Publications

Peptide vaccination against tumor-associated antigens remains one of the most common methods of immunization in cancer vaccine clinical trials. Although peptide vaccination has been reported to increase circulating antigen-specific T-cells, they have had limited clinical efficacy and there is a necessity to increase their capacity to generate strong antitumor responses. We sought to improve the clinical efficacy of peptide-based vaccines in cancer immunotherapy of metastatic melanoma using a LHRH agonist (leuprolide) as adjuvant. Seventy HLA-A*0201 stage IIb-IV melanoma patients were vaccinated with class I HLA-A*0201-restricted gp100209-2M peptide and stratified for HLA-DP4 restriction. HLA-DP4 patients were also vaccinated with class II HLA-DP4-restricted MAGE-3243-258 peptide. Patients from both groups were randomized to receive 2 doses of leuprolide or not. Here we report the increase in PBMC TREC levels at week 24 after peptide vaccination, which was independent of the leuprolide treatment. This change was mirrored by a small increase in the TREC-enriched CD8CD45RAROCD27CD103, but not the TREC-enriched CD4CD45RAROCD31 T-cell population. Serum concentration of 2 important factors for thymopoiesis was measured: insulin growth factor 1 (IGF-1) levels were not changed, whereas a moderate increase in IL-7 levels was noted in the sera of all patients 6 weeks after vaccination. Increased expression of CD127 (IL-7 receptor-α) at week 24, compared with baseline, was only seen in the CD8CD45RAROCD27CD103 T-cell population. Our results suggest that leuprolide has no effect on thymic output when used as peptide vaccine adjuvant, but IFA-based peptide vaccination may unexpectedly affect the thymus by increasing thymic output of new T cells.

BACKGROUND

Rapid means of ruling in or ruling out tuberculosis (TB) would permit more efficient management of patients starting antiretroviral treatment (ART).

OBJECTIVE

To assess the diagnostic and prognostic utility of C-reactive protein (CRP) among patients being screened for TB before ART in a South African ART clinic.

DESIGN

Patients were microbiologically screened for TB regardless of symptoms; serum CRP was measured, and mortality at 3 months was assessed.

RESULTS

Among 496 patients (median CD4 count 171 cells/l), culture-positive TB was diagnosed in 81 (16.3%). CRP concentrations were much higher among TB cases (median 57.8 mg/l, IQR 20.0202.7) than in those without TB (6.4 mg/l, IQR 2.121.8, P < 0.001). Very low (<1.5 mg/l) CRP concentrations excluded TB (100% negative predictive value), whereas very high concentrations (>400 mg/l) were strongly predictive of TB (100% positive predictive value). However, these thresholds encompassed only 14.3% and 2.0%, respectively, of all patients screened and identified only 12.3% of TB cases. CRP concentrations ≥50 mg/l were associated with poor prognostic characteristics, higher mycobacterial load, disseminated disease and greater mortality risk.

CONCLUSION

CRP concentrations identified groups of patients with very high or very low TB risk, but only in an unacceptably small minority of patients screened. However, in those with confirmed TB, CRP concentrations had useful prognostic value.

Despite the introduction 40 years ago of the inexpensive and effective four-drug (isoniazid, rifampicin, pyrazinamide and ethambutol) treatment regimen, tuberculosis (TB) continues to cause considerable morbidity and mortality worldwide. For the first time since the 1960s, new and novel drugs and regimens for all forms of TB are emerging. Such regimens are likely to utilize both repurposed drugs and new chemical entities, and several of these regimens are now progressing through clinical trials. This article covers current concepts and recent advances in TB drug discovery and development, including an update of ongoing TB treatment trials, newer clinical trial designs, TB biomarkers and adjunct host-directed therapies.