HspE7 treatment of pediatric recurrent respiratory papillomatosis: final results of an open-label trial.

Objectives: We sought to evaluate the effectiveness of HspE7, a recombinant fusion protein of Hsp65 from Mycobacterium bovis BCG and E7 protein from human papillomavirus 16, to improve the clinical course of pediatric patients with recurrent respiratory papillomatosis.

Methods: An open-label, single-arm intervention study was conducted in 8 university-affiliated medical centers. Twenty-seven male and female patients with recurrent respiratory papillomatosis, ages 2 to 18 years, were enrolled and followed up to 60 weeks.

CoVal fusions: a therapeutic vaccine platform using heat shock proteins to treat chronic viral infection and cancer.

We have developed an immunization platform which combines heat shock proteins (Hsp) with protein antigens, such as viral or cancer targets, into a single recombinant fusion protein. Pre-clinical data demonstrate the ability of Hsp fusion proteins to induce antigen-specific cytotoxic T lymphocytes, Type 1 cytokines and anti-tumour immunity. One Hsp fusion protein, HspE7, is now in clinical development for therapy of diseases caused by human papillomavirus (HPV).

Activity of HspE7, a novel immunotherapy, in patients with anogenital warts.

Purpose: Human papillomavirus causes anogenital squamous intraepithelial lesions, warts, and cancer. Treatment of squamous intraepithelial lesions to prevent cancer often requires extensive surgery. We tested a human papillomavirus-specific immunotherapy, HspE7, as a potential alternative.

Phase II trial of tirapazamine combined with cisplatin in chemotherapy of advanced malignant melanoma.

Purpose: A phase II study was undertaken to determine the efficacy of tirapazamine (TPZ) combined with cisplatin (cDDP) in patients with metastatic melanoma.

Patients And Methods: Between June 1994 and November 1995, 48 patients with metastatic melanoma were treated with TPZ (260 mg/m2, administered intravenously over two hours) followed in one-hour by cDDP (75 mg/m2 over one hour) every 21 days. Sixteen patients had received prior chemotherapy, and 13 of these had failed to respond to prior cDDP.

Evaluation of low dose continuous infusion 5-fluorouracil in patients with advanced and recurrent renal cell carcinoma. A Southwest Oncology Group Study.

Background: The response rate of metastatic renal cell cancer to cytotoxic therapy over the last 10 years has been 5.6%. Low dose continuous 5-fluorouracil (5-FU) has demonstrated efficacy in other cytotoxic refractory tumors, such as pancreas, colorectal, and recurrent breast.

Phase II evaluation of amonafide in advanced sarcoma: a Southwest Oncology Group study.

Soft tissue sarcomas are generally resistant to most chemotherapeutic agents, and individuals with advanced disease have a poor prognosis. We evaluated amonafide, a new drug that has significant activity against several tumor cell lines, to determine its activity against sarcomas. Amonafide was administered to 18 patients with advanced soft tissue sarcoma (16 of whom had received prior chemotherapy) at a dose of 300 mg/m2 over 60 min daily for 5 days.

5-fluorouracil and interferon-alpha-2a in advanced colorectal cancer. Results of two treatment schedules.

Background: Potential synergy between 5-fluorouracil (5-FU) and interferon alpha-2a (IFN-alpha-2a) has been demonstrated in the treatment of colorectal carcinoma. Continuous low-dose infusion of 5-FU may have superior response rates to bolus 5-FU in these malignancies. This report presents results of two Phase II trials using these principles in colorectal cancer.

Prolonged, alternating chemotherapy for extensive small cell lung cancer. A Southwest oncology Group study.

Background: Etoposide may be schedule dependent in small cell lung cancer (SCLC), and some data suggest a benefit for increased dose intensity in this disease. This study attempted to optimize dose intensity using an outpatient program that included prolonged, oral etoposide administration.

Methods: Cisplatin-etoposide (PE) and cyclophosphamide, doxorubicin, and vincristine (CAV) were alternated at monthly intervals in patients with extensive SCLC.

Evaluation of cisplatin intensity in metastatic non-small-cell lung cancer: a phase III study of the Southwest Oncology Group.

Purpose: To test the concept that cisplatin dose-intensity is important in the treatment of non-small-cell lung cancer (NSCLC), the Southwest Oncology Group (SWOG) performed a randomized trial comparing standard-dose cisplatin (SDCP) 50 mg/m2 days 1 and 8 on a 28-day cycle for eight cycles, high-dose cisplatin (HDCP) 100 mg/m2 days 1 and 8 for four cycles, and high-dose cisplatin plus mitomycin (HDCP-M) 8 mg/m2 day 1. To isolate the effects of dose-intensity versus total dose, the planned cumulative cisplatin dose was 800 mg/m2 in each arm.

Patients And Methods: Between July 1988 and April 1990, 356 patients were enrolled and 323 were eligible and assessable.

A randomized phase II trial of trimetrexate or didemnin B for the treatment of metastatic or recurrent squamous carcinoma of the uterine cervix: a Southwest Oncology Group trial.

Patients with measurable metastatic or recurrent squamous carcinoma of the uterine cervix who had failed prior surgery or radiation therapy were enrolled on this randomized phase II study. Twenty-seven eligible patients were assigned to receive didemnin B at either 2.6 mg/m2 iv every 28 days (sixteen patients) or at 5.

Acquired factor VIII inhibitor.

Development of a circulating inhibitor of the coagulant activity of factor VIII is a rare event producing a clinical picture similar to that of classic hemophilia. A case of autoimmune factor VIII inhibitor has been presented. Although a hemostatic response was rapidly achieved with the infusion of factor IX concentrates, immunosuppressive therapy was initiated.

Phase II trial of recombinant DNA gamma-interferon in advanced colorectal cancer: a Southwest Oncology Group study.

Fifty evaluable patients with advanced colorectal cancer, but without prior chemotherapy or immunotherapy, were randomized to one of two schedules of recombinant gamma-interferon (rGIFN). Twenty-four evaluable patients received rGIFN as a 2-h intravenous infusion daily x 5 every other week at a starting dose of 4.0 x 10(6) IU/m2/day (arm I).

Mechanisms of interaction of interferon and 5-fluorouracil in solid tumors.

Recent clinical trials demonstrate the combined activity of 5-fluorouracil (5-FU) and interferon (IFN) in advanced colon cancer. Several possibilities exist for explaining the interaction. Interferon may alter the pharmacokinetics of 5-FU infusion by increasing the steady state concentration.

Abrogation of interferon-induced resistance to interferon-activated major histocompatibility complex-unrestricted killers by treatment of a melanoma cell line with 5-fluorouracil.

Advanced cancer responds clinically to combined therapy with recombinant interferon-alpha and 5-fluorouracil. Although the two agents may interact in the biosynthetic pathway for thymidine, we investigated, as an alternative mechanism, the regulation of susceptibility of the A375 human melanoma to natural killers activated by interferon. A375 were preincubated with 5-fluorouracil, interferon, or both sequentially prior to assay as targets for cell-mediated killing.

Phase II study of recombinant alpha-interferon in malignant melanoma.

Ninety-seven evaluable patients with measurable, advanced, malignant melanoma were treated with recombinant alpha interferon in a cooperative phase II efficacy trial, whose primary objective was to estimate the response rate. Interferon (rIFN alpha-2a, Roferon-A) was injected subcutaneously daily for 70 days. Dose was escalated in four steps from three million units to 36 million units over ten days.

A phase II trial of recombinant tumor necrosis factor in patients with metastatic colorectal adenocarcinoma: a Southwest Oncology Group study.

Tumor necrosis factor (TNF) induces hemorrhagic necrosis in the Meth A mouse tumor model and has shown cytostatic and cytotoxic antitumor effects against a wide range of human tumors both in vitro and as human tumor xenografts in nude mice. Because of in vitro activity against colorectal tumors and antitumor responses in colon cancer patients in phase I trials, this phase II study was undertaken. Patients were treated with TNF administered daily for 5 days/week every other week at a dose of 150 micrograms/m2/day as a 30-min i.

Lack of common haplotype among four family members with late-onset Kaposi's sarcoma.

Kaposi's sarcoma is associated with an increased frequency of HLA-DR5. The hypothesized model of a susceptibility gene in linkage disequilibrium with DR5 may be tested by haplotype analysis in familial Kaposi's sarcoma. Our finding of no common haplotype among afflicted members of a family provides evidence against the hypothesized linkage.

Therapy of advanced gastric carcinoma. The Georgetown-Lombardi Cancer Center experience.

Gastric carcinoma, despite a decreasing incidence in the United States over the past 40 years, is the seventh most common cause of cancer death in this country and remains a significant worldwide problem. The 5-fluorouracil, Adriamycin (doxorubicin), and mitomycin (FAM) chemotherapy regimen, which was initially reported by Georgetown in 1979, has become a standard for advanced gastric carcinoma with response rates in the 40% range. The FAM regimen as well as subsequent trials conducted at Georgetown and our current approach to management of this tumor are discussed.

Interferon alfa-2b/melphalan/prednisone in previously untreated patients with multiple myeloma: a phase I-II trial.

Interferon alfa-2b (Intron A; Schering Plough) has been shown to be active in advanced previously treated multiple myeloma (MM). Recent in vitro evidence has suggested synergy between cytotoxic agents and interferon alfa-2b. This phase I-II protocol was initiated to study interferon alfa-2b in combination with melphalan and prednisone.

Immunotoxicity of multiple dosing regimens of free doxorubicin and doxorubicin entrapped in cardiolipin liposomes.

We have shown that doxorubicin entrapped in cardiolipin liposomes retain antitumour efficacy in mice but had diminished cardiac uptake and cardiotoxicity. Such liposomes are preferentially taken up by spleen. In a previous study we showed that a single dose of liposomal doxorubicin is not more toxic than free doxorubicin with regard to immunologic parameters including generation of cytotoxicity for histocompatibility alloantigens and mitogenic responsiveness.

Alpha-2-interferon/melphalan/prednisone in previously untreated patients with multiple myeloma: a phase I-II trial.

Alpha-2-interferon (IFN) has demonstrable activity in advanced, relapsing, or refractory multiple myeloma. Because of the in vitro synergism between the IFNs and cytotoxic agents, we conducted a trial of 30 previously untreated patients with multiple myeloma utilizing various doses of alpha-2-IFN in combination with standard oral doses of melphalan and prednisone. The combination was well-tolerated without unusual or unexpected toxic effects.

Treatment of cancer-associated hemolytic uremic syndrome with staphylococcal protein A immunoperfusion.

Plasma perfusion over filters containing staphylococcal protein A (SPA) was used to treat 11 patients with adenocarcinoma who developed a hemolytic uremic syndrome. Immunoperfusion resulted in complete clearance of pretreatment elevated levels of circulating immune complexes in eight of the 11 patients with normalization of complement values depressed at the start of the therapy in seven. A significant rise in platelets and erythrocyte counts was achieved in nine patients, and stabilization of progressive renal impairment was achieved in six.

Comparative immunotoxicity of free doxorubicin and doxorubicin encapsulated in cardiolipin liposomes.

The immunologic and pharmacologic effects of free doxorubicin and of doxorubicin entrapped in liposomes were compared in mice at a dose of 20 mg/kg. Liposomes for encapsulation of doxorubicin were prepared by using 39.35 mumol drug, 19.

Augmentation of natural immunity and correlation with tumor response in melanoma patients treated with human lymphoblastoid interferon.

Thirty-two melanoma patients treated with lymphoblastoid alpha interferon (Wellferon) were studied for augmentation of five putative parameters of natural immunity including natural killing (NK), antibody-dependent cellular cytotoxicity (ADCC), cell-mediated inhibition of growth in culture of a murine tumor (GIA), and the size of the OKTIO+ and Leu 7+ subpopulations of peripheral blood mononuclear cells (OKTIO and Leu7). This study confirms and extends our previous conclusions that interferon increases GIA and OKTIO. The increases occurred at 24 hr after interferon, both early and late in the course of treatment, and were dose dependent.