CD40-activated B cell cancer vaccine improves second clinical remission and survival in privately owned dogs with non-Hodgkin's lymphoma.

Cell-based active immunotherapy for cancer is a promising novel strategy, with the first dendritic cell (DC) vaccine achieving regulatory approval for clinical use last year. Manufacturing remains arduous, especially for DC vaccines, and the prospect of using cell-based immunotherapy in the adjuvant setting or in combination with chemotherapy remains largely untested. Here, we used a comparative oncology approach to test the safety and potential efficacy of tumor RNA-loaded, CD40-activated B cells in privately owned dogs presenting with non-Hodgkin's lymphoma (NHL), a clinical scenario that represents not only a major problem in veterinary medicine but also a bona fide spontaneous animal model for the human condition. When administered to NHL dogs in remission after induction chemotherapy, CD40-B cells electroporated ex vivo with autologous tumor RNA safely stimulated immunity in vivo. Although chemotherapy plus CD40-B vaccination did not improve time-to-progression or lymphoma-specific survival compared to dogs treated with chemotherapy alone, vaccination potentiated the effects of salvage therapy and improved the rate of durable second remissions as well as subsequent lymphoma-specific survival following salvage therapy. Several of these relapsed dogs are now long-term survivors and free of disease for more than a year. Overall, these clinical and immunological results suggest that cell-based CD40 cancer vaccination is safe and synergizes with chemotherapy to improve clinical outcome in canine NHL. More broadly, our findings underscore the unique value of clinical investigations in tumor-bearing companion animals.

Clinical and pharmacokinetic characteristics of intracavitary administration of pegylated liposomal encapsulated doxorubicin in dogs with splenic hemangiosarcoma.

BACKGROUND: Canine splenic hemangiosarcoma (HSA) is a fatal malignancy, and most affected dogs die within a few months of diagnosis. Most dogs present with signs from tumor rupture, resulting in hemoabdomen and intra-abdominal dissemination. The abdomen is also the main site of disease recurrence. HYPOTHESIS: Intraperitoneal (IP) administration of doxorubicin will delay or prevent intra-abdominal tumor recurrence and prolong survival in dogs with HSA. ANIMALS: Fourteen dogs with splenic HSA. METHODS: A prospective, unmasked, uncontrolled clinical trial. After staging of disease status and splenectomy, pegylated liposomal encapsulated doxorubicin was administered intraperitoneally (1 mg/kg body weight) every 3 weeks for 4 cycles. All dogs were monitored for recurrence of HSA. Samples of plasma and abdominal fluid were collected for measurement of doxorubicin concentration and pharmacokinetic analysis. Nonlinear mixed-effect modeling was used to describe the pharmacokinetics of liposomal doxorubicin administered IP. RESULTS: All 14 dogs died, 12 because of HSA and 2 from other causes. Postmortem examination was performed on 12 dogs. All 12 dogs died because of HSA-related causes and had hepatic metastases and hemoabdomen. The IP-treated dogs had fewer serosal, mesenteric, and omental metastases than historical controls treated with systemic doxorubicin. Results of the postmortem examination and pharmacokinetic analysis confirmed that IP delivery of doxorubicin resulted in an effective drug concentration with a clearance comparable with that after i.v. delivery. CONCLUSIONS AND CLINICAL IMPORTANCE: IP pegylated liposomal encapsulated doxorubicin administration did not prevent intraabdominal recurrence of HSA in dogs.

Association between ovarihysterectomy and feline mammary carcinoma.

The etiopathogenesis of feline mammary carcinoma is not well understood. Although putative, risk factors include breed, reproductive status, and regular exposure to progestins. An association between age at ovarihysterectomy (OHE) and mammary carcinoma development has not been established. Therefore, a case-control study was performed to determine the effects of OHE age, breed, progestin exposure, and parity on feline mammary carcinoma development. Cases were female cats diagnosed with mammary carcinoma by histological examination of mammary tissue. Controls were female cats not diagnosed with mammary tumors selected from the same biopsy service population. Controls were frequency matched to cases by age and year of diagnosis. Questionnaires were sent to veterinarians for 308 cases and 400 controls. The overall questionnaire response rate was 58%. Intact cats were significantly overrepresented (odds ratio [OR] 2.7, confidence interval [CI] = 1.4-5.3, P < .001) in the mammary carcinoma population. Cats spayed prior to 6 months of age had a 91% reduction in the risk of mammary carcinoma development compared with intact cats (OR 0.9, CI = 0.03-0.24). Those spayed prior to 1 year had an 86% reduction in risk (OR 0.14, CI = 0.06-0.34). Parity did not affect feline mammary carcinoma development, and too few cats had progestin exposure to determine association with mammary carcinoma. Results indicate that cats spayed before 1 year of age are at significantly decreased risk of feline mammary carcinoma development.

Clinical characteristics of mammary carcinoma in male cats.

There is little information regarding mammary tumors in male cats. The purpose of this study was to characterize the clinical characteristics of mammary carcinoma in male cats, compare this malignancy to the disease in female cats, and identify prognostic factors. Thirty-nine male cats with mammary carcinoma were identified. One pathologist reviewed the biopsies from all cats, and complete follow-up information regarding outcome was available for 27 cats. Information collected included signalment, age at neutering, history of progestin therapy, age at tumor diagnosis, size of tumor, type of surgery (lumpectomy, simple mastectomy, or radical mastectomy), results of clinical staging, adjunctive therapies, time to local recurrence, survival, and cause of death. The mean age at tumor diagnosis (12.8 years) was slightly older than that reported in female cats. The incidence of local tumor recurrence in 9 of 20 (45%) cats was similar to that reported in females. A history of progestin therapy was present in 8 of 22 (36%) cats for which this information was known. The median time to local recurrence was 310 days (range 127-1,363 days), and overall median survival was 344 days (range 14-2,135 days). Tumor size and lymphatic invasion were identified as negative prognostic factors. This study indicates that mammary carcinoma in the male cat has many similarities to the disease in females, with an aggressive clinical course in most cats.

Efficacy and toxicity of a dose-intensified doxorubicin protocol in canine hemangiosarcoma.

The purpose of this study was to evaluate the efficacy and toxicity of a single-agent, dose-intensified doxorubicin protocol in canine hemangiosarcoma (HSA). Canine HSA is a highly malignant tumor, and most affected dogs die within 6 months of diagnosis. Doxorubicin is the most, and possibly the only, effective chemotherapeutic drug for this malignancy, but it provides only moderate improvement in survival. On the basis of previous studies reporting similar survival in dogs treated with doxorubicin as a single agent and doxorubicin-based combination chemotherapy and the concept of summation dose intensity, a dose-intensified single-agent doxorubicin protocol was initiated. Twenty dogs with HSA were recruited to participate in this study. Workup and staging were performed according to standard practice. Chemotherapy was initiated within 3 weeks of surgery. Doxorubicin was scheduled to be administered at 30 mg/m2 i.v. every 2 weeks for a total of 5 treatments. The dogs were monitored for toxicity and signs of recurrence during and at regular intervals after chemotherapy. The protocol was tolerated well. No dogs were hospitalized because of adverse effects or developed clinical signs consistent with doxorubicin-induced cardiomyopathy. There was a significant difference in survival in dogs with stage I and I1 HSA compared with dogs with stage III HSA. with median survival times of 257, 210, and 107 days, respectively. These results are slightly better than the historical control with respect to toxicity and efficacy but are not statistically different from what is achieved with standard treatments. There was no association between dose intensity and outcome.