Identification of a panel of tumor-associated antigens from breast carcinoma cell lines, solid tumors and testis cDNA libraries displayed on lambda phage

BACKGROUND: Tumor-associated antigens recognized by humoral effectors of the immune system are a very attractive target for human cancer diagnostics and therapy. Recent advances in molecular techniques have led to molecular definition of immunogenic tumor proteins based on their reactivity with autologous patient sera (SEREX). METHODS: Several high complexity phage-displayed cDNA libraries from breast carcinomas, human testis and breast carcinoma cell lines MCF-7, MDA-MB-468 were constructed. The cDNAs were expressed in the libraries as fusion to bacteriophage lambda protein D. Lambda-displayed libraries were efficiently screened with sera from patients with breast cancer. RESULTS: A panel of 21 clones representing 18 different antigens, including eight proteins of unknown function, was identified. Three of these antigens (T7-1, T11-3 and T11-9) were found to be overexpressed in tumors as compared to normal breast. A serological analysis of the 21 different antigens revealed a strong cancer-related profile for at least five clones (T6-2, T6-7, T7-1, T9-21 and T9-27). CONCLUSIONS: Preliminary results indicate that patient serum reactivity against five of the antigens is associated with tumor disease. The novel T7-1 antigen, which is overexpressed in breast tumors and recognized specifically by breast cancer patient sera, is potentially useful in cancer diagnosis

A pilot study on the effect of acetyl-L-carnitine in paclitaxel-and cisplatin-induced peripheral neuropathy

Aims and background: In addition to bone marrow suppression and renal toxicity, neurotoxicity is a commonly occurring side effect of widely used chemotherapeutic agents like taxanes, cisplatin and vinca alkaloids. Neurotoxicity can cause antitumor therapy discontinuation or dose regimen modification. The aim of the present exploratory study was to investigate the activity of acetyl-L-carnitine in reversing peripheral neuropathy in patients with chemotherapy-induced peripheral neuropathy. Methods and study design: Twenty-seven patients (16 males and 11 females) with paclitaxel and/or cisplatin-induced neuropathy (according to WHO recommendations for the grading of acute and subacute toxic effects) were enrolled. Patients received at least one cisplatin- (n = 5) or one paclitaxel- (n = 11) based regimen, or a combination of both (n = 11). Patients with chemotherapy-induced peripheral neuropathy were treated with acetyl-L-carnitine 1 g/die iv infusion over 1-2 h for at least 10 days. Results: Twenty-six patients were evaluated for response having completed at least 10 days of acetyl-L-carnitine therapy (median, 14 days; range, 10-20). At least one WHO grade improvement in the peripheral neuropathy severity was shown in 73% of the patients. A case of insomnia related to ALC treatment was reported in one patient. Acetyl-L-carnitine seems to be an effective and well-tolerated agent for the treatment of chemotherapy-induced peripheral neuropathy. Conclusions: Our preliminary results should be confirmed in double-blind, placebo controlled studies

Effectiveness and safety of an induction therapy with epoetin alfa in anemic cancer patients receiving concomitant chemotherapy

Background. Epoetin alfa, administered at standard dosages of 10,000-20,000 IU three times weekly or 40,00060,000 IU once weekly, has been shown to significantly increase hemoglobin (Hb) levels, decrease transfusion requirements, and improve quality-of-life parameters in patients undergoing chemotherapy. Objective. This open-label, nonrandomized, historically controlled study was conducted to evaluate the efficacy and safety of an induction dose of epoetin alfa in patients with moderate or severe anemia who were receiving chemotherapy. Methods. Nineteen patients with solid tumors and Hb levels <9.0 g/dl were enrolled. The patients received single s.c. injections of epoetin alfa, 40,000 IU, on study days 1, 4, 7, 10, and 13, and were then observed for the following 30 days. Nineteen other cancer patients who had matching characteristics and had received epoetin alfa, 10,000 IU, three times weekly for the 45-day study period, served as historical controls. The primary efficacy variable was change in Hb level from baseline to days 15 (similar toweek 2) and 45 (similar toweek 6.5). Secondary efficacy variables included the percent response (Hb increase A g/dl) and percent major response (Hb increase 2:2 g/dl) at days 15 and 45, the durations of response and major response after day 45, the proportion of patients transfused within the 45 study days, the changes in Eastern Cooperative Oncology Group performance status score at days 15 and 45, and the ability to maintain the planned chemotherapy dose (dose intensity) over the 45-day study. Results. Mean increases in IIb level in the epoetin alfa 40,000 IU group were significantly greater than those in the historical control group both at day 15 and at day 45. The increase in Hb level in the control group approximated increases reported with standard 3-times-weekly epoetin alfa at day 15 but was somewhat lower than the increases typically seen by day 45, presumably due to the fact that, in the present study, the epoetin alfa dose was not doubled in initial nonresponders, as is commonly done with standard epoetin alfa treatment. The rates of major response for epoetin alfa 40,000 IU patients (37% at day 15 and 84% at day 45) were higher than those for control patients (16% and 21%, respectively). Also, the transfusion rate was lower and performance status scores were better in the epoetin alfa 40,000 IU patients than in the control patients. In all, 74% of epoetin alfa 40,000 IU patients versus 47% of control patients received 100% of the planned chemotherapy dose. Epoetin alfa was well tolerated in both treatment groups. Conclusions. Results of this study suggest that epoetin alfa at a dose of 40,000 IU administered five times over 2 weeks may confer even higher response rates than those seen with standard dosing regimens. These encouraging results support further study of the proposed induction dose of epoetin alfa in a larger, randomized, prospectively controlled trial

Weekly vinorelbine and docetaxel as second-line chemotherapy for pretreated non-small cell lung cancer patients: A phase I-II trial

Docetaxel was proven to be effective as second-line therapy for patients with advanced NSCLC after failure of platinum-basedi front-line chemotherapy. We designed this phase I/II study to define the Maximum Tolerated Dose of weekly docetaxel combined with weekly vinorelbine, and subsequently evaluate tolerability and activity of this schedule in NSCLC patients who were progressive after treatment with either cisplatin and gemcitabine or carboplatin and paclitaxel regimens. To be eligible for the study, patients were required to have a WHO performance status ≤2, failure after at least two cycles of first platinum-based chemotherapy, and no prior treatment with docetaxel and vinorelbine. A total of 27 patients were enrolled in this phase I/II study. A weekly docetaxel dose of 25 mg/m2 was recommended in combination with fixed vinorelbine dose of 20 mg/m2, and 24 patients were treated at this dose level. Severe neutropenia (62%) and febrile neutropenia (29%) were the most frequent toxicities, with 83% of patients requiring dose modification or delay. In the phase II study, 5 (21%) patients obtained a partial response, 8 (33%) patients had stable disease, whereas 10 (42%) patients progressed. After a median follow-up of 18.7 months, median survival was 8 months, with 30% surviving at 1 year. Regardless of the use of weekly docetaxel schedule, this regimen was highly myelosuppressive, and did not seem to improve response rate and survival compared to single-agent docetaxel. No further developments of this schedule are warranted

A study of the humoral immune response of breast cancer patients to a panel of human tumor antigens identified by phage display

Objective: In this article we provide evidence of a significant spontaneous humoral response in cancer patients. Methods: A panel of tumor-associated antigens, previously identified through serological screening of phage-displayed cDNA libraries from solid human tumors, breast carcinoma cell lines and human testis by employing breast cancer patient sera, was used in this study to survey sera from 182 patients with known disease histories and clinical stages. Results: This analysis reveals a statistically significant association between tumor disease and presence in peripheral blood of IgG antibodies against four autoantigens. One of these antigens (D7-1) is particularly interesting in that the antibody response against it grows with cancer progression from stages I through IV, with an incidence of 13.2, 13.5, 18.2 and 27%, respectively. The significance of this stage-dependent increase in the incidence is confirmed by the Mantel-Haenszel Chi-squared test (P = 0.001). Conclusions: Our data confirm association between breast cancer diagnosis of patients and presence in their peripheral blood of antibodies against several autoantigens identified by phage display. © 2006 International Society for Preventive Oncology