: Rodent models of cancer lack many features associated with the disease in humans. Because dogs closely share an environment with humans, as well as comparable pathophysiology of cancer, they represent a powerful model with which to study novel approaches to cancer treatment. AREAS COVERED: The authors summarize the weaknesses of rodent models of cancer and the ongoing need for better animal models with which to study potential therapeutic approaches. The homology of cancer in dogs and humans is described, along with examples specific to several common cancer types. EXPERT OPINION: Laboratory mice and rats will continue to play a central role in cancer research; however, because of a variety of limitations, pet dogs with spontaneous cancer offer unique opportunities for research and should be included in the preclinical development of therapeutic compounds. Environmental homology between dogs and humans, along with biological and molecular similarities present circumstances that strengthen the translational rigor of studies conducted using canine patients. Progress will depend on a sufficient number of dogs to be diagnosed with cancer and available for use in studies; and essential to this will be the availability of enhanced resources for diagnosis of cancer in canine patients and reliable coordination between research scientists, veterinarians, and physicians.

Phase I clinical trial of the use of zinc phthalocyanine tetrasulfonate as a photosensitizer for photodynamic therapy in dogs.

OBJECTIVE: To determine the threshold for acute toxicosis of parenterally administered zinc phthalocyanine tetrasulfonate (ZnPcS(4)), a candidate second-generation photosensitizer, in mice and evaluate the compound's safety in a phase I clinical trial of ZnPcS(4)-based photodynamic therapy (PDT) in pet dogs with naturally occurring tumors. ANIMALS: Male Swiss-Webster mice and client-owned dogs with naturally occurring neoplasms. PROCEDURES: For the study of acute toxicosis, mice were given graded doses of ZnPcS(4). To determine safety, a rapid-titration phase I clinical trial of ZnPcS(4)-based PDT in tumor-bearing dogs was conducted. RESULTS: In mice, administration of >or= 100 mg of ZnPcS(4)/kg resulted in renal tubular necrosis 24 hours after IP injection. In tumor-bearing dogs, ZnPcS(4) doses

Assessment of anemia as an independent predictor of response to chemotherapy and survival in dogs with lymphoma: 96 cases (1993-2006).

OBJECTIVE: To determine whether the presence of anemia (Hct < or = 37%) at the time of diagnosis of lymphoma is a negative prognostic indicator for response to treatment and survival time in dogs that are undergoing chemotherapy. DESIGN: Retrospective case series. Animals-96 dogs with lymphoma that were receiving chemotherapy. Procedures-Information regarding signalment, initial hematologic data, chemotherapy protocol, clinical response, and date of death was retrospectively collected from medical records of dogs with lymphoma. Univariate, multivariate, and survival analyses were performed to determine the effect of anemia on initial response to chemotherapy and on survival time. RESULTS: Overall, dogs without anemia (n = 56) were 4 times as likely as dogs with anemia (40) to have a complete response following chemotherapy. Anemic dogs had a significantly shorter median survival time (139 days), compared with survival time of nonanemic dogs (315 days). Subset analysis of dogs with multicentric lymphoma (matched for clinical stage and chemotherapy protocol) revealed that the dogs with anemia (n = 24) had a significantly shorter median survival time (101 days), compared with survival time of dogs without anemia (24; 284 days). Other variables were not associated with survival time. CONCLUSIONS AND CLINICAL RELEVANCE: These findings suggested that anemia is a negative prognostic factor for dogs with lymphoma that are undergoing chemotherapy. Further investigation will be necessary to determine the impact of resolution of anemia on clinical outcome in dogs with lymphoma.

Evaluation of cisplatin administered with piroxicam in dogs with transitional cell carcinoma of the urinary bladder.

OBJECTIVE: To evaluate the antitumor activity and toxic effects of a conservative dose of cisplatin administered in combination with piroxicam to dogs with transitional cell carcinoma (TCC) of the urinary bladder. DESIGN: Clinical trial (nonrandomized, noncontrolled). ANIMALS: 14 client-owned dogs with histologically confirmed TCC of the urinary bladder. PROCEDURES: Each dog was treated with cisplatin (50 mg/m(2), i.v., q 21 d [reduced to 40 mg/m(2), i.v., q 21 d because of toxic effects]) and piroxicam (0.3 mg/kg [0.14 mg/lb], PO, q 24 h). A CBC, serum biochemical analyses, and urinalysis were performed prior to each cisplatin treatment. Tumor staging (determined from thoracic and abdominal radiographic and urinary bladder ultrasonographic findings) was performed before treatment and at 6-week intervals during treatment. RESULTS: 5 dogs received only 1 dose of cisplatin because of the rapid progression of disease (n = 2) or toxic effects (3). With regard to the neoplastic disease among the other 9 dogs, 1 had partial remission, 5 had stable disease, and 3 had progressive disease after 6 weeks of treatment. Median progression-free interval was 78 days (range, 20 to 112 days). Median survival time was 307 days (range, 29 to 929 days). Moderate to severe renal toxicosis and moderate to severe gastrointestinal toxicosis developed in 5 and 8 dogs, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Because of minimal efficacy and associated renal and gastrointestinal toxicosis, administration of cisplatin (40 to 50 mg/m(2)) with piroxicam cannot be recommended for treatment of dogs with TCC of the urinary bladder.

Phase II clinical trial of combination chemotherapy with dexamethasone for lymphoma in dogs.

Dogs with histologically confirmed lymphoma were treated with a 14-week induction chemotherapy protocol that included dexamethasone. A phase II clinical trial was done using a standard two-stage design. Complete remission occurred in 21 (88%) dogs, with a median initial progression-free interval of 186 days. Toxicity was mild and self-limiting in the majority of dogs.

Effect of different components of laser immunotherapy in treatment of metastatic tumors in rats.

Induction of a long-term tumor-specific immunity is the ultimate cure of metastatic cancers. Laser immunotherapy is a novel approach that aims at the tumor-directed stimulation of the immune system of the host. It involves an intratumor administration of a laser-absorbing dye and an immunoadjuvant, followed by noninvasive laser irradiation. Previous studies using glycated chitosan (GC) as immunoadjuvant and indocyanine green (ICG) as laser-absorbing dye have shown positive effects of the treatment on metastatic breast tumors in rats. In vivo experiments showed promising results such as: (a) eradication of treated primary tumors; (b) regression of untreated metastases; (c) induced antitumor immune response; and (d) long-term resistance to tumor rechallenge. In this study, rats bearing metastatic breast tumors and metastatic prostate tumors were treated with various combinations of the three components of laser immunotherapy. The rat survival rates and profiles of primary and metastatic tumors, after treatment by individual components and various combinations of the components, were analyzed. In the treatment of breast tumors, all of the experimental groups without immunoadjuvant showed little or no positive effect. The use of GC, either by itself or in combination with other components, had a noticeable impact on the survival rate of tumor-bearing rats. However, it was the combination of all of the three components that resulted in the highest cure rate. Three different concentrations of GC, 0.5, 1, and 2%, were also used to treat the metastatic breast tumors. The results showed that 1% GC was most effective in laser immunotherapy. In the treatment of metastatic prostate tumors, both the laser-ICG and laser-ICG-GC treatments significantly reduced the growth of primary tumors and lung metastases. Long-term survival of the rats bearing the prostate tumors was also observed after the laser immunotherapy treatment in our preliminary studies. These results revealed the important function of the immunoadjuvant in laser immunotherapy.

Influence of asparaginase on a combination chemotherapy protocol for canine multicentric lymphoma.

Combination chemotherapy is superior to single-agent chemotherapy for treating canine lymphoma, but the effect of each drug on efficacy remains unknown. By comparing 34 dogs treated with a modified cyclophosphamide, vincristine, prednisone (COP) chemotherapy protocol and 42 dogs given asparaginase in the induction phase of the same protocol, the effect of asparaginase on the chemotherapeutic protocol was determined. Both groups were compared based on clinical response at 2 weeks and 6 weeks, and on the progression-free interval. Asparaginase did not significantly increase the likelihood of a clinical remission or prolong the initial progression-free interval in the dogs studied.

bcl-2 and MIB-1 labeling indexes in cats with lymphoma.

Immunohistochemistry was used to examine feline lymphoid tumors for bcl-2 and MIB-1 expression. Tumor tissues from 29 cats were selected to represent 2 groups--cats that did not respond to chemotherapy and cats that responded to therapy. Median bcl-2 immunoreactivity was 60%, and median MIB-1 reactivity was 47%. There was no significant difference in median survival time between cats with tumors with high levels of bcl-2 expression and those with low levels of expression. There was no significant difference in median survival time between cats with tumors with high levels of MIB-1 expression and those with low levels of expression. Mean bcl-2 immunoreactivity was significantly (P = .0004) higher in low-grade (73.2%) than in high-grade (16.9%) lymphomas, whereas the mean MIB-1 immunoreactivity was significantly (P = .0201) higher in high-grade (61.2%) lymphomas than in low-grade (35.0%) lymphomas. The mean bcl-2 immunoreactivity was significantly (P = .0042) greater in T-cell lymphomas (66.8%) than in B-cell lymphomas (22.8%), whereas the mean MIB-1 immunoreactivity was significantly (P = .0052) lower in T-cell lymphomas (36.4%) than in B-cell lymphomas (65.2%). Although expression of bcl-2 and MIB-1 did not appear to be linked to responses to chemotherapy in cats with lymphoma, the data suggest a possible role for these regulatory proteins in the biology of feline lymphomas.

Photodynamic therapy for the treatment of intranasal tumors in 3 dogs and 1 cat.

Three dogs and 1 cat with intranasal tumors were treated with pyropheophorbide-a-hexyl ether-based photodynamic therapy (PDT). PDT was well tolerated by all the animals, and no adverse effects from photosensitizer injection, such as cutaneous photosensitization, were observed. Facial swelling was observed in all animals after each PDT treatment but resolved spontaneously within 72 hours after treatment. All animals had a decrease in severity of epistaxis, frequency of sneezing, and amount of nasal discharge after PDT. Clinical signs were controlled for variable time, although long-term responses were comparable with radiation therapy in 2 animals. This small case series demonstrates another application for PDT in veterinary medicine. On the basis of these findings. further studies are warranted to define the role of PDT in the management of intranasal tumors in dogs and cats.

Phototoxic effects of 635-nm light on canine transitional cell carcinoma cells incubated with 5-aminolevulinic acid.

OBJECTIVE: To determine whether transitional cell carcinoma (TCC) cells incubated in media containing 5-aminolevulinic acid (ALA) would produce sufficient protoporphyrin IX (PpIX) to cause lethal phototoxic effects when exposed to 635-nm light. SAMPLE POPULATION: Canine TCC cells (K9TCC). PROCEDURE: Cultured K9TCC cells were exposed to graded doses of ALA, and PpIX concentrations were determined. Cells then were exposed to various doses of 635-nm light from a diode laser, and cell viability was assayed. RESULTS: Production of PpIX was dependent on time and dose of ALA. The K9TCC cells incubated with ALA produced sufficient PpIX to cause lethal phototoxic effects when exposed to 635-nm light. Phototoxic effects were dependent on time and dose of ALA. Increasing laser power density and energy density decreased cell survival. CONCLUSIONS AND CLINICAL RELEVANCE: ALA is an effective photosensitizer for in vitro photodynamic treatment of K9TCC cells. Further studies are warranted to assess the safety and efficacy of ALA as a photosensitizer for use in treating dogs with TCC. Impact for Human Medicine-On the basis of this study, dogs with TCC may be useful in the development of protocols for ALA-based photodynamic therapy of humans affected with muscle-invasive bladder cancer.

Concurrence between clinical and pathologic diagnoses in a veterinary medical teaching hospital: 623 cases (1989 and 1999).

OBJECTIVE: To determine whether there was a decline in the percentage of dogs undergoing necropsies and whether there was substantial agreement or disagreement between clinical and pathologic diagnoses. DESIGN: Retrospective study. ANIMALS: 623 dogs. PROCEDURE: Medical records of hospitalized dogs that died or were euthanatized and necropsied at a veterinary teaching hospital in 1989 and 1999 were reviewed. Clinical and pathologic diagnoses were recorded and compared. RESULTS: There was a significant decline in the necropsy rate of hospitalized dogs that died or were euthanatized in 1999, compared with 1989. In both 1989 and 1999, there was disagreement between the clinical and pathologic diagnoses in approximately a third of the cases. CONCLUSIONS AND CLINICAL RELEVANCE: Despite improved diagnostic methods, the accuracy of diagnosis did not improve significantly in 1999, compared with 1989. Necropsy is the best method to assess overall diagnostic accuracy. Increased availability of teaching funds may promote efforts to have necropsies performed in veterinary teaching hospitals.

Histologic comparison of skin biopsy specimens collected by use of carbon dioxide or 810-nm diode lasers from dogs.

OBJECTIVE: To compare histologic artifacts caused by carbon dioxide (CO2) or 810-nm diode surgical lasers used to obtain small biopsy specimens of skin from healthy dogs. DESIGN: Prospective study. ANIMALS: 4 dogs. PROCEDURE: 21 skin biopsy specimens were collected from each dog. Three biopsy specimens were obtained with a CO2 or an 810-nm diode laser at 3 operating settings each, and 3 biopsy specimens were obtained with a 6-mm biopsy punch instrument (controls). After processing, biopsy specimens were examined for artifacts related to laser-tissue interactions. Microscopically visible char was measured from the lateral edge of each specimen obtained with a laser. RESULTS: There were no significant differences among mean char distances in biopsy specimens obtained with the CO2 laser at various settings. Mean char distance was significantly greater in all skin biopsy specimens obtained with the diode laser, compared with those obtained with the CO2 laser. Mean char distance was significantly greater in biopsy specimens obtained with the 810-nm diode laser at high power, compared with biopsy specimens obtained with the 810-nm diode laser at low power. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that the CO2 laser caused less thermal injury at margins of skin biopsy specimens; therefore, if a surgical laser is used for removal of cutaneous masses or to obtain skin biopsy specimens, use of the CO2 laser is recommended. Veterinarians performing a biopsy by using a surgical laser should be aware that laser-induced artifacts may render small biopsy specimens useless for providing accurate histologic diagnosis.

Photodynamic therapy for companion animals with cancer.

Photodynamic therapy is an emerging form of cancer therapy in veterinary medicine, which capitalizes on a photochemical reaction to kill malignant cells. Photodynamic therapy has been used to successfully treat a variety of veterinary cancers, with documented efficacy similar to radiation therapy. However, equipment expense and availability of photosensitizer have limited the widespread use of photodynamic therapy by veterinarians.

Sentinel lymph node mapping of invasive urinary bladder cancer in animal models using invisible light.

OBJECTIVES: With conventional methodology, sentinel lymph node (SLN) mapping of invasive urinary bladder cancer is technically challenging. This study was performed to determine the utility of invisible, near-infrared fluorescent (NIRF) light for patient-specific SLN mapping, in real time under complete image guidance. METHODS: Lymphatic tracers, injection volume, NIRF excitation fluence rate, light collection of emitted fluorescence, and degree of bladder distension were systematically optimized in normal dogs and pigs. SLN mapping was then performed in pet dogs with naturally occurring invasive transitional cell carcinoma (InvTCC) of the urinary bladder, which closely mimics the human disease. RESULTS: NIRF albumin (hydrodynamic diameter [HD], 7.4 nm) and NIRF quantum dots (15-20 nm HD) injected into the bladder wall resulted in identification of draining lymph nodes (LNs) in under 3 min. In both species, considerable variability in the lymphatic drainage was observed among individuals. Optimal SLN mapping was achieved with the use of superficial, serosal injection of NIRF tracer, with the bladder distended to an intraluminal pressure of 20-40 cm H(2)O. In dogs with InvTCC, NIRF tracers identified SLNs that were confirmed histologically to harbor metastases. CONCLUSIONS: The use of invisible NIRF light permits real-time, patient-specific identification of SLNs that drain bladder cancer. Intraluminal bladder pressure is a key parameter that needs to be controlled for optimal results.

Effect of wavelength on low-intensity laser irradiation-stimulated cell proliferation in vitro.

BACKGROUND AND OBJECTIVES: There exist contradictory reports about low-intensity laser light-stimulated cell proliferation. The purpose of this study was to determine the effect of wavelength on proliferation of cultured murine cells. STUDY DESIGN/MATERIALS AND METHODS: Proliferation of primary cell cultures was measured after irradiation with varying laser wavelengths. RESULTS: Fibroblasts proliferated faster than endothelial cells in response to laser irradiation. Maximum cell proliferation occurred with 665 and 675 nm light, whereas 810 nm light was inhibitory to fibroblasts. CONCLUSIONS: These observations suggest that both wavelength and cell type influence the cell proliferation response to low-intensity laser irradiation.

Selective laser-induced hyperthermia for the treatment of spontaneous tumors in dogs.

Indocyanine green (ICG), with spectral absorption at 800-810 nm, is a chromophore that strongly absorbs and converts near-infrared laser energy into thermal energy. By directly injecting ICG into a tumor, selective tumor hyperthermia during laser irradiation occurs. In this study, 4 dogs with spontaneous tumors were injected in situ with a 0.25% wt/vol ICG solution and immediately irradiated with 810 nm laser energy. Thermal data were collected from multiple thermocouples placed within the tumor and tumor response was recorded. Tissue heating to ≥ 42°C was observed in all tumors. One dog had a complete remission, one dog had stable disease for 12 weeks, and the other 2 dogs developed progressive disease shortly after treatment. Results from this study demonstrate that chromophore-enhanced laser-induced hyperthermia can effectively and selectively heat canine tumors. However, tumor size and pigmentation of overlying skin are potentially limiting factors to the success of this novel c ancer treatment.