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Introduction: Despite the advent of HIV cure-related clinical trials (HCRCT) for people living with HIV (PLWH), the risks and uncertainty involved raise ethical issues. Although research has provided insights into the levers and barriers to PLWH and physicians' participation in these trials, no information exists about stakeholders' preferences for HCRCT attributes, about the different ways PLWH and physicians value future HCRCT, or about how personal characteristics affect these preferences. The results from the present study will inform researchers' decisions about the most suitable HCRCT strategies to implement, and help them ensure ethical recruitment and well-designed informed consent. Methods: Between October 2016 and March 2017, a discrete choice experiment was conducted among 195 virally controlled PLWH and 160 physicians from 24 French HIV centres. Profiles within each group, based on individual characteristics, were obtained using hierarchical clustering. Trade-offs between five HCRCT attributes (trial duration, consultation frequency, moderate (digestive disorders, flu-type syndrome, fatigue) and severe (allergy, infections, risk of cancer) side effects (SE), outcomes) and utilities associated with four HCRCT candidates (latency reactivation, immunotherapy, gene therapy and a combination of atency reactivation and immunotherapy), were estimated using a mixed logit model. Results: Apart from severe SE--the most decisive attribute in both groups--PLWH and physicians made different trade-offs between HCRCT attributes, the latter being more concerned about outcomes, the former about the burden of participation (consultation frequency and moderate SE). These different trades-offs resulted in differences in preferences regarding the four candidate HCRCT. PLWH significantly preferred immunotherapy, whereas physicians preferred immunotherapy and combined therapy. Despite the heterogeneity of characteristics within the PLWH and physician profiles, results show some homogeneity in trade-offs and utilities regarding HCRCT. Conclusions: Severe SE, not outcomes, was the most decisive attribute determining future HCRCT participation. Particular attention should be paid to providing clear information, in particular on severe SE, to potential participants. Immunotherapy would appear to be the best HCRCT candidate for both PLWH and physicians. However, if the risk of cancer could be avoided, gene therapy would become the preferred strategy for the latter and the second choice for the former. Keywords: HIV eradication/remission; therapeutic HIV vaccine trial; social sciences; discrete choice experiment; preferences; ethics; clinical trial design recommendations; mixed logit mode, (1) | INTRODUCTION HIV cure research, a desired but risky and 'uncomfortable' innovation [1], raises several ethical questions [2-6]. More specifically, to test the effectiveness of new HIV cure-related clinical [...]

Adoptive immunotherapy is a potentially curative therapeutic approach for patients with advanced cancer. However, the in vitro expansion of antitumor T cells prior to infusion inevitably incurs differentiation towards effector T cells and impairs persistence following adoptive transfer. Epigenetic profiles regulate gene expression of key transcription factors over the course of immune cell differentiation, proliferation, and function. Using comprehensive screening of chemical probes with defined epigenetic targets, we found that JQ1, an inhibitor of bromodomain and extra-terminal motif (BET) proteins, maintained [CD8.sup.+] T cells with functional properties of stem cell-like and central memory T cells. Mechanistically, the BET protein BRD4 directly regulated expression of the transcription factor BATF in [CD8.sup.+] T cells, which was associated with differentiation of T cells into an effector memory phenotype. JQ1treated T cells showed enhanced persistence and antitumor effects in murine T cell receptor and chimeric antigen receptor gene therapy models. Furthermore, we found that histone acetyltransferase p300 supported the recruitment of BRD4 to the BATF promoter region, and p300 inhibition similarly augmented antitumor effects of the adoptively transferred T cells. These results demonstrate that targeting the BRD4-p300 signaling cascade supports the generation of superior antitumor T cell grafts for adoptive immunotherapy., Introduction Adoptive immunotherapy is a promising therapeutic option for cancer patients. Antitumor T cell grafts can be expanded from tumor-infiltrating lymphocytes or tumor antigen-specific T cells in the peripheral blood [...]

Sepsis is a systemic inflammatory response induced by an infection, leading to organ dysfunction and mortality. Historically, sepsis-induced organ dysfunction and lethality were attributed to the interplay between inflammatory and anti-inflammatory responses. With advances in intensive care management and goal-directed interventions, early sepsis mortality has diminished, only to surge later after 'recovery' from acute events, prompting a search for sepsis-induced alterations in immune function. Sepsis is well known to alter innate and adaptive immune responses for sustained periods after clinical 'recovery,' with immunosuppression being a prominent example of such alterations. Recent studies have centered on immune-modulatory therapy. These efforts are focused on defining and reversing the persistent immune cell dysfunction that is associated with mortality long after the acute events of sepsis have resolved., Introduction Sepsis is the constellation of symptoms occurring when an infection leads to a systemic inflammatory response (1), including fever, leukocytosis or leukopenia, decreased vascular resistance frequently leading to hypotension [...]

Adoptive cell transfer (ACT) of purified naive, stem cell memory, and central memory T cell subsets results in superior persistence and antitumor immunity compared with ACT of populations containing more-differentiated effector memory and effector T cells. Despite a clear advantage of the less-differentiated populations, the majority of ACT trials utilize unfractionated T cell subsets. Here, we have challenged the notion that the mere presence of less- differentiated T cells in starting populations used to generate therapeutic T cells is sufficient to convey their desirable attributes. Using both mouse and human cells, we identified a T cell-T cell interaction whereby antigen- experienced subsets directly promote the phenotypic, functional, and metabolic differentiation of naive T cells. This process led to the loss of less- differentiated T cell subsets and resulted in impaired cellular persistence and tumor regression in mouse models following ACT. The T memory-induced conversion of naive T cells was mediated by a nonapoptotic Fas signal, resulting in Akt- driven cellular differentiation. Thus, induction of Fas signaling enhanced T cell differentiation and impaired antitumor immunity, while Fas signaling blockade preserved the antitumor efficacy of naive cells within mixed populations. These findings reveal that T cell subsets can synchronize their differentiation state in a process similar to quorum sensing in unicellular organisms and suggest that disruption of this quorum-like behavior among T cells has potential to enhance T cell-based immunotherapies., Introduction Adoptive cell transfer (ACT), the ex vivo expansion and reinfusion of antigen-specific (Ag-specific) T cells, represents a potentially curative treatment for patients with advanced cancer (1-4) and viral-reactivation syndromes [...]

Multiple myeloma (MM) is an age-dependent hematological malignancy. Evaluation of immune interactions that drive MM relies on in vitro experiments that do not reflect the complex cellular stroma involved in MM pathogenesis. Here we used Vk*MYC transgenic mice, which spontaneously develop MM, and demonstrated that the immune system plays a critical role in the control of MM progression and the response to treatment. We monitored Vk*MYC mice that had been crossed with Cd226 mutant mice over a period of 3 years and found that CD226 limits spontaneous MM development. The CD226dependent anti-myeloma immune response against transplanted Vk*MYC MM cells was mediated both by NK and [CD8.sup.+] T cells through perforin and IFN-γ pathways. Moreover, CD226 expression was required for optimal antimyeloma efficacy of cyclophosphamide (CTX) and bortezomib (Btz), which are both standardly used to manage MM in patients. Activation of costimulatory receptor CD137 with mAb (4-1BB) exerted strong antimyeloma activity, while inhibition of coinhibitory receptors PD-1 and CTLA-4 had no effect. Taken together, the results of this study provide in vivo evidence that CD226 is important for MM immunosurveillance and indicate that specific immune components should be targeted for optimal MM treatment efficacy. As progressive immunosuppression associates with MM development, strategies aimed to increase immune functions may have important therapeutic implications in MM., Introduction Multiple myeloma (MM) is the second most common hematological malignancy in the world (1). Despite recent progress in new therapeutic options, this disease remains incurable, with a median survival [...]

BACKGROUND. Previous efforts to preserve β cell function in individuals with type 1 diabetes (T1D) have focused largely on the use of single immunomodulatory agents administered within 100 days of diagnosis. Based on human and preclinical studies, we hypothesized that a combination of low-dose anti-thymocyte globulin (ATG) and pegylated granulocyte CSF (G-CSF) would preserve β cell function in patients with established T1D (duration of T1D >4 months and METHODS. A randomized, single-blinded, placebo-controlled trial was performed on 25 subjects: 17 subjects received ATG (2.5 mg/kg intravenously) followed by pegylated G-CSF (6 mg subcutaneously every 2 weeks for 6 doses) and 8 subjects received placebo. The primary outcome was the 1-year change in AUC C-peptide following a 2-hour mixed-meal tolerance test (MMTT). At baseline, the age (mean ± SD) was 24.6 ± 10 years; mean BMI was 25.4 ± 5.2 kg/[m.sup.2]; mean A1c was 6.5% ± 1.1%; insulin use was 0.31 ± 0.22 units/kg/d; and length of diagnosis was 1 ± 0.5 years. RESULTS. Combination ATG/G-CSF treatment tended to preserve β cell function in patients with established T1D. The mean difference in MMTT-stimulated AUC C-peptide between treated and placebo subjects was 0.28 nmol/l/min (95% CI 0.001-0.552, P = 0.050). A1c was lower in ATG/G-CSF-treated subjects at the 6-month study visit. ATG/G-CSF therapy was associated with relative preservation of Tregs. CONCLUSIONS. Patients with established T1D may benefit from combination immunotherapy approaches to preserve β cell function. Further studies are needed to determine whether such approaches may prevent or delay the onset of the disease. TRIAL REGISTRATION. Clinicaltrials.gov NCT01106157. FUNDING. The Leona M. and Harry B. Helmsley Charitable Trust and Sanofi., Introduction Type 1 diabetes (T1D) is the end result of autoimmune-mediated destruction of insulin-producing β cells (1). To date, most efforts seeking to ameliorate the autoimmune process and reverse hyperglycemia [...]