Safety and immunogenicity of the PRAME cancer immunotherapeutic in metastatic melanoma: results of a phase I dose escalation study.

PURPOSE: The PRAME tumour antigen is expressed in several tumour types but in few normal adult tissues. A dose-escalation phase I/II study (NCT01149343) assessed the safety, immunogenicity and clinical activity of the PRAME immunotherapeutic (recombinant PRAME protein (recPRAME) with the AS15 immunostimulant) in patients with advanced melanoma. Here, we report the phase I dose-escalation study segment. PATIENTS AND METHODS: Patients with stage IV PRAME-positive melanoma were enrolled to 3 consecutive cohorts to receive up to 24 intramuscular injections of the PRAME immunotherapeutic. The RecPRAME dose was 20, 100 or 500 µg in cohorts 1, 2 and 3, respectively, with a fixed dose of AS15. Adverse events (AEs), including predefined dose-limiting toxicity (DLT) and the anti-PRAME humoral response (ELISA), were coprimary end points. Cellular immune responses were evaluated using in vitro assays. RESULTS: 66 patients were treated (20, 24 and 22 in the respective cohorts). AEs considered by the investigator to be causally related were mostly grade 1 or 2 injection site symptoms, fatigue, chills, fever and headache. Two DLTs (grade 3 brain oedema and proteinuria) were recorded in two patients in two cohorts (cohorts 2 and 3). All patients had detectable anti-PRAME antibodies after four immunisations. Percentages of patients with predefined PRAME-specific-CD4+T-cell responses after four immunisations were similar in each cohort. No CD8+ T-cell responses were detected. CONCLUSIONS: The PRAME immunotherapeutic had an acceptable safety profile and induced similar anti-PRAME-specific humoral and cellular immune responses in all cohorts. As per protocol, the phase II study segment was initiated to further evaluate the 500 µg PRAME immunotherapeutic dose. TRIAL REGISTRATION NUMBER: NCT01149343, Results.

dsRNA induces apoptosis through an atypical death complex associating TLR3 to caspase-8.

Toll-like receptor 3 (TLR3) is a pattern-recognition receptor known to initiate an innate immune response when stimulated by double-stranded RNA (dsRNA). Components of TLR3 signaling, including TIR domain-containing adapter inducing IFN-α (TRIF), have been demonstrated to contribute to dsRNA-induced cell death through caspase-8 and receptor interacting protein (RIP)1 in various human cancer cells. We provide here a detailed analysis of the caspase-8 activating machinery triggered in response to Poly(I:C) dsRNA. Engagement of TLR3 by dsRNA in both type I and type II lung cancer cells induces the formation of an atypical caspase-8-containing complex that is devoid of classical death receptors of the TNFR superfamily, but instead is physically associated to TLR3. The recruitment of caspase-8 to TLR3 requires RIP1, and is negatively modulated by cellular inhibitor of apoptosis protein (cIAP)2-TNF receptor-associated factor (TRAF)2-TNFR-associated death domain (TRADD) ubiquitin ligase complex, which regulates RIP1 ubiquitination. Intriguingly, unlike Fas- or TRAILR-dependent death signaling, caspase-8 recruitment and activation within the TLR3 death-signaling complex appears not to be stringently dependent on Fas-associated with death domain (FADD). Our findings uncover a novel aspect of the molecular mechanisms involved during apoptosis induced by the innate immune receptor TLR3 in cancer cells.

[Patency of the artery responsible for myocardial infarction: role on ventricular function and long-term outcome]. / Perméabilité de l'artère responsable de l'infarctus myocardique: influence sur la fonction ventriculaire et évolution à long terme.

Out of 3,171 consecutive patients referred for coronary angiography, 240 were selected on the following criteria: recent primary myocardial infarction, single vessel coronary disease, no angioplasty or coronary surgery after the angiography which was performed 20 to 90 days after the onset of myocardial infarction. The patients were divided into 2 groups according to whether the artery responsible for infarction was patent (Group I: 115 patients) or not (Group II: 125 patients). The left ventricular ejection fraction was significantly higher in Group I (58 +/- 10.8%) than in Group II (53.7 +/- 11.3%) and end systolic and end diastolic left ventricular volumes were greater in Group II (51.8 +/- 22 ml/m2 and 88 +/- 22 ml/m2 respectively). Long-term follow-up (56 +/- 25 months in Group I and 61 +/- 26 months in Group II) was possible in 112 patients in Group I and 123 patients in Group II. Of the 7 patients who died in group II, 4 deaths were of cardiac origin; in addition, 2 cases of sustained ventricular tachycardia were observed in this group. None of the 6 deaths observed in Group I was of cardiac origin and there were no cases of ventricular tachycardia (p = 0.05). The functional status was identical in the two groups at the end of the study. These results suggest that the patency of the coronary artery responsible for myocardial infarction at a distance from the acute event is associated with better left ventricular function and a better long term prognosis.