Post-Transplant Nivolumab Plus Unselected Autologous Lymphocytes in Refractory Hodgkin Lymphoma: A Feasible and Promising Salvage Therapy Associated With Expansion and Maturation of NK Cells.

Immune checkpoint inhibitors (CI) have demonstrated clinical activity in Hodgkin Lymphoma (HL) patients relapsing after autologous stem cell transplantation (ASCT), although only 20% complete response (CR) rate was observed. The efficacy of CI is strictly related to the host immune competence, which is impaired in heavily pre-treated HL patients. Here, we aimed to enhance the activity of early post-ASCT CI (nivolumab) administration with the infusion of autologous lymphocytes (ALI). Twelve patients with relapse/refractory (R/R) HL (median age 28.5 years; range 18-65), underwent lymphocyte apheresis after first line chemotherapy and then proceeded to salvage therapy. Subsequently, 9 patients with progressive disease at ASCT received early post-transplant CI supported with four ALI, whereas 3 responding patients received ALI alone, as a control cohort. No severe adverse events were recorded. HL-treated patients achieved negative PET scan CR and 8 are alive and disease-free after a median follow-up of 28 months. Four patients underwent subsequent allogeneic SCT. Phenotypic analysis of circulating cells showed a faster expansion of highly differentiated NK cells in ALI plus nivolumab-treated patients as compared to control patients. Our data show anti-tumor activity with good tolerability of ALI + CI for R/R HL and suggest that this setting may accelerate NK cell development/maturation and favor the expansion of the "adaptive" NK cell compartment in patients with HCMV seropositivity, in the absence of HCMV reactivation.

Extracorporeal photopheresis for the treatment of acute and chronic graft-versus-host disease in adults and children: best practice recommendations from an Italian Society of Hemapheresis and Cell Manipulation (SIdEM) and Italian Group for Bone Marrow Transplantation (GITMO) consensus process.

BACKGROUND: Extracorporeal photopheresis (ECP) is an effective treatment for both acute and chronic graft-versus-host disease (GVHD) in children and adults. Despite the large use of this treatment, a large heterogeneity in current application of ECP has been reported so far and recent evidence brought novel issues into some specific topics. Consensus-based recommendations ameliorate the appropriateness in daily clinical practice and, in turn, optimize the use of health care resources. STUDY DESIGN AND METHODS: Two Italian scientific societies, the Italian Society of Hemapheresis and Cell Manipulation (SIdEM) and the Italian Group for Bone Marrow Transplantation (GITMO), joined to develop and disseminate recommendations on appropriate application of ECP treatment in patients with GVHD. Accordingly, SIdEM and GITMO named an expert panel that first selected 16 questions that were considered relevant for clinical practice: the questions were subsequently addressed through a revision of the available literature and in consensus meetings. The whole group discussed the proposed recommendations according to the nominal group technique. RESULTS: The above-described approach in turn allowed the panel to agree on 47 practice recommendations. SIdEM and GITMO will disseminate such recommendations to the national transplant centers. CONCLUSION: In conclusion, SIdEM and GITMO have made a scientific effort to provide a useful tool to physicians involved in the field, thus supporting daily clinical practice, as well as strategic decisions in the setting of ECP treatment of GVHD.

Short exposure of albumin to high concentrations of malondialdehyde does not mimic physiological conditions.

Malondialdehyde (MDA), a major lipid peroxidation product, spontaneously binds to, and modifies proteins. In vivo, proteins are physiologically exposed to micromolar MDA concentrations for long periods. In order to mimic this process in vitro, protein modification is often performed by short exposure to millimolar MDA concentrations, also in order to generate antigenic structures for antibody production. However, in our study, spectrophotometric and fluorimetric characteristics, electrophoretic migration, susceptibility to trypsin digestion and reactivity to antibodies indicated substantial differences between albumin incubated with millimolar MDA concentrations for a short period of time and albumin incubated with micromolar MDA concentrations for a long period of time. Therefore, our study showed that short incubation of albumin with millimolar MDA concentrations does not mimic the consequences of albumin exposure to long incubation with micromolar MDA concentrations. This casts doubts on the real possibility that antibodies, elicited with proteins modified with millimolar MDA concentrations for a short period, could detect all MDA-modified proteins in vivo. Moreover, natural antibodies against albumin, modified with micromolar MDA concentrations, have been detected in the serum of healthy blood donors, which appears to justify the existence of these kinds of modified proteins in vivo.

Oxidative stress and antioxidant defence in a healthy nonagenarian population.

Results on oxidative markers during ageing are not consistent throughout the scientific literature; however, successful ageing may depend on better ability to cope with oxidative stress. A previous study of ours showed that successful ageing could actually be related to enhanced response to oxidatively modified proteins. In this study, a healthy nonagenarian population (OVER-90) was examined for various blood oxidative biomarkers and compared with a healthy population of blood donors (age range, 23-66 years). Blood glutathione, both total (tGSH) and oxidised (GSSG), and total plasmatic antioxidant status were maintained in the OVER-90 at a level similar to the control population. Sulphydryl (sulfhydryl) groups and glutathione peroxidase (GPx) were instead decreased. The results are discussed in a possible unifying view: the OVER-90 population could possess a globally preserved antioxidant ability, though some signs of oxidative damage are present and some structures could be 'sacrificed' in order to keep the redox equilibrium.

Anti malondialdehyde-adduct immunological response as a possible marker of successful aging.

Contrasting results have been obtained by various researchers about oxidative markers of aging. In this study, a healthy over-90-year-old population was examined for various plasma oxidative biomarkers and compared with a healthy population of blood donors (age range 23-66). Plasma malondialdehyde (MDA), evaluated by means of the thiobarbituric acid test, was significantly higher in the over-90-year-old population, confirming the presence of increased lipoperoxidation in old age. The antibody titre against MDA-protein adducts, considered a marker of lipoperoxidative protein damage in vivo, was evaluated in an ELISA test, completely home made and calibrated versus a concentrated pool of human plasma; this antibody titre was significantly higher in the over-90-year-old population. Plasma vitamin E, evaluated in RP-HPLC, was not significantly different between the two groups. Plasma protein-bound carbonyls, a marker of oxidative protein damage, were measured with the 2,4-dinitrophenylhydrazine assay; their level in the over-90-year-old population was lower than in the blood donors. The higher antibody titre against MDA-adducts may result in protection against accumulation of oxidatively damaged proteins by enhancing their removal, and, together with the preserved plasma vitamin E level, it may endow over-90-year-olds with an especially efficient antioxidant profile. The low level of protein carbonyl might reflect the more efficient removal of damaged proteins.