Olivier Hermine’s research while affiliated with French Institute of Health and Medical Research and other places

Background Masitinib is an orally administered tyrosine kinase inhibitor that targets activated cells of the innate neuroimmune system. We have studied the neuroprotective action of masitinib on the manifestations of experimental autoimmune encephalitis (EAE) induced axonal and neuronal damage. EAE is a model of neuroimmune-driven chronic neuroinflammation and therefore highly relevant to masitinib’s mechanism of action in neurodegenerative diseases. Importantly, neuronal damage, or prevention thereof, can be rapidly assessed by measuring serum neurofilament light chain (NfL) concentration in EAE-induced mice. Methods EAE induction was performed in healthy female C57BL/6 mice via active MOG 35–55 peptide immunization. Treatments were initiated 14 days post EAE induction. On day-0, 39 mice with established EAE symptoms were randomly assigned to 3 treatment groups (n = 13): EAE control, masitinib 50 mg/kg/day (M50), and masitinib 100 mg/kg/day (M100). The treatment started on day-1 and ended on day-15. Blood samples were collected on day-1 and day-8, via tail vein sampling, and on day-15, via intracardiac puncture. Assessments included quantification of serum NfL levels along the disease duration, cytokine quantification at day-15, and clinical assessments. Results Masitinib treatment significantly (p < 0.0001) limited NfL production with respect to control; specifically, relative change in serum NfL concentration at day-8 was 43% and 60% lower for the M50 and M100 groups, respectively. Likewise, for the assessment of absolute serum NfL at day-8 and day-15, there was a significantly lower NfL concentration for masitinib treatment as compared with control. Furthermore, EAE mice treated with masitinib showed significantly lower concentrations of several well-established pro-inflammatory cytokines relative to control at day-15. A beneficial effect of masitinib on functional performance was also observed, with both M50 and M100 groups showing significantly less relative deterioration in grip strength at day-15 as compared with control (p < 0.001). Conclusion This study is the first demonstration that masitinib, a drug that targets the innate as opposed to the adaptive neuroimmune system, can lower serum NfL levels, and by extension therefore, neuronal damage, in a neuroimmune-driven neurodegenerative disease model. Overall, findings indicate that masitinib has a neuroprotective effect under conditions of chronic neuroinflammation and therefore plausible disease-modifying activity across a broad range of neurodegenerative diseases.

In mantle cell lymphoma, early progression of disease has been associated with short overall survival. The impact of clinical, pathological, and treatment strategies on the risk of early relapse has not been assessed in a large cohort of patients. We performed a pooled analysis of patients recruited in France from six randomized first-line MCL trials. Among 1386 treated MCL patients, 1280 were evaluable for POD24 status: 299 (23.4%) with a POD24 event and 981 (76.6%) without. Patients with a POD24 event had a median OS of 9.3 months (95% CI 8.4–11.8) versus not reached (95% CI 97.8–NR) for those without POD24 events. The median post-relapse OS of patients with a late relapse was also significantly longer at 49.4 months (HR = 0.39; 95% CI 0.31–0.48; P < 0.001) as compared to POD24 patients. Baseline variables (age, performance status, B symptoms, LDH/ULN, leukocytes, blastoid variant, and Ki-67 > 30%) were significantly associated with the risk of POD24, independent of ASCT. Among responding patients at end-of-induction (n = 1105) who had received ASCT, anti-CD20 maintenance was associated with a decreased risk of POD24 (OR = 0.37; 95% CI 0.1–1.0). Using this large data set of patients in clinical trials, we confirm that POD24 status is strongly associated with subsequent OS in MCL. Rituximab maintenance provided significant protection against the risk of POD24, independent of ASCT. Progression within 2 years should be considered as a primary endpoint in future studies.

Cellular therapies have been cornerstones of the treatment of mantle cell lymphoma (MCL) for decades and have helped to improve the outcome of this formerly very unfavourable B-cell lymphoma considerably. Current established roles of cellular therapies include autologous hematopoietic cell transplantation (HCT) as part of first-line therapy, chimeric antigen receptor-engineered T-cells (CART) for relapsed/refractory MCL, and allogeneic HCT for settings in which CARTs have failed or are unavailable. Therapeutic innovations have recently entered the MCL treatment landscape and are moving upstream in treatment algorithms, challenging the existing management principles. The purpose of this paper is to give some guidance regarding how to best use cellular therapies in this increasingly complex environment. Due to differences in CART labels, available non-cellular treatment options, and philosophy between the American and the European health systems, we found it reasonable to contrast the American and European perspectives on defined standard scenarios, which are often overlapping but show discrepancies in some important aspects.

In sickle cell disease (SCD), the β6Glu→Val substitution in the β-globin leads to red blood cell sickling. The transplantation of autologous, genetically modified hematopoietic stem and progenitor cells (HSPCs) is a promising treatment option for patients with SCD. We completed a Phase I/II open-label clinical trial (NCT03964792) for patients with SCD using a lentiviral vector (DREPAGLOBE) expressing a potent anti-sickling β-globin. The primary endpoint was to evaluate the short-term safety and secondary endpoints included the efficacy and the long-term safety. We report on the results after 18 to 36 months of follow-up. No drug-related adverse events or signs of clonal hematopoiesis were observed. Despite similar vector copy numbers in the drug product, gene-marking in peripheral blood mononuclear cells and correction of the clinical phenotype varied from one patient to another. Single-cell transcriptome analyses show that in the patients with poor engraftment, the most immature HSCs display an exacerbated inflammatory signature (via IL-1 or TNF-α and interferon signaling pathways). This signature is accompanied by a lineage bias in the HSCs. Our clinical data indicates that the DREPAGLOBE-based gene therapy (GT) is safe. However, its efficacy is variable and probably depends on the number of infused HSCs and intrinsic, engraftment-impairing inflammatory alterations in HSCs. Trial: NCT03964792

Neuropilin-1 is henceforth a relevant target in cancer treatment; however, its way of action remains partly elusive, and the development of small inhibitory molecules is therefore required for its study. Here, we report that two small-sized neuropilin antagonists (NRPa-47 and NRPa-48), VEGF-A165/NRP-1 binding inhibitors, are able to decrease VEGF-Rs phosphorylation and to modulate their downstream cascades in the triple-negative breast cancer cell line (MDA-MB-231). Nevertheless, NRPas exert a divergent pathway regulation of MAPK phosphorylation, such as JNK-1/-2/-3, ERK-1/-2, and p38β/γ/δ-kinases, as well as their respective downstream targets. However, NRPa-47 and NRPa-48 apply a common down-regulation of the p38α-kinase phosphorylation and their downstream targets, emphasising its central regulating role. More importantly, none of the 40 selected kinases, including SAPK2a/p38α, are affected in vitro by NRPas, strengthening their specificity. Taken together, NRPas induced cell death by the down-modulation of pro-apoptotic and anti-apoptotic proteins, cell death receptors and adaptors, heat shock proteins (HSP-27/-60/-70), cell cycle proteins (p21, p27, phospho-RAD17), and transcription factors (p53, HIF-1α). In conclusion, we showed for the first time how NRPas may alter tumour cell signalling and contribute to the down-modulation of the cancer therapeutic key factor p38α-kinase phosphorylation. Thus, the efficient association of NRPas and p38α-kinase inhibitor strengthened this hypothesis.

Although refrigerated storage slows the metabolism of volunteer donor RBCs, which is essential in transfusion medicine, cellular aging still occurs throughout this in vitro process. Storage-induced microerythrocytes (SMEs) are morphologically-altered senescent RBCs that accumulate during storage and are cleared from circulation following transfusion. However, the molecular and cellular alterations that trigger clearance of this RBC subset remain to be identified. Using a staining protocol that sorts long-stored SMEs (i.e., CFSEhigh) and morphologically-normal RBCs (CFSElow), these in vitro aged cells were characterized. Metabolomics analysis identified depletion of energy, lipid-repair, and antioxidant metabolites in CFSEhigh RBCs. By redox proteomics, irreversible protein oxidation primarily affected CFSEhigh RBCs. By proteomics, 96 proteins, mostly in the proteostasis family, had relocated to CFSEhigh RBC membranes. CFSEhigh RBCs exhibited decreased proteasome activity and deformability; increased phosphatidylserine exposure, osmotic fragility, and endothelial cell adherence; and were cleared from the circulation during human spleen perfusion ex vivo. Conversely, molecular, cellular, and circulatory properties of long-stored CFSElow RBCs resembled those of short-stored RBCs. CFSEhigh RBCs are morphologically and metabolically altered, have irreversibly oxidized and membrane-relocated proteins, and exhibit decreased proteasome activity. In vitro aging during storage selectively alters metabolism and proteostasis in these storage-induced senescent RBCs targeted for clearance.

The deregulated activation of the phosphoinositide 3-kinase (PI3K) pathway is a hallmark of aggressive tumors with metabolic plasticity, eliciting their adaptation to the microenvironment and resistance to chemotherapy. A significant gap lies between the biological features of PI3K-driven tumors and the specific targeting of their vulnerabilities. Here, we explore the metabolic liabilities of PI3K-altered T-cell acute lymphoblastic leukemia (T-ALL), an aggressive hematological cancer with dismal outcomes. We report a metabolic crosstalk linking glutaminolysis and glycolysis driven by PI3K signaling alterations. Pharmaceutical inhibition of mTOR reveals the singular plasticity of PI3K-altered cells toward the mobilization of glutamine as a salvage pathway to ensure their survival. Subsequently, the combination of glutamine degradation and mTOR inhibition demonstrates robust cytotoxicity in PI3K-driven solid and hematological tumors in pre-clinical and clinical settings. We propose a novel therapeutic strategy to circumvent metabolic adaptation and efficiently target PI3K-driven cancer.