Phase I study of bortezomib with weekly paclitaxel in patients with advanced solid tumours.

BACKGROUND: The combination of a proteasome inhibitor with a taxane has potential clinical synergism that prompted a clinical test. PATIENTS AND METHODS: The maximum tolerated dose (MTD) and recommended dose (RD) of intravenous (i.v.) Bortezomib (B) (days 1, 4, 8, 11) and i.v. Paclitaxel (PTX) (days 1, 8) every 3 weeks was evaluated in patients with advanced solid tumours. The RD was tested in patients with breast, ovarian and prostate cancer. At the RD, microarray analysis of transcriptional profiles was carried out before and after the first dosing in peripheral blood mononuclear cells (PBMC). RESULTS: Thirty-one patients were enrolled and 22 were treated at the RD that corresponded to B 1.3mg/m(2) and PTX 100mg/m(2). The main toxicity was cumulative peripheral neuropathy (76% of patients; grade 3-4 in 9%) that required treatment discontinuation in six patients, followed by diarrhoea (55%) and fatigue (41%). Nine partial responses (30%) were observed (three breast cancer, four ovary, two prostate patients). Significant (p<0.05) and consistent changes (>70% of patients) in transcriptome were observed. CONCLUSIONS: The incidence of peripheral neuropathy and the anti-tumour activity comparable to that of single-agent PTX do not support further development of this regimen.

Human lymphocyte proliferation responses following primary immunization with rabies vaccine as neoantigen.

Evaluation of the T-cell immune response following primary antigenic challenge with a neoantigen is a critical aspect of assessment of the cellular immune response. While many antigens can be used to accurately assess in vitro T-cell proliferation to a recall antigen, only a few neoantigens have been tested for their capacities to measure T-cell responses in vitro to a primary immunization. Rabies vaccination is an excellent candidate for the testing of T-cell proliferation responses to a primary immunization because few individuals have been exposed to rabies virus antigens. In the present study 14 rabies vaccine-naïve, healthy adult volunteers were immunized against rabies virus, and T-cell proliferation and antibody responses were measured before and after vaccination. Optimal lymphocyte proliferation to soluble rabies virus antigen occurred after 8 days in culture. The average level of uptake of tritiated thymidine postimmunization was 29,620 +/- 4,448 cpm, whereas preimmunization levels were 12,660 +/- 3,448 cpm (P = 0.002). All individuals showed increases in rabies virus antibody titers from <0.05 to 5.59 +/- 1.64 IU/ml. The degree of proliferation to tetanus toxoid as a recall antigen was similar to the response to rabies virus antigen among the cohort. Due to high levels of preimmunization proliferation, four subjects failed to demonstrate a twofold increase in response to rabies virus antigen. The high levels of T-cell responses may be due to a viral superantigen effect in some individuals. Rabies vaccination offers a safe and effective means for measurement of both T- and B-cell immune responses to a neoantigen in healthy and immune suppressed individuals.