Human anti-mouse antibody suppression with cyclosporin A.

BACKGROUND: Cyclosporin was used in an attempt to suppress the formation of human antimouse antibody (HAMA) after administration of murine monoclonal antibodies. METHODS: Thirteen patients were given oral cyclosporin (8.6-15 mg/kg/day) starting 2 days before administration of technetium-99m (99mTc) labeled F(ab')2 (3 patients) or Fab (10 patients) murine antibody fragment. Six to nine days later, patients received either rhenium-186 (186Re)-labeled F(ab')2 or an intact antibody. Cyclosporin was continued for 14 days after the second antibody administration. RESULTS: Five patients (38%) did not develop elevated HAMA titers for up to 8 weeks after antibody administration. These five patients had a median cyclosporin concentration of 726 ng/ml, while the eight patients who developed HAMA had a median cyclosporin level of 364 ng/ml. In contrast, when not given cyclosporin, 86% (24/28) of patients developed HAMA after receiving two doses of F(ab')2, and 100% (15/15) developed HAMA after receiving Fab followed by intact antibody. Toxicity from cyclosporin included elevation concentrations of bilirubin and creatinine, and increased blood pressure, which rapidly resolved after the cyclosporin was discontinued. CONCLUSIONS: This study demonstrates that cyclosporin given from 2 days before until 2 weeks after administration of either a F(ab')2 or intact murine antibody can suppress HAMA formation. This strategy may permit administration of repeated doses of murine-antibody-based radioimmunotherapy.

Clinical experience with rhenium-186-labeled monoclonal antibodies for radioimmunotherapy: results of phase I trials.

Rhenium is a radionuclide with physical and chemical properties suitable for radioimmunotherapy. Two Phase I trials were carried out using 186Re-labeled murine monoclonal antibodies. Patients with refractory metastatic epithelial carcinoma received single doses of either 186Re-labeled intact NR-LU-10, a pancarcinoma antibody, 25-120 mCi/m2 (n = 15) or 186Re-labeled F(ab')2 fragment of NR-CO-02, an anti-CEA variant antibody, 25-200 mCi/m2 (n = 31). Prior to radioimmunotherapy, tumor localization of antibody was confirmed by 99mTc-labeled NR-LU-10 Fab or 99mTc-labeled NR-CO-02 F(ab')2 imaging. Dose-limiting myelosuppression was observed at 120 mCi/m2 following 186Re-NR-LU-10 intact antibody and at 150 mCi/m2 following NR-CO-02 F(ab')2 fragment in heavily pretreated patients. In patients with minimal prior therapy, a maximum tolerated dose for NR-CO-02 F(ab')2 was not reached by 200 mCi/m2. Non-marrow toxicity was minimal. Human anti-mouse antibody developed in all patients receiving intact NR-LU-10, and in 86% patients receiving F(ab')2 NR-CO-02. One patient treated with 186Re NR-CO-02 achieved a partial response. We conclude that 186Re-labeled antibody can be safely administered with significant toxicity limited to marrow.

Recombinant leukocyte A interferon therapy for advanced hairy cell leukemia. Therapeutic and immunologic results.

Hairy cell leukemia is a lymphoproliferative disorder characterized clinically by cytopenias. Standard therapy following variable periods of disease stability consists of splenectomy that often restores normal hematologic parameters for periods ranging from weeks to years. Fifteen patients (five without prior splenectomy or chemotherapy) were treated with 3 X 10(6) units per day of recombinant leukocyte A interferon and 14 of 15 patients completed eight weeks of therapy and were evaluated for response. There was one complete and 12 partial responses for an overall response rate of 93 percent. All of these patients' conditions have remained in complete or partial remissions and they continue to receive interferon with a median follow-up of six months. Coincident with the normalization of peripheral blood counts was a return of natural killer activity and normalization of immunologic surface markers as determined by monoclonal antibodies. This study confirms and extends earlier observations with natural alpha-interferon and indicates that recombinant leukocyte A interferon in low daily doses is also very effective treatment for hairy cell leukemia. In fact, it may be the best single modality of therapy for inducing both hematologic and immunologic recovery of these patients and deserves consideration as initial therapy.

Phase II trial of recombinant leukocyte A interferon in patients with advanced chronic lymphocytic leukemia.

Recombinant leukocyte A interferon is a highly purified single molecular species of alpha-interferon prepared by recombinant DNA methods. In 1982, a phase II trial to evaluate the efficacy of recombinant leukocyte A interferon for patients with previously treated chronic lymphocytic leukemia was begun, and 19 patients were entered in this study. Patients received one of two dose schedules depending on their pretreatment platelet counts. Those with platelet counts greater than 100,000/mm3 received 50 X 10(6) units/m2 intramuscularly three times weekly, with dose reductions to 25 X 10(6) units/m2 and 5 X 10(6) units/m2 for unacceptable toxicity. Those with platelet counts less than 100,000/mm3 received 5 X 10(6) units/m2 intramuscularly three times weekly. Toxicity was dose-dependent and included fever, chills, fatigue, anorexia, myalgias, headache, leukopenia, and thrombocytopenia. Response was evaluable in all but one of the patients entered in this study. Two of the 12 patients treated with 50 X 10(6) units/m2 had a partial response, three had no response, and seven had progressive disease. Of the six patients starting at 5 X 10(6) units/m2 in whom response was evaluable, two had no response and four had progressive disease. Five patients with progressive disease (three at 50 X 10(6) units/m2 and two at 5 X 10(6) units/m2) had an acceleration of disease while receiving recombinant leukocyte A interferon. It is concluded that the dose and schedule of recombinant leukocyte A interferon therapy tested in this study are not effective in previously treated patients with advanced chronic lymphocytic leukemia.

Atypical tumor lysis syndrome in a patient with T cell lymphoma treated with recombinant leukocyte interferon.

Biochemical and clinical signs of tumor lysis syndrome developed in a 57-year-old man with recurrent T cell lymphoma during therapy with recombinant leukocyte A interferon. When therapy was interrupted due to thrombocytopenia and later resumed, biochemical changes compatible with tumor lysis recurred. This is the first case of tumor lysis syndrome observed during therapy with a biologic response modifier, a new class of agents entering cancer clinical trials. The atypical features of the clinical presentation and possible implications of these observations are discussed.

Treatment of advanced non-Hodgkin's lymphoma with recombinant leukocyte A interferon.

We report the results of a trial of recombinant leukocyte A interferon in previously treated patients with non-Hodgkin's lymphoma who were no longer responsive to chemotherapy. Patients received recombinant leukocyte A interferon (50 X 10(6) U per square meter of body-surface area) by intramuscular injection three times weekly for three months or longer. Forty-five patients were enrolled in the study, and 37 were evaluated for a response. Thirteen of 24 (54 per cent) evaluable patients with low-histologic-grade non-Hodgkin's lymphoma had objective responses (nine partial responses and four histologically confirmed complete responses). Two of six (33 per cent) with intermediate-grade lymphoma responded (one partially and one completely), and one of seven (14 per cent) with high-grade lymphoma had a partial response. The median duration of responses was eight months. Four of the five complete responders have continued to receive maintenance interferon and have been in complete remission for 3, 7, 9, and 12 months, respectively; one had a recurrence at a site of previous disease seven months after interferon had been stopped. Side effects were noted in most patients. All 16 responders had been heavily pretreated with combination chemotherapy, including doxorubicin in 8 of the 16. These results suggest that recombinant leukocyte A interferon may be an effective new therapy for some patients with low- and intermediate-grade non-Hodgkin's lymphoma.

Treatment of canine transmissible venereal tumor by intravenous administration of protein A.

To determine if protein A can induce tumoricidal effects, transmissible venereal tumor-bearing dogs were treated by intravenous protein A administration. Each dog in the experimental group was treated twice a week with protein A, 100 micrograms/kg body weight, for a total of 10 treatments. Control dogs were treated with a 0.9% sodium chloride solution. No decrease in tumor volume attributable to protein A treatment was observed. However, transient healing of ulcerated tumors was observed in two dogs in the protein A-treated group but not in any in the control group. Following the first inoculation of protein A, a significant transient increase in polymorphonuclear cells and a significant transient decrease in lymphocyte and monocyte counts was detected, with a return of the counts to pretreatment levels by 24 h after the last protein A treatment. Intravenous protein A administration also failed to induce tumor regression in a guinea pig and a murine tumor model. These results suggest that the antitumor effects observed in protein A immunoadsorption studies have not been induced by leakage of protein A into the circulation.

High-dose VP-16-213 and autologous bone marrow transplantation for refractory malignancies: a phase I study.

VP-16-213, a congener of epipodophyllotoxin, is a useful chemotherapeutic agent especially against small-cell carcinoma of the lung, germ cell carcinoma, and lymphoma. The standard dose of this drug is limited by myelosuppression. Autologous transplantation of cryopreserved bone marrow assures the restoration of hematopoiesis after marrow ablative cytotoxic therapy. By using this technique, VP-16-213 was dose-escalated using a Fibonacci scheme from the previous highest dose administered to humans (1,500 mg/m2) to 2,700 mg/m2 (900 mg/m2 per day for three consecutive days). At 2,700 mg/m2, severe extramedullary toxicity of the mucous membranes was observed in three of three courses. At the next highest dose (2,400 mg/m2), two of 18 courses (11%, p less than 0.01) resulted in severe mucositis, thus defining this dose as the maximally tolerated dose based on extramedullary toxicities. As anticipated, myelotoxicity was severe but based on the kinetics of marrow recovery, VP-16-213 in these doses appeared not to be marrow ablative. Based on responses observed in this study, high-dose VP-16-213 should be explored in phase II studies or used in combination chemotherapy.

Randomized study of high-dose versus low-dose methotrexate in the treatment of extensive small cell lung cancer.

Forty patients with extensive small cell lung cancer randomly received either high-dose or low-dose methotrexate with leucovorin rescue in combination with cycles of cyclophosphamide, doxorubicin, and vincristine alternating with cycles of VP-16, vincristine, and hexamethylmelamine. Nineteen patients were treated with the high-dose methotrexate regimen, and 21 received the low-dose methotrexate treatment protocol; both treatment groups were similar in median age, performance status and spread of disease. Response rates (74 percent for high-dose therapy; 67 percent for low-dose therapy), median survival (nine months versus nine months), and overall survival were similar for the two treatment groups. Myelosuppression was equivalent in both treatment groups but moderate to severe mucositis developed more often when patients were treated with the high-dose methotrexate regimen as compared with low-dose methotrexate therapy (p less than 0.001). Central nervous system recurrences developed after three patients received high-dose methotrexate therapy. This study indicates that when used with other antineoplastic agents, high-dose methotrexate therapy does not improve the remission rate or survival nor does it decrease central nervous system metastasis in patients with small cell lung cancer when compared with standard doses of methotrexate; high-dose methotrexate is associated with greater cost and toxicity.

Cyclophosphamide, doxorubicin, and cisplatin in the treatment of advanced non-small cell lung cancer.

Fifty-four patients with non-small cell lung cancer were treated with a combination of cyclophosphamide, doxorubicin, and cisplatin (CAP). A 35% response rate was seen, with a median survival of 380 days for the responders, compared to median survival times of 150 days for the nonresponders and 229 days for the group. Twenty-four percent of these patients had received prior treatment. All of the nonresponding patients had died by 438 days, whereas eight of 19 responders lived greater than 425 days. The survival curve the nonresponders was similar to that for a historical control group not given chemotherapy. These data indicate that this drug regimen has some efficacy in the treatment of non-small cell lung cancer.

Cancer and the kidney: complications of neoplasms.

Various renal complications occur during the course of neoplastic disease. The therapeutic and prognostic implications differ according to the reversibility of both the underlying malignancy and the superimposed complications in the kidney. Since the mechanisms of renal failure vary significantly in patients with different types of malignancy, it is essential to avoid generalizations about etiologic factors or likely outcomes of the disease processes. The pathophysiologic abnormalities should be determined in each patient, and the reversibility of both the neoplastic and problems assessed before therapeutic decisions are made. This often requires a team effort by the internist, oncologist, nephrologist, urologist and, most importantly, the patient.

Unusual survival after pulmonary artery sarcoma.

A 46-year-old man with a primary sarcoma of the pulmonary artery is presented. The tumor was responsive to radiotherapy, and the patient is the longest reported survivor of this rare disease. The tumor spread distally in the pulmonary vasculature, with probable embolization to the central nervous system, and he died 27 months after the initial diagnosis, with sudden massive hemoptysis. Pulmonary artery sarcomas are a rare cause of obstruction of the right ventricular outflow. The course of our patient suggests that early recognition and therapy may provide some of these patients with effective palliation and prolonged survival.

The unrecognized extragonadal germ cell cancer syndrome.

Within 3 years we saw 12 patients diagnosed initially as having poorly differentiated or undifferentiated carcinomas who, we believe, actually had extragonadal germinal cancers. Serum levels of the beta subunit of human chorionic gonadotropin (beta-HCG) or alpha-fetoprotein were useful in suggesting and supporting the diagnosis: Levels of one or the other were elevated in six of 10 patients in whom they were measured but levels of both, in only one patient. Staining of histologic specimens for beta-HCG or alpha-fetoprotein showed intracellular localization of one of these markers in the cancer cells of all four patients studied. All patients responded to therapy (11 treated with chemotherapy with or without radiotherapy, one with excision and radiotherapy only), with complete remissions in seven of 12. Two of the patients who had a complete remission have experienced relapse, and five have continued in disease-free remission from more than 8 to more than 56 months. Histologically atypical extragonadal germ cell neoplasms may be commoner than previously supposed. Physicians should consider this treatable and potentially curable cancer in selected patients having poorly differentiated or undifferentiated carcinomas.

Cushing's syndrome with small cell carcinoma of the uterine cervix.

A 28 year old white women was found to have a cervical tumor in the 25th week of pregnancy. Pathologic examination revealed a nonkeratinizing small cell carcinoma. After delivery by cesarean section, pelvic lymph node exploration was carried out, and all 15 nodes were free of tumor. Her condition was staged as II-A, and she was treated with local radiation. Metastatic disease became manifest almost a year later and was histologically similar to her primary disease. A Cushingoid appearance was noticed and plasma cortisol levels were elevated. Twenty-four hour urinary 17-hydroxycorticosteroid (17-OHCS) and 17-ketosteroid (17-KS) levels were elevated and failed to suppress with dexamethasone. Plasma adrenocorticotropin (ACTH) level was elevated. Electron microscopic examination of the tumor tissue revealed neurosecretory granules. Immunoperoxidase stains for ACTH were positive. The patient's course was one of progressive decline and eventual death. A literature review revealed two other cases in which carcinoma of the uterine cervix was considered to be the source of ectopic ACTH. Some small cell carcinomas of the cervix may arise from cells of the APUD series. Small cell carcinoma of the uterine cervix may behave differently from the more commonly encountered keratinizing and large cell nonkeratinizing carcinomas of the cervix and may not respond as well to standard therapy. Ectopic hormone production, production of abnormal peptides or of vasoactive amines may be more common in small cell carcinoma of the cervix than is currently recognized, and these products may be clinically useful as tumor markers.