Phase I clinical evaluation of carboplatin in tumor-bearing cats: a Veterinary Cooperative Oncology Group study.

BACKGROUND: The dosage of carboplatin in cats has been reported anecdotally and experimentally in non-tumor-bearing cats, but the dosage for carboplatin treatment in tumor-bearing cats has yet to be defined in a prospective clinical trial. PURPOSE: To determine the maximally tolerated dose (MTD) and dose-limiting toxicosis (DLT) of carboplatin in tumor-bearing cats. CATS: Fifty-nine cats with measurable solid tumors. METHODS: The starting dose of carboplatin was 160 mg/m(2) of body surface area IV. Doses were increased by 20 mg/m(2) in cohorts of 3-14 cats until the MTD was reached. RESULTS: The 59 cats entered into this multi-institutional phase I study received 1 or more doses of carboplatin at various dosages and were evaluated for toxicity, response to treatment, or both. The MTD was 240 mg/m(2) and neutropenia was the DLT. For the 1st cycle of treatment in 44 cats evaluated for neutropenia, 6 episodes of grade 3 or greater neutropenia occurred on days 7 (n=1), 14 (n=4), and 21 (n=1). There was no evidence of drug-induced nephrotoxicosis or pulmonary edema. Preliminary evidence of antitumor activity was observed in 7 of 59 (11.9%; 95% CI, 5.6-22.8%) cats evaluated for response to treatment. There was 1 complete response (cutaneous hemangiosarcoma) and 6 partial responses (4 injection site sarcomas, 1 oral squamous cell carcinoma, 1 lymphoma). Responses were of short duration (median, 42 days; range, 7-168 days). CONCLUSIONS AND CLINICAL IMPORTANCE: The dose of carboplatin recommended to treat tumor-bearing cats is 240 mg/m(2) IV every 3-4 weeks.

Intralymphatic injection of BCG into rhesus monkeys.

Since the route of administration of BCG may have an important function in immunotherapy, we investigated intralymphatic administration to direct BCG to the lymph nodes. Multiple injections of high doses of BCG were administered to 6 rhesus monkeys via the dorsal lymphatics of the lower limb. A suppurative lymphadenitis was observed along the lower limb and in the inguinal area in 5 of the 6 monkeys. However, many of the complications reported with other routes of administration were not observed. Granulomatous reactions and histiocytic responses developed in lymph nodes on the injected sides of the pelvis and distant nodes as well as in the liver. The intralymphatic route is the method by which high doses of nonspecific immunostimulants were delivered to regional lymph nodes. The efficacy of this approach remains to be established in tumor-bearing animals and humans.

Phase I clinical trial with a human major histocompatibility complex nonrestricted cytotoxic T-cell line (TALL-104) in dogs with advanced tumors.

The human TALL-104 cell line is endowed with a uniquely potent MHC nonrestricted tumoricidal activity across several species. In view of the potential applicability of TALL-104 cells as an anticancer agent, this study was conducted to evaluate the possible toxicity and efficacy of this new cell therapy in a superior animal model with spontaneous tumors. Nineteen canine cases with advanced, refractory malignancies of various histological types were entered in the study. All dogs had failed all other available treatments and had very limited life expectancy. Cyclosporin A was administered p.o. (10 mg/kg/day) starting from the day before TALL-104 cell administration throughout the treatment to prevent rejection of the xenogeneic effectors. Lethally irradiated (40 Gy) TALL-104 cells (10(8)/kg) were administered systemically following two treatment schedules. In the first schedule, the cells were given every other day for 2 weeks in a row and then once a week for 3 additional weeks; in the second schedule, TALL-104 cells were administered daily for a total of 5 days. None of the 19 cases showed significant clinical or laboratory toxicity; in addition, none of the dogs had to be withdrawn from the study because of immediate adverse reactions to the infusions. The severe side effects usually associated with classical lymphokine-activated killer therapy in association with high doses of interleukin 2, such as "capillary leak syndrome," were absent in this study. Remarkably, TALL-104 therapy induced various degrees of antitumor effects in 7 of the 19 dogs, including 1 complete response (continuing at +13 months), three partial responses (duration of 2 months, 3 months, and continuing at +2 months), and three transient responses. Clinical responses and immunological parameters correlated well in each case. Taken together, these data indicate that systemic administration of lethally irradiated TALL-104 cells in the absence of exogenous interleukin 2 may be regarded as a safe and promising adjuvant type of treatment for advanced cancer patients.

Successful treatment of canine malignant histiocytosis with the human major histocompatibility complex nonrestricted cytotoxic T-cell line TALL-104.

The human MHC nonrestricted cytotoxic T-cell line TALL-104 exerts potent antitumor effects in animal models with both induced and spontaneous cancers. The present report documents the ability of systemically delivered TALL-104 cells to induce durable clinical remissions in four of four dogs with malignant histiocytosis (MH). The animals received multiple i.v. injections of lethally irradiated (40 Gy) TALL-104 cells at a dose of 10(8) cells/kg, with (two dogs) or without (two dogs) cyclosporin A, followed by monthly boosts. No significant clinical or laboratory toxicities developed during cell therapy; interestingly, a strong correlation was found between the dogs' clinical and immunological responses. One dog with advanced disease (intrathoracic involvement) refractory to chemotherapy achieved a complete remission (CR) within 2 months of the first TALL-104 cell infusion. This dog died 14 months later of unrelated causes: histological analysis of its organs postmortem revealed no evidence of neoplasia, thus confirming the achievement of CR also at the pathological level. The other three dogs with MH that at diagnosis had multiple s.c. and cutaneous lesions and lymphadenopathy, but no visceral involvement, were treated with TALL-104 cells as single agent (no chemotherapy was administered). Two of these dogs achieved a CR soon after cell therapy, and the third dog had two long-lasting partial responses; CR in this dog was later achieved by combined administration of chemotherapy and cell therapy. None of the three dogs that received cell therapy at diagnosis developed visceral disease in the approximately 9-22 months of follow-up. The clinical responses experienced by all four MH cases to TALL-104 cell therapy suggest the high responsiveness of this canine tumor to these xenogeneic effectors and their therapeutic potential even in the most aggressive forms of the disease.

Adjuvant treatment of canine osteosarcoma with the human cytotoxic T-cell line TALL-104.

The human cytotoxic T-cell line TALL-104 has been used successfully to treat cancer in experimental mouse models with implanted tumors and in dogs with spontaneously occurring malignancies. This study investigated the efficacy of TALL-104 cells given in an adjuvant setting to dogs with appendicular osteosarcoma after surgery and chemotherapy. Of the 23 dogs enrolled in the study, 20 had undergone amputation of the affected limb, and 3 had undergone limb salvage surgery. After surgery, all dogs but one received cisplatin (CDDP) chemotherapy (60 mg/m2 i.v. every 21 days x 1-4 cycles). Four dogs also received one to six cycles of CDDP before limb amputation. After CDDP therapy, dogs without overt metastasis received gamma-irradiated (40 Gy) TALL-104 cells systemically (10(8)/kg) for 5 consecutive days, followed by 2-day monthly boosts (at the same dose) for a total of 9 months. Of the 23 dogs treated, 9 survive disease-free at 12.1-29.5 months after surgery, 11 died of metastatic disease between 5 and 21.5 months, 1 experienced a relapse in the lung 9.5 months after surgery but is still alive without further treatment at 13 months, 1 developed severe discopathy at 4 months after surgery, and 1 developed progressive neuropathy at 5.9 months after surgery. The overall median survival time is 11.5 months, and the median disease-free interval is 9.8 months. Our cell therapy results compare favorably with historical median survival times (up to 9 months) and disease-free intervals (up to 7.5 months) of dogs with osteosarcoma receiving standard therapy (surgery and chemotherapy) and support the effectiveness of adjuvant TALL-104 cell administration in preventing or delaying disease recurrence in these dogs.

Adoptive therapy of canine metastatic mammary carcinoma with the human MHC non-restricted cytotoxic T-cell line TALL-104.

Adoptive transfer of human TALL-104 killer cells into a dog with metastatic mammary adenocarcinoma resulted in 50% reduction of the largest lung metastasis and stabilization of the other lesions for 10 weeks, accompanied by the development of tumor-specific immune responses. Upon halting cell therapy, the dog developed new lung lesions within 10 weeks and died of slowly progressive disease. TALL-104 cell therapy of mice bearing the dog's tumor xenograft induced 65% reduction of local tumor growth and regression of lung metastases in 100% of the animals. The overall findings indicate the therapeutic potential of TALL-104 cells for canine mammary tumors.

In vivo destruction of canine lymphoma mediated by murine monoclonal antibodies.

The effect of murine anti-canine lymphoma monoclonal antibodies (MAbs) on tumor cell lysis by thioglycolate activated murine macrophages in vitro and tumor growth inhibition in athymic mice was studied. All IgG1 and IgG2a MAbs tested were able to promote specific destruction of canine lymphoma 17-71 cell line by activated macrophages. A correlation between higher ADCC activity and MAb isotype was not clearly evident. In vivo IgG2a and IgG1 MAbs inhibited the growth of canine lymphoma. These results suggest that MAbs of IgG type have potential in immunotherapy of dogs with lymphoma since they have high tumoricidal activity in vivo.

Chemotherapy of canine hemangiosarcoma with doxorubicin and cyclophosphamide.

Sixteen dogs with a histologic diagnosis of hemangiosarcoma were treated with surgery and doxorubicin/cyclophosphamide. The patients' characteristics, ie, age, size, and breed, were similar to those of previous studies. Historic controls for surgery alone were used to evaluate efficacy of the chemotherapy. The results show a trend of improved survival in dogs with localized disease (Stage I) receiving combination therapy. The median survival was 250 days, with a mean of 403 days. The survival times for dogs with stage I, II, and III disease was also improved with combination therapy, when compared to historical controls treated with surgery alone. The overall median survival was 202 days with a mean of 285 days. Toxicities included mild to moderate neutropenia (9 of 16) and clinical signs, such as lethargy, anorexia, vomiting, diarrhea, and fever (13 of 16). Three dogs had severe neutropenia requiring hospitalization and supportive care. One dog died from sepsis and related complications. Chemotherapy with doxorubicin and cyclophosphamide appears to improve survival with acceptable morbidity in patients with early stage disease.

Treatment of relapsed canine lymphoma with doxorubicin and dacarbazine.

Fifteen dogs with relapsed lymphoma were treated with doxorubicin and dacarbazine (ADIC) to reinduce remission. All the dogs' lymphomas had become resistant to prior therapy with doxorubicin alone. Five of the 15 dogs had a complete response to the first treatment with ADIC, and three had partial responses. Of the eight dogs receiving a second cycle, two had complete responses, and one had a partial response. One dog that received a third ADIC treatment no longer responded. The median survival time from the first ADIC treatment for all dogs was 45 days (range, 18-241 days). The five dogs having complete responses to the first ADIC treatment had a median survival time of 105 days (range, 45-241 days) after this treatment. Toxicity due to ADIC treatment was acceptable and did not exceed that seen when doxorubicin was given as a single agent. The treatment resulted in severe neutropenia in three dogs. One dog died due to neutropenic sepsis. Vomiting, diarrhea, and anorexia occurred, but were tolerable, resulting in hospitalization in only one instance. ADIC is apparently a useful chemotherapeutic combination to reinduce remission in some dogs with relapsed lymphoma.

In vitro immune monitoring of antibody response in dogs given chemoimmunotherapy for lymphoma.

Clinical remission in 30 dogs with lymphoma was induced with a combination of vincristine, L-asparaginase, cyclophosphamide, and doxorubicin HCl, administered sequentially, and then an autochthonous tumor cell vaccine, given intralymphatically, as maintenance therapy. Humoral antibody amounts were monitored in 11 dogs, using a solid-phase bead-type radioimmunoassay. The median survival of the 30 dogs was 13 months from the start of chemotherapy (range, 7 to 25 months; mean, 13.8). The median remission duration was 16 weeks (range, 9 to 98 weeks; mean, 26.8). Correlation between increase in amount of humoral antibody was significant (P = 0.0001 to 0.012), before and after chemoimmunotherapy, in dogs responding to therapy, compared with that in dogs not responding to therapy.

Chemotherapy of lymphoma in 75 cats.

Seventy-five cats with lymphoma were treated with combination sequential chemotherapy consisting of vincristine, cyclophosphamide, and methotrexate. Thirty-nine cats had mediastinal, 16 had multicentric, 14 had alimentary, and 6 had renal lymphoma. The median survival time of the 75 cats was 8 weeks, with a mean of 32 weeks. Sixty-two cats had follow-up evaluation until death or cure and had a median survival time of 7 weeks, with a mean of 37 weeks. Of the 62 cats, 32 (52%) attained complete remission, with a median remission duration of 16 weeks and a mean of 46 weeks. The addition of prednisolone and/or L-asparaginase to the protocol did not improve the results. Sixteen cats with multicentric lymphoma had the longest survival times (median, 18 months) and remission durations (median, 25 months). Prognostic factors were evaluated in each anatomic form of lymphoma.

Chemotherapy of advanced mammary adenocarcinoma in 14 cats.

Fourteen cats with advanced mammary adenocarcinoma were treated with doxorubicin HCl and cyclophosphamide. All cats had inoperable or recurrent disease, and 9 cats had metastasis to the thorax. Eleven of the cats were available for long-term evaluation; 3 had complete response to chemotherapy, with survival times of 180, 283, and 344 days; 2 had partial response, with survival times of 45 and 149 days; 2 had stabilization of disease, with survival times of 170 and 182 days; and 4 had no response, with survival times of 4, 47, 67, and 106 days.

Malignant angioendotheliomatosis with retinal detachments in a dog.

A Golden Retriever with bilateral conjunctival hyperemia, chemosis, and blepharospasm was determined to have malignant angioendotheliomatosis, which is an uncommon neoplastic disorder of dogs and human beings. It was believed to be of endothelial origin, but evidence in human beings indicates a lymphoid origin. The histogenesis of the disease in the dog was confirmed to be of lymphoid origin by use of a canine lymphoma-specific immunoperoxidase assay. The prognosis for malignant angioendotheliomatosis in dogs is poor, but with early diagnosis, the condition is potentially manageable.

Chemoimmunotherapy of canine lymphoma with adjuvant canine monoclonal antibody 231.

Chemoimmunotherapy with adjuvant CL/MAb 231 offers an alternative treatment approach for canine lymphoma. Results of treatment and prognostic factors are discussed and compared with previously published chemotherapy results.

Immunomodulation of hematopoietic tumors.

Immunotherapy has been used in a variety of hematopoietic and solid tumors. Because patients with leukemia and lymphoma are immunosuppressed, immunomodulation with chemotherapy may be beneficial. Chemoimmunotherapy of canine lymphoma is discussed.

Oral tumors: the surgeon and the medical oncologist.

Aggressive surgery has been the primary treatment for oral tumors through the 1980s. A review of the results of such treatment is presented. A new approach using neoadjuvant chemotherapy is proposed in order to improve long-term prognosis in malignant oral tumors.

Canine lymphoma-associated antigens defined by murine monoclonal antibodies.

Lymphoma in dogs resembles human non-Hodgkin's lymphoma in pathological presentation, immunophenotype, and response to therapy, thus representing a good model for comparative studies with human disease. Monoclonal antibodies (MAbs) were derived from mice immunized with a dog lymphoma cell line. Three MAbs were selected for further application in immunophenotyping and immunotherapy. The binding specificities, antigen characterization, and isotypes for these MAbs are described.

Cytolytic activity of murine anti-dog lymphoma monoclonal antibodies with canine effector cells and complement.

Peripheral blood leukocytes (PBL), nonadherent lymphocytes, and adherent monocytes separated from freshly isolated blood of 15 dogs were analyzed for their ability to mediate antibody-dependent cell-mediated cytotoxicity (ADCC) in combination with murine anti-tumor monoclonal antibodies (MAbs). Canine monocytes isolated from most donors by adherence to gelatin-fibronectin-coated plastic surface presented high ADCC activity against the canine lymphoma 17-71 tumor cell line in combination with antilymphoma MAbs 231 (IgG2a) and 234-2a (IgG2a). Canine lymphocytes generally showed lower ADCC activity than total PBL or monocytes. Canine PBL effector cells showed high ADCC activity against the human colorectal carcinoma SW948 cell line using the Y-6-specific MAb isotype switch variants 55-2 IgG3, 55-2 IgG1, 55-2 IgG2b, and 55-2 IgG2a. Analysis of the role of murine MAb isotypes on ADCC activity against tumors by canine cells using anti-human tumor class-switch variant MAbs and a panel of anti-canine lymphoma MAbs of different IgG subclass revealed the highest ADCC activity with MAbs of the IgG2a and IgG3 subclasses. IgG2a antilymphoma MAbs were also able to lyse tumor cells in complement-dependent cytotoxicity (CDC) assay. These results suggest the potential value of MAbs of IgG3 and IgG2a subclasses in immunotherapy against canine lymphoma.

Enhanced antitumor effects with intralymphatic delivery using bacillus Calmette-Guerin in animal models.

This study compares the effectiveness of various routes of administration of Bacillus Calmette-Guerin (BCG) utilizing the New Zealand white (NZW) rabbit V2 carcinoma model. The routes compared were intratumor, intravenous, scarification, subcutaneous, and intralymphatic. Primary tumor regression, disease-free interval, and survival were measured. The disease-free interval and survival for the intralymphatic group were significantly longer (p less than 0.05) than all groups except the scarification group. That group had a prolonged survival as compared with all groups except the intralymphatic group. The intralymphatic route of administration was the most effective method in causing local tumor regression and curtailing metastasis. This study clearly demonstrates that the intralymphatic route requires further mechanistic studies and clinical investigation as a means for delivering biological response modifiers.