-
[show abstract]
[hide abstract]
ABSTRACT: Patients:Soft tissue sarcomas are uncommon malignancies with few therapeutic options for recurrent or metastatic disease. Dolastatin-10 (Dol-10) is a pentapeptide anti-microtubule agent that binds to tubulin sites distinct from vinca alkaloids. Based on the novel mechanism of action, limited activity of other anti-microtubular agents, and anti-neoplastic activity in pre-clinical screening of Dol-10, this multi-institutional phase II study was conducted to determine the objective response rate of Dol-10 in recurrent or metastatic soft tissue sarcomas that had not been treated with chemotherapy outside of the adjuvant setting. Methods: Dol-10 was given intravenously at a dose of 400 mug/m(2) and repeated every 21 days. Toxicities were assessed using the Common Toxicity Criteria (version 2.0). Radiographic studies and tumor measurements were repeated every two cycles to assess response [Miller AB, et al. Cancer 1981; 47(1): 207].Results: Dol-10 was associated with hematological toxicity and with some vascular toxicities. There was no significant gastrointestinal, hepatic or renal toxicity. There was one death on study due to respiratory failure. There were no objective responses in 12 patients treated with Dol-10.Discussion: Based on this phase II trial, further study of Dol-10 on this schedule is not recommended in advanced or metastatic soft tissue sarcomas.
Sarcoma 01/2004; 8(4):107-11.
-
M von Mehren,
P Arlen,
J Gulley,
A Rogatko,
H S Cooper,
N J Meropol,
R K Alpaugh,
M Davey, S McLaughlin,
M T Beard,
K Y Tsang,
J Schlom,
L M Weiner
[show abstract]
[hide abstract]
ABSTRACT: Granulocyte macrophage colony-stimulating factor (GM-CSF) has been shown to be an effective vaccine adjuvant because it enhances antigen processing and presentation by dendritic cells. ALVAC-CEA B7.1 is a canarypox virus encoding the gene for the tumor-associated antigen carcinoembryonic antigen (CEA) and for a T-cell costimulatory molecule, B7.1. After an initial dose escalation phase, this study evaluated vaccination with 4.5 x 10(8) plaque-forming units ALVAC-CEA B7.1 alone (n = 30) or with GM-CSF (n = 30) in patients with advanced CEA-expressing tumors to determine whether the addition of the adjuvant GM-CSF enhances induction of CEA-specific T-cells. Patients were vaccinated with vaccine intradermally every other week for 8 weeks. GM-CSF was given s.c. for 5 days beginning 2 days before vaccination. Patients with stable or responding disease after four immunizations received monthly boost injections alone or with GM-CSF. Biopsies of vaccine sites were obtained 48 h after vaccination to evaluate leukocytic infiltration and CEA expression. Induction of peripheral blood CEA-specific T-cell precursors was assessed in HLA-A2 positive patients by an ELISPOT assay looking for the production of IFN-gamma. Therapy was well tolerated. All of the patients had evidence of leukocytic infiltration and CEA expression in vaccine biopsy sites. In the patients receiving GM-CSF, leukocytic infiltrates were greater in cell number but were less likely to have a predominant lymphocytic infiltrate compared with patients receiving vaccine in the absence of the cytokine adjuvant. After four vaccinations, CEA-specific T-cell precursors were statistically increased in HLA-A2 positive patients who received vaccine alone. However, the GM-CSF plus vaccine cohort of HLA-A2 positive did not demonstrate a statistically significant increase in their CEA-specific T-cell precursor frequencies compared with baseline results. The number of prior chemotherapy regimens was negatively correlated with the generation of a T-cell response, whereas there was a positive correlation between the number of months from the last chemotherapy regimen and the T-cell response. ALVAC-CEA B7.1 is safe in patients with advanced, recurrent adenocarcinomas that express CEA, is associated with the induction of a CEA-specific T-cell response in patients treated with vaccine alone but not with vaccine and GM-CSF, and can lead to disease stabilization for up to 13 months.
Clinical Cancer Research 06/2001; 7(5):1181-91. · 7.74 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Coordinated presentation of antigen and costimulatory molecules has been shown to result in the induction of an antigen-specific T-cell response rather than the development of anergy. This study evaluated the vaccine ALVAC-CEA B7.1, a canary pox virus that has been engineered to encode the gene for the tumor-associated antigen carcinoembryonic antigen (CEA) and B7.1, a T-cell costimulatory molecule. Patients with CEA-expressing tumors were immunized with 2.5 x 10(7) (n = 3), 1.0 x 10(8) (n = 6), and 4.5 x 10(8) (n = 30) plaque-forming units intradermally every other week for 8 weeks. Patients with stable or responding disease received monthly boost injections. Biopsies of vaccine sites were obtained 48 h after vaccination to evaluate leukocytic infiltration and CEA expression. Induction of CEA-specific T-cell precursors was assessed by an ELISPOT assay looking for the production of IFN-gamma. Therapy was well tolerated, without significant toxicity attributable to vaccine. All patients had evidence of leukocytic infiltration and CEA expression in vaccine biopsy sites. Six patients with elevated serum CEA values at baseline had declines in their levels lasting 4-12 weeks. These patients all had stable disease after four vaccinations. After four vaccinations, patients who were HLA-A-2-positive demonstrated increases in their CEA-specific T-cell precursor frequencies to a CEA-A2-binding peptide from baseline. The number of prior chemotherapy regimens was inversely correlated with the ability to generate a T-cell response. ALVAC-CEA B7.1 is safe in patients with advanced, recurrent adenocarcinomas that express CEA, and it is associated with the induction of a CEA-specific T-cell response.
Clinical Cancer Research 07/2000; 6(6):2219-28. · 7.74 Impact Factor
