Platelet transfusion refractoriness and anti-HLA immunization.

Platelet transfusion refractoriness (PTR), defined as an unsatisfactory post-transfusion platelet count increment, is a common complication of patients receiving multiple transfusions. Different strategies are described in the management of PTR. In this work, we demonstrate the efficacy of the detection and identification of anti-HLA antibodies in the recipient using a threshold of 3000 mean fluorescence intensity (MFI), and the seek of donors not expressing HLA antigens against which the patient is immunized.

Adoptive T Cell Therapy in Solid Tumors: State-of-the Art, Current Challenges, and Upcoming Improvements.

In solid tumors, three main complementary approaches of adoptive T-cell therapies were successively developed: tumor-infiltrating lymphocytes, chimeric antigen receptor engineered T cells, and high-affinity T-cell receptor engineered T cells. In this review, we summarized rational and main results of these three adoptive T-cell therapies in solid tumors field and gave an overview of encouraging data and their limits. Then, we listed the major remaining challenges (including tumor antigen loss, on-target/off-tumor effect, tumor access difficulties and general/local immunosubversion) and their lines of research. Finally, we gave insight into the ongoing trials in solid tumor.

[Cell therapy in all its forms]. / La thérapie cellulaire dans tous ses états.

Immunotherapy strategies have revolutionized the management of a significant number of patients in recent years, whether they are undergoing treatment for hematologic malignancies or solid tumors. This therapeutic class is extensive, ranging from antibodies targeting immune checkpoint molecules to adoptive cell therapy strategies, including bispecific antibodies and anticancer vaccines. All these strategies are currently in active development. Adoptive cell therapy involves the infusion of normal or genetically modified immune cells into a patient with the aim of restoring strong antitumor immunity, primarily associated with the cytotoxicity of T lymphocytes. Currently, there are three major adoptive cell therapy strategies: allogeneic hematopoietic stem cell transplantation, CAR-T cell therapy, and TCR-T cell therapy. The objective of this article is to describe the mechanisms of action of these three strategies as well as their current advantages, limitations and constraints.

[The circulating PD-L1: An emerging predictive biomarker for immune checkpoint inhibitors response]. / Le taux circulant de PD-L1 : un biomarqueur émergent de réponse aux inhibiteurs de checkpoints immunitaires.

Immune checkpoint inhibitors (ICI) have recently become the standard of care for many metastatic solid tumors, with considerable improvements in patient prognosis. However, a non-negligible proportion of patients does not respond to this type of treatment, making it essential to identify predictive factors of this response in order to better adapt the therapy. Among the biomarkers that have been most extensively studied in recent years, tumor PD-L1 levels come out on top, with controversial results for predicting response to ICI. The determination of circulating PD-L1 (or soluble PD-L1) in peripheral blood seems to be an interesting emerging biomarker. Indeed, several studies have investigated its prognostic value, and/or its potential predictive value of response to immunotherapy, and it would appear that there is a correlation between the level of soluble PD-L1 and the level of tumor aggressiveness and therefore prognosis. Furthermore, the results suggest that higher PD-L1 levels are associated with a poorer response to immunotherapy, although this remains to be confirmed in large-scale studies.

Temporal regulation of transgene expression controlled by amino acid availability in human T cells.

T cell therapy strategies, from allogeneic stem cell transplantation toward genetically-modified T cells infusion, develop powerful anti-tumor effects but are often accompanied by side effects and their efficacy remains sometimes to be improved. It therefore appears important to provide a flexible and easily reversible gene expression regulation system to control T cells activity. We developed a gene expression regulation technology that exploits the physiological GCN2-ATF4 pathway's ability to induce gene expression in T cells in response to one essential amino acid deficiency. We first demonstrated the functionality of NUTRIREG in human T cells by transient expression of reporter genes. We then validated that NUTRIREG can be used in human T cells to transiently express a therapeutic gene such as IL-10. Overall, our results represent a solid basis for the promising use of NUTRIREG to regulate transgene expression in human T cells in a reversible way, and more generally for numerous preventive or curative therapeutic possibilities in cellular immunotherapy strategies.

Prevalence of FGF23 elevation in patients with hypophosphatemia.

BACKGROUND AND AIMS: To investigate the contribution of FGF23 in explaining the cases of hypophosphatemia observed in clinical practice, we aimed to determine for the first time the prevalence of FGF23 elevation in patients with hypophosphatemia and to describe the different mechanisms of FGF23-related hypophosphatemic disorders. MATERIALS AND METHODS: We performed a prospective, observational, multicenter, cohort study of 260 patients with hypophosphatemia. Blood measurements (PTH, 1,25-dihydroxyvitamin D, bone alkaline phosphatase, 25-hydroxyvitamin D, and FGF23) were performed on a Liaison XL® (DiaSorin) analyzer. RESULTS: Primary elevation of FGF23 (>95.4 pg/mL) was reported in 10.4% (95CI: 7.0-14.7) of patients (n = 27) with hypophosphatemia, suggesting that at least 1 in 10 cases of hypophosphatemia was erroneously attributed to an etiology other than FGF23 elevation. Patients with elevated blood FGF23 were grouped according to the etiology of the FGF23 elevation. Thus, 10 patients had a renal pathology, chronic kidney disease or post-renal transplantation condition. The remaining patients (n = 17) had the following etiologies: malignancies (n = 9), benign pancreatic tumor (n = 1), post-cardiac surgery (n = 4), cirrhosis (n = 2), and chronic obstructive pulmonary disease (n = 1). CONCLUSION: In order to improve patient management, it seems essential to better integrate plasma FGF23 measurement into the routine evaluation of hypophosphatemia.

[CAR-T cells development in solid tumors]. / Développement des CAR-T cells dans les tumeurs solides.

CAR-T cells have produced very promising results in the field of onco-hematology and have been rapidly approved for marketing in France for several years now. In solid tumors, current results are more disappointing. Indeed, many hurdles come in the way. Tumor vascularization, the strongly immunosuppressive microenvironment, the loss of the target antigen as well as T cell exhaustion are part of the explanation of those results. Hence many researchers are working to develop strategies to counteract these resistance mechanisms. Arming CAR-T cells with BiTEs, with immune checkpoint inhibitors or with interleukins seem to be effective ways to improve antitumor efficacy. Other strategies including vaccines association or local delivery of the CAR-T cells look very promising. Many Phase I studies are investigating these new strategies and are expected to improve the previous results obtained to date in this area.

Faecal microbiota transplantation to prevent complications after allogeneic stem cell transplantation for haematological malignancies: a study protocol for a randomised controlled phase-II trial (the FMT-allo study).

INTRODUCTION: Allogeneic haematopoietic stem-cell transplantation (allo-HSCT) is a major treatment for many haematological malignancies. The procedure has a good success rate but high transplant-related toxicity (TRM). TRM is mostly related to graft-versus-host disease (GvHD) and infectious complications. Alterations of the intestinal microbiota plays a major role in the development of allo-HSCT complications. The gut microbiota could be restored by faecal microbiota transplantation (FMT). However, there are no published randomised studies assessing the efficacy of FMT for GvHD prophylaxis. METHODS AND ANALYSIS: This prospective, open-label, multi-centre, parallel-group, randomised phase-II clinical trial has been designed to assess the effect of FMT on toxicity in patients treated with myeloablative allo-HSCT for haematological malignancy. Based on Fleming's single-stage sample size estimation procedure, the design plans to include 60 male and female patients aged 18 or over per arm, to be randomly assigned to two groups, one with and one without (control group) FMT. The primary endpoint is GvHD-free relapse-free survival rate at 1 year after allo-HSCT. Secondary endpoints are outcome measures of the impact of FMT on allo-HSCT-related morbidity and mortality (overall survival and progression-free survival at 1 and 2 years, haematological parameters, infectious complications, tolerance and safety of FMT). The primary endpoint will be evaluated according to assumptions of the single-stage Fleming design, compared between groups by a log-rank test and further investigated in a multivariate marginal structural Cox model taking into account centre effect. The proportional-hazard hypothesis will be verified using Schoenfeld's test and by plotting residuals. ETHICS AND DISSEMINATION: The local institutional review board (CPP Sud-Est II, France) issued approval on 27 January 2021. The French national authorities issued approval on 15 April 2021. The outcome of the study will be disseminated via peer-reviewed publications and at congresses. TRIAL REGISTRATION NUMBER: NCT04935684.

[T cell-based immunotherapies in solid tumors]. / Approches d'immunothérapie cellulaire T dans les tumeurs solides.

In solid tumors, adoptive T cell therapies based on ex vivo amplification of antitumor T cell are represented by three main complementary approaches : (i) tumor infiltrating lymphocytes (TILs) which are amplified in vitro before reinjection to the patient, (ii) chimeric antigen receptor (CAR) engineered T cells and (iii) T cell receptor (TCR) engineered T cells. Despite encouraging results, some obstacles remain, such as optimal target selection and tumor microenvironment. In this Review, we discuss pros and cons of these different therapeutic strategies that may open new perspectives in the treatment of solid tumors.

[Intestinal microbiota and allogeneic stem cell transplantation]. / Microbiote intestinal et allogreffe de cellules souches hématopoïétiques.

Allogeneic hematopoïetic stem cell transplantation is one of the most efficient curative treatment for acute leukemia. But it is also a heavy process with an important risk of complications, particularly infection and graft versus host disease. Increasing data in literature show that an alteration of the intestinal microbiota of allogeneic stem cell recipients is associated with these complications. Indeed, treatments used during conditioning regimen lead to an impaired microbiota, which cannot fulfill its protective functions anymore. To limit this microbiota impairment, we could restore a healthy microbiota by a fecal microbiota transplantation, which has already shown its efficiency in the treatment of Clostridium difficile infection. The aim of this review is to describe the intestinal microbiota, the link between microbiota and complications of allogeneic stem cells transplantation, and the recent published data on fecal microbiota transplantation in this field.

MNDA controls the expression of MCL-1 and BCL-2 in chronic lymphocytic leukemia cells.

The myeloid nuclear differentiation antigen (MNDA) is a stress-induced protein that promotes degradation of the anti-apoptotic factor MCL-1 and apoptosis in myeloid cells. MNDA is also expressed in normal lymphoid cells and in B-cell clones isolated from individuals with chronic lymphocytic leukemia (CLL), a disease characterized by abnormal apoptosis control. We found that MNDA expression levels inversely correlate with the amount of the anti-apoptotic proteins MCL-1 and BCL-2 in human CLL samples. We report that in response to chemotherapeutic agents that induce genotoxic stress, MNDA exits its typical nucleolar localization and accumulates in the nucleoplasm of CLL and lymphoid cells. Then, MNDA binds chromatin at Mcl1 and Bcl2 genes and affects the transcriptional competence of RNA polymerase II. Our data also reveal that MNDA specifically associates with Mcl1 and Bcl2 (pre-) mRNAs and favors their rapid turnover as a prompt response to genotoxic stress. We propose that this rapid dynamic tuning of RNA levels, which leads to the destabilization of Mcl1 and Bcl2 transcripts, represents a post-transcriptional mechanism of apoptosis control in CLL cells. These results provide an explanation of previous clinical data and corroborate the finding that higher MNDA expression levels in CLL are associated with a better clinical course.

[The CAR-T cells are here]. / Les CAR-T cells sont là !

Due to immunotherapy, a new era of treatment is opening up for the treatment of solid cancers and hematological tumors. T cells genetically modified with a chimeric antigen receptor (CAR-T cells) have recently been proved efficient in hematological malignancies expressing CD19. On June 20th 2018, the European Medicines Agency gave a favorable opinion on two types of anti-CD19 CAR-T cells - tisagenlecleucel and axicabtagène ciloleucel - in the management of malignant hemopathies B after two lines of treatment. Their remarkable efficacy has been demonstrated in the first clinical trials conducted in the United States, but they present new and potentially serious side effects (cytokine release syndrome, neurotoxicity, among others). However, this new class of gene therapy raises practical problems regarding its production circuit, its delivery conditions and its high cost.

[Pomalidomide for multiple myeloma]. / Pomalidomide dans les myélomes multiples.

Pomalidomide is a second-generation immunomodulatory drug (IMID). Its efficiency overtakes its predecessors' (thalidomide, lenalidomide), with less toxicity. It is indicated in the treatment of refractory or relapsed multiple myeloma, associated to dexamethasone. It is available in France since 2013, following the results of different studies.

[Ibrutinib prescription in B-cell lymphoid neoplasms]. / Rationnel et modalités de prescription de l'ibrutinib dans les hémopathies lymphoïdes B.

Ibrutinib is a new-targeted therapy that irreversibly and specifically inhibits the Bruton's Tyrosine Kinase (BTK), a key component of the signaling pathways of B cells. The results are very encouraging as monotherapy in the treatment of chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenström's macroglobulinemia. Following the results of recent studies, ibrutinib is now available in France for these three diseases.