A phase I study of the optimized cryptic peptide TERT(572y) in patients with advanced malignancies.

OBJECTIVE: It was the aim of this study to evaluate the safety of the optimized cryptic peptide TERT(572Y) in pretreated patients with advanced cancer. METHODS: Nineteen patients with progressive and chemotherapy-refractory tumors received escalated doses (2-6 mg) of 2 subcutaneous injections of the optimized TERT(572Y) peptide followed by 4 subcutaneous injections of the native TERT(572) peptide every 3 weeks. Both TERT peptides were coinjected with adjuvant Montanide ISA51. Toxicity was evaluated every 3 weeks and peptide-specific CD8+ cells were detected by flow cytometry using TERT(572Y) tetramers. RESULTS: Fourteen out of 19 patients completed the vaccination program. No grade III/IV toxicity was observed. Grade I anemia was observed in 4 patients and local skin reaction at the injection site in 11 patients. Other nonhematologic toxicities were mild, and no late toxicity was observed after a median postvaccination follow-up period of 10.7 months. There was no dose-limiting toxicity. Peripheral blood TERT(572Y)-specific CD8+ lymphocytes were detected in 13 out of 14 evaluable patients after 2 injections with the optimized TERT(572Y) peptide. There was no complete or partial response, but 4 patients (21%) with persistent TERT(572Y)-specific CD8+ experienced stable disease for a median of 10.5 months. CONCLUSION: TERT(572Y) peptide vaccine is well tolerated and effective in eliciting specific TERT(572Y) CD8+ lymphocytes in pretreated cancer patients, demonstrating that cryptic peptides could be used in cancer immunotherapy.

Alterations of CD43 expression in transfusion-dependent myelodysplastic syndromes.

CD43 is a sialylated glycoprotein expressed on the surface of most haemopoietic cells and has been implicated in cell adhesion and signaling. It has previously been shown that CD43 expression is altered in patients with myelodysplastic syndrome (MDS). This raised the question of whether the alteration is associated with transfusions in these patients. We studied the expression of this antigen on peripheral blood leucocytes in two groups of patients with refractory anaemia, 22 transfused and 20 non-transfused. We found decreased expression of CD43 on the monocytes and neutrophils of patients receiving transfusions. Other activation molecules were studied (CD11b, CD18) and were found up-regulated suggesting the existence of activated leucocytes in these patients. The increased levels of soluble vascular cellular endothelial molecule after transfusions in these patients suggested vascular endothelial activation in the absence of infection. Given together, these results show that decreased CD43 in the transfused group of MDS patients is associated with an activated endothelial phenotype.

Opioids are non-competitive inhibitors of nitric oxide synthase in T47D human breast cancer cells.

Opioids and nitric oxide (NO) interact functionally in different systems. NO-generating agents decrease the activity of opioid agonists, prevent opioid tolerance, and are used in opioid withdrawal syndromes. There exist, however, few reports indicating a direct interaction of the two systems. T47D human breast cancer cells in culture express opioid receptors, and opioid agonists inhibit their growth, while they release high amounts of the NO-related molecules NO(2-)/NO(3-)to the culture medium. We have used this system to assay a possible direct interaction of opiergic and nitric oxide systems. Our results show that delta- or mu-acting opioid agonists do not modify the release of NO(2-)/NO(3-). In contrast, kappa-acting opioid agonists (ethylketocyclazocine, and alpha(S1)-casomorphine) decrease the release of NO(2-)/NO(3-), in a time- and dose-dependent manner. The general opioid antagonist diprenorphine (10(-6) M) produce a similar NO(2-)/NO(3-)release inhibition, indicating a possible non-opioid-receptor mediated phenomenon. In addition, ethylketocyclazocine, alpha(S1)-casomorphin and diprenorphine directly inhibit NOS activity: agonists, interact with both calcium-dependent and independent NOS-isoforms, while the antagonist diprenorphine modifies only the activity of the calcium-dependent fraction of the enzyme. Analysis of this interaction revealed that opioids modify the dimeric active form of NOS, through binding to the reductase part of the molecule, acting as non-competitive inhibitors of the enzyme. This interaction opens interesting new possibilities for tumor biology and breast cancer therapy.