Counterproductive effects of anti-CD38 and checkpoint inhibitor for the treatment of NK/T cell lymphoma.

Introduction: Natural killer/T cell lymphoma (NKTL) is an aggressive malignancy associated with poor prognosis. This is largely due to limited treatment options, especially for relapsed patients. Immunotherapies like immune checkpoint inhibitors (ICI) and anti-CD38 therapies have shown promising but variable clinical efficacies. Combining these therapies has been suggested to enhance efficacy. Methods: We conducted a case study on a relapsed NKTL patient treated sequentially with anti-CD38 followed by ICI (anti-PD1) using cytometry analyses. Results and Discussion: Our analysis showed an expected depletion of peripheral CD38+ B cells following anti-CD38 treatment. Further analysis indicated that circulating anti-CD38 retained their function for up to 13 weeks post-administration. Anti-PD1 treatment triggered re-activation and upregulation of CD38 on the T cells. Consequently, these anti-PD1-activated T cells were depleted by residual circulating anti-CD38, rendering the ICI treatment ineffective. Finally, a meta-analysis confirmed this counterproductive effect, showing a reduced efficacy in patients undergoing combination therapy. In conclusion, our findings demonstrate that sequential anti-CD38 followed by anti-PD1 therapy leads to a counterproductive outcome in NKTL patients. This suggests that the treatment sequence is antithetic and warrants re-evaluation for optimizing cancer immunotherapy strategies.

Inhibition of TREM-2 Markedly Suppresses Joint Inflammation and Damage in Experimental Arthritis.

The triggering receptors expressed on myeloid cells (TREMs) are a family of activating immune receptors that regulate the inflammatory response. TREM-1, which is expressed on monocytes and/or macrophages and neutrophils, functions as an inflammation amplifier and plays a role in the pathogenesis of rheumatoid arthritis (RA). Unlike TREM-1, the role in RA of TREM-2, which is expressed on macrophages, immature monocyte-derived dendritic cells, osteoclasts, and microglia, remains unclear and controversial. TREM-2 ligands are still unknown, adding further uncertainty to our understanding of TREM-2 function. Previously, we demonstrated that TREM-1 blockade, using a ligand-independent TREM-1 inhibitory peptide sequence GF9 rationally designed by our signaling chain homooligomerization (SCHOOL) model of cell signaling, ameliorates collagen-induced arthritis (CIA) severity in mice. Here, we designed a TREM-2 inhibitory peptide sequence IA9 and tested it in the therapeutic CIA model, either as a free 9-mer peptide IA9, or as a part of a 31-mer peptide IA31 incorporated into lipopeptide complexes (IA31-LPC), for targeted delivery. We demonstrated that administration of IA9, but not a control peptide, after induction of arthritis diminished release of proinflammatory cytokines and dramatically suppressed joint inflammation and damage, suggesting that targeting TREM-2 may be a promising approach for the treatment of RA.

PD-1 Immune Checkpoint Blockade and PSGL-1 Inhibition Synergize to Reinvigorate Exhausted T Cells.

Chronic viral infections where the antigen persists long-term, induces an exhaustion phenotype in responding T cells. It is now evident that immune checkpoints on T cells including PD-1, CTLA-4, and PSGL-1 (Selplg) are linked with the differentiation of exhausted cells. Chronic T cell receptor signaling induces transcriptional signatures that result in the development of various exhausted T cell subsets, including the stem-like T cell precursor exhausted (Tpex) cells, which can be reinvigorated by immune checkpoint inhibitors (ICIs). While PSGL-1 has been shown to inhibit T cell responses in various disease models, the cell-intrinsic function of PSGL-1 in the differentiation, maintenance, and reinvigoration of exhausted T cells is unknown. We found Selplg-/- T cells had increased expansion in melanoma tumors and in early stages of chronic viral infection. Despite their increase, both WT and Selplg-/- T cells eventually became phenotypically and functionally exhausted. Even though virus-specific Selplg-/- CD4+ and CD8+ T cells were increased at the peak of T cell expansion, they decreased to lower levels than WT T cells at later stages of chronic infection. We found that Selplg-/- CD8+ Tpex (SLAMF6hiTIM3lo, PD-1+TIM3+, TOX+, TCF-1+) cell frequencies and numbers were decreased compared to WT T cells. Importantly, even though virus-specific Selplg-/- CD4+ and CD8+ T cells were lower, they were reinvigorated more effectively than WT T cells after anti-PD-L1 treatment. We found increased SELPLG expression in Hepatitis C-specific CD8+ T cells in patients with chronic infection, whereas these levels were decreased in patients that resolved the infection. Together, our findings showed multiple PSGL-1 regulatory functions in exhausted T cells. We found that PSGL-1 is a cell-intrinsic inhibitor that limits T cells in tumors and in persistently infected hosts. Additionally, while PSGL-1 is linked with T cell exhaustion, its expression was required for their long-term maintenance and optimal differentiation into Tpex cells. Finally, PSGL-1 restrained the reinvigoration potential of exhausted CD4+ and CD8+ T cells during ICI therapy. Our findings highlight that targeting PSGL-1 may have therapeutic potential alone or in combination with other ICIs to reinvigorate exhausted T cells in patients with chronic infections or cancer.

Orally Bioavailable Enzymatic Inhibitor of CD38, MK-0159, Protects against Ischemia/Reperfusion Injury in the Murine Heart.

CD38 is one of the major nicotinamide adenine dinucleotide (NAD+)- and nicotinamide adenine dinucleotide phosphate (NADP+)-consuming enzymes in mammals. NAD+, NADP+, and their reduced counterparts are essential coenzymes for numerous enzymatic reactions, including the maintenance of cellular and mitochondrial redox balance. CD38 expression is upregulated in age-associated inflammation as well as numerous metabolic diseases, resulting in cellular and mitochondrial dysfunction. Recent literature studies demonstrate that CD38 is activated upon ischemia/reperfusion (I/R), leading to a depletion of NADP+, which results in endothelial damage and myocardial infarction in the heart. Despite increasing evidence of CD38 involvement in various disease states, relatively few CD38 enzymatic inhibitors have been reported to date. Herein, we describe a CD38 enzymatic inhibitor (MK-0159, IC50 = 3 nM against murine CD38) that inhibits CD38 in in vitro assay. Mice treated with MK-0159 show strong protection from myocardial damage upon cardiac I/R injury compared to those treated with NAD+ precursors (nicotinamide riboside) or the known CD38 inhibitor, 78c.

miR-141-3p promotes retinoblastoma progression via inhibiting sushi domain-containing protein 2.

Retinoblastoma, often referred to as eye cancer, is a common primary pediatric intraocular malignancy. In this framework, micro ribose nucleic acids (miRNAs) play essential roles in retinoblastoma oncogenesis and development. However, the function and mechanism of the miR-141-3p/sushi domain-containing protein 2 (SUSD2) axis in retinoblastoma are unclear. To address these issues, miR-141-3p and SUSD2 expressions between the retinoblastoma patients and the normal control are identified by analyzing the Gene Expression Omnibus (GEO) datasets. Moreover, bioinformatics analysis, a dual-luciferase reporter assay, functional loss, and gain together with rescue experiments are employed to explore the biological function and molecular mechanisms of the miR-141-3p/SUSD2 axis in retinoblastoma oncogenesis and development. Our data showed that SUSD2 levels are considerably decreased in retinoblastoma cells and tissues. SUSD2 overexpression inhibited viability, promoting apoptosis of retinoblastoma cells and inhibiting tube formation of primary human umbilical vein endothelial cells (HUVECs) in vitro. The bioinformatics analysis and dual-luciferase reporter tests showed that SUSD2 is directly regulated by miR-141-3p. The miR-141-3p inhibition suppressed retinoblastoma growth and angiogenesis, while miR-141-3p overexpression increased retinoblastoma growth and angiogenesis, which is partially reversed when SUSD2 is over-expressed both in vivo and in vitro. In conclusion, SUSD2 is a tumor-suppressor in retinoblastoma. miR-141-3p/SUSD2 axis played an essential role in regulating angiogenesis and retinoblastoma progression, serving as a new biomarker for management of retinoblastoma.

SAR442085, a novel anti-CD38 antibody with enhanced antitumor activity against multiple myeloma.

Anti-CD38 monoclonal antibodies (mAbs) represent a breakthrough in the treatment of multiple myeloma (MM), yet some patients fail to respond or progress quickly with this therapy, highlighting the need for novel approaches. In this study we compared the preclinical efficacy of SAR442085, a next-generation anti-CD38 mAb with enhanced affinity for activating Fcγ receptors (FcγR), with first-generation anti-CD38 mAb daratumumab and isatuximab. In surface plasmon resonance and cellular binding assays, we found that SAR442085 had higher binding affinity than daratumumab and isatuximab for FcγRIIa (CD32a) and FcγRIIIa (CD16a). SAR442085 also exhibited better in vitro antibody-dependent cellular cytotoxicity (ADCC) against a panel of MM cells expressing variable CD38 receptor densities including MM patients' primary plasma cells. The enhanced ADCC of SAR442085 was confirmed using NK-92 cells bearing low and high affinity FcγRIIIa (CD16a)-158F/V variants. Using MM patients' primary bone marrow cells, we confirmed that SAR442085 had an increased ability to engage FcγRIIIa, resulting in higher natural killer (NK) cell activation and degranulation against primary plasma cells than preexisting Fc wild-type anti-CD38 mAbs. Finally, using huFcgR transgenic mice that express human Fcγ receptors under the control of their human regulatory elements, we demonstrated that SAR442085 had higher NK cell-dependent in vivo antitumor efficacy and better survival than daratumumab and isatuximab against EL4 thymoma or VK*MYC myeloma cells overexpressing human CD38. These results highlight the preclinical efficacy of SAR442085 and support the current evaluation of this next-generation anti-CD38 antibody in phase I clinical development in patients with relapsed/refractory MM.

Outcomes of anti-CD38 isatuximab plus pomalidomide and dexamethasone in five relapsed myeloma patients with prior exposure to anti-C38 daratumumab: case series.

Objectives: Daratumumab is the first anti-CD38 monoclonal antibody (Mab) used to treat myeloma in the newly diagnosed setting and in the relapsed setting. Isatuximab, another Mab targeting a specific epitope on the CD38 receptor, was recently approved in the UK in combination with pomalidomide and dexamethasone (IsaPomDex) to treat myeloma patients who received three prior lines of therapy. However, there is a lack of understanding of whether using a prior anti-CD38 Mab (e.g. daratumumab) can affect the efficacy of another Mab (e.g. isatuximab), when the latter is used to treat a subsequent relapse.Methods: We performed a UK-wide outcomes study of IsaPomDex in the real-world. In this case series, we report a detailed descriptive analysis of the characteristics and clinical outcomes of five IsaPomDex patients in UK routine practice (Patients I to V), with a prior exposure to daratumumab.Results: Age range was 51-77 years with two patients >70 and three patients <70 years. The cytogenetic risk was standard in two patients, high in two patients and not known in one patient. Prior daratumumab regimen were monotherapy (dara-mono) in one patient (II), and daratumumab with bortezomib and dexamethasone (DVd) in four patients. Responses to prior daratumumab were: very good partial response (VGPR) in two patients (I and III), minor response-stable disease (MR-SD) in one patient (II), and progressive disease (PD) in two patients (IV and V). Median (range) number of IsaPomDex cycles received was 2 (1-4). Outcomes of IsaPomDex were PD in three patients (II, IV and V) and a response in two patients. Response categories were: MR-SD in patient I and PR in patient III.Discussion: Despite the limitations of our case series, we described the first UK real-world report of IsaPomDex outcomes in myeloma patients with a prior exposure to daratumumab.Conclusion: Large prospective studies are required to further evaluate myeloma outcomes in this setting.

Extracellular vesicles produced by the human commensal gut bacterium Bacteroides thetaiotaomicron affect host immune pathways in a cell-type specific manner that are altered in inflammatory bowel disease.

The gastrointestinal (GI) tract harbours a complex microbial community, which contributes to its homeostasis. A disrupted microbiome can cause GI-related diseases, including inflammatory bowel disease (IBD), therefore identifying host-microbe interactions is crucial for better understanding gut health. Bacterial extracellular vesicles (BEVs), released into the gut lumen, can cross the mucus layer and access underlying immune cells. To study BEV-host interactions, we examined the influence of BEVs generated by the gut commensal bacterium, Bacteroides thetaiotaomicron, on host immune cells. Single-cell RNA sequencing data and host-microbe protein-protein interaction networks were used to predict the effect of BEVs on dendritic cells, macrophages and monocytes focusing on the Toll-like receptor (TLR) pathway. We identified biological processes affected in each immune cell type and cell-type specific processes including myeloid cell differentiation. TLR pathway analysis highlighted that BEV targets differ among cells and between the same cells in healthy versus disease (ulcerative colitis) conditions. The in silico findings were validated in BEV-monocyte co-cultures demonstrating the requirement for TLR4 and Toll-interleukin-1 receptor domain-containing adaptor protein (TIRAP) in BEV-elicited NF-kB activation. This study demonstrates that both cell-type and health status influence BEV-host communication. The results and the pipeline could facilitate BEV-based therapies for the treatment of IBD.

TREM2 is thyroid hormone regulated making the TREM2 pathway druggable with ligands for thyroid hormone receptor.

Triggering receptor expressed on myeloid cells-2 (TREM2) is a cell surface receptor on macrophages and microglia that senses and responds to disease-associated signals to regulate the phenotype of these innate immune cells. The TREM2 signaling pathway has been implicated in a variety of diseases ranging from neurodegeneration in the central nervous system to metabolic disease in the periphery. Here, we report that TREM2 is a thyroid hormone-regulated gene and its expression in macrophages and microglia is stimulated by thyroid hormone and synthetic thyroid hormone agonists (thyromimetics). Our findings report the endocrine regulation of TREM2 by thyroid hormone, and provide a unique opportunity to drug the TREM2 signaling pathway with orally active small-molecule therapeutic agents.

Maralixibat: First Approval.

Maralixibat (Livmarli™) is an orally-administered, small-molecule ileal bile acid transporter (IBAT) inhibitor being developed by Mirum Pharmaceuticals for the treatment of rare cholestatic liver diseases including Alagille syndrome (ALGS), progressive familial intrahepatic cholestasis (PFIC) and biliary atresia. Maralixibat received its first approval on 29 September 2021, in the USA, for use in the treatment of cholestatic pruritus in patients with ALGS 1 year of age and older. Maralixibat is also under regulatory review for ALGS in Europe, and clinical development for cholestatic liver disorders including ALGS in patients under 1 year of age, PFIC and biliary atresia is continuing in several other countries. This article summarises the milestones in the development of maralixibat leading to this first approval for ALGS.

NSP9 of SARS-CoV-2 attenuates nuclear transport by hampering nucleoporin 62 dynamics and functions in host cells.

Nuclear pore complexes (NPC) regulate molecular traffics on nuclear envelope, which plays crucial roles during cell fate specification and diseases. The viral accessory protein NSP9 of SARS-CoV-2 is reported to interact with nucleoporin 62 (NUP62), a structural component of the NPC, but its biological impact on the host cell remain obscure. Here, we established new cell line models with ectopic NSP9 expression and determined the subcellular destination and biological functions of NSP9. Confocal imaging identified NSP9 to be largely localized in close proximity to the endoplasmic reticulum. In agreement with the subcellular distribution of NSP9, association of NSP9 with NUP62 was observed in cytoplasm. Furthermore, the overexpression of NSP9 correlated with a reduction of NUP62 expression on the nuclear envelope, suggesting that attenuating NUP62 expression might have contributed to defective NPC formation. Importantly, the loss of NUP62 impaired translocation of p65, a subunit of NF-κB, upon TNF-α stimulation. Concordantly, NSP9 over-expression blocked p65 nuclear transport. Taken together, these data shed light on the molecular mechanisms underlying the modulation of host cells during SARS-CoV-2 infection.

The GRP94 Inhibitor PU-WS13 Decreases M2-like Macrophages in Murine TNBC Tumors: A Pharmaco-Imaging Study with 99mTc-Tilmanocept SPECT.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancers and is not eligible for hormone and anti-HER2 therapies. Identifying therapeutic targets and associated biomarkers in TNBC is a clinical challenge to improve patients' outcome and management. High infiltration of CD206+ M2-like macrophages in the tumor microenvironment (TME) indicates poor prognosis and survival in TNBC patients. As we previously showed that membrane expression of GRP94, an endoplasmic reticulum chaperone, was associated with the anti-inflammatory profile of human PBMC-derived M2 macrophages, we hypothesized that intra-tumoral CD206+ M2 macrophages expressing GRP94 may represent innovative targets in TNBC for theranostic purposes. We demonstrate in a preclinical model of 4T1 breast tumor-bearing BALB/c mice that (i) CD206-expressing M2-like macrophages in the TME of TNBC can be specifically detected and quantified using in vivo SPECT imaging with 99mTc-Tilmanocept, and (ii) the inhibition of GRP94 with the chemical inhibitor PU-WS13 induces a decrease in CD206-expressing M2-like macrophages in TME. This result correlated with reduced tumor growth and collagen content, as well as an increase in CD8+ cells in the TME. 99mTc-Tilmanocept SPECT imaging might represent an innovative non-invasive strategy to quantify CD206+ tumor-associated macrophages as a biomarker of anti-GRP94 therapy efficacy and TNBC tumor aggressiveness.

Efficacy and safety of maralixibat treatment in patients with Alagille syndrome and cholestatic pruritus (ICONIC): a randomised phase 2 study.

BACKGROUND: Alagille syndrome is a rare genetic disease that often presents with severe cholestasis and pruritus. There are no approved drugs for management. Maralixibat, an apical, sodium-dependent, bile acid transport inhibitor, prevents enterohepatic bile acid recirculation. We evaluated the safety and efficacy of maralixibat for children with cholestasis in Alagille syndrome. METHODS: ICONIC was a placebo-controlled, randomised withdrawal period (RWD), phase 2b study with open-label extension in children (aged 1-18 years) with Alagille syndrome (NCT02160782). Eligible participants had more than three times the normal serum bile acid (sBA) levels and intractable pruritus. After 18 weeks of maralixibat 380 µg/kg once per day, participants were randomly assigned (1:1) to continue maralixibat or receive placebo for 4 weeks. Subsequently, all participants received open-label maralixibat until week 48. During the long-term extension (204 weeks reported), doses were increased up to 380 µg/kg twice per day. The primary endpoint was the mean sBA change during the RWD in participants with at least 50% sBA reduction by week 18. Cholestastic pruritus was assessed using observer-rated, patient-rated, and clinician-rated 0-4 scales. The safety population was defined as all participants who had received at least one dose of maralixibat. This trial was registered with ClinicalTrials.gov, NCT02160782, and is closed to recruitment. FINDINGS: Between Oct 28, 2014, and Aug 14, 2015, 31 participants (mean age 5·4 years [SD 4·25]) were enrolled and 28 analysed at week 48. Of the 29 participants who entered the randomised drug withdrawal period, ten (34%) were female and 19 (66%) were male. In the RWD, participants switched to placebo had significant increases in sBA (94 µmol/L, 95% CI 23 to 164) and pruritus (1·7 points, 95% CI 1·2 to 2·2), whereas participants who continued maralixibat maintained treatment effect. This study met the primary endpoint (least square mean difference -117 µmol/L, 95% CI -232 to -2). From baseline to week 48, sBA (-96 µmol/L, -162 to -31) and pruritus (-1·6 pts, -2·1 to -1·1) improved. In participants who continued to week 204 (n=15) all improvements were maintained. Maralixibat was generally safe and well tolerated throughout. The most frequent adverse events were gastrointestinal related. Most adverse events were self-limiting in nature and mild-to-moderate in severity. INTERPRETATION: In children with Alagille syndrome, maralixibat is, to our knowledge, the first agent to show durable and clinically meaningful improvements in cholestasis. Maralixibat might represent a new treatment paradigm for chronic cholestasis in Alagille syndrome. FUNDING: Mirum Pharmaceuticals.

Design, synthesis and biological evaluation of macrocyclic derivatives as TRK inhibitors.

Tropomyosin receptor kinases (TRKA, TRKB, TRKC) are transmembrane receptor tyrosine kinases, which are respectively encoded by NTRK1, NTRK2, and NTRK3 genes. Herein, we reported the design, synthesis and Structure-Activity Relationship (SAR) investigation of a series of macrocyclic derivatives as new TRK inhibitors. Among these compounds, compound 9e exhibited strong kinase inhibitory activity (TRKG595R IC50 = 13.1 nM) and significant antiproliferative activity in the Ba/F3-LMNA-NTRK1 cell line (IC50 = 0.080 µM) and compound 9e has shown a better inhibitory effect (IC50 = 0.646 µM) than control drug LOXO-101 in Ba/F3-LMNA-NTRK1-G595R cell line. These results indicate that compound 9e is a potential TRK inhibitor for further investigation.

Discovery of Active Ingredients Targeted TREM2 by SPR Biosensor-UPLC/MS Recognition System, and Investigating the Mechanism of Anti-Neuroinflammatory Activity on the Lignin-Amides from Datura metel Seeds.

As a new target protein for Alzheimer's disease (AD), the triggering receptor expressed on myeloid Cells 2 (TREM2) was expressed on the surface of microglia, which was shown to regulate neuroinflammation, be associated with a variety of neuropathologic, and regarded as a potential indicator for monitoring AD. In this study, a novel recognition system based on surface plasmon resonance (SPR) for the TREM2 target spot was established coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC-MS), in order to screen the active ingredients targeting TREM2 from Datura metel seeds. The results showed that four lignan-amides were discovered as candidate compounds by SPR biosensor-UPLC/MS recognition analysis. According to the guidance of the active ingredients discovered by the system, the lignin-amides from Datura metel seeds (LDS) were preliminarily identified as containing 27 lignan-amides, which were enriched compositions by the HP-20 of Datura metel seeds. Meanwhile, the anti-inflammatory activity of LDS was evaluated in BV2 microglia induced by LPS. Our experimental results demonstrated that LDS could reduce NO release in LPS-treated BV2 microglia cells and significantly reduce the expression of the proteins of inducible Nitric Oxide Synthase (iNOS), cyclooxygenase 2 (COX-2), microtubule-associated protein tau (Tau), and ionized calcium-binding adapter molecule 1 (IBA-1). Accordingly, LDS might increase the expression of TREM2/DNAX-activating protein of 12 kDa (DAP12) and suppress the Toll-like receptor SX4 (TLR4) pathway and Recombinant NLR Family, Pyrin Domain Containing Protein 3 (NLRP3)/cysteinyl aspartate specific proteinase-1 (Caspase-1) inflammasome expression by LDS in LPS-induced BV2 microglial cells. Then, the inhibitory release of inflammatory factors Interleukin 1 beta (IL-1ß), Interleukin 6 (IL-6), and Tumor necrosis factor-alpha (TNFα) inflammatory cytokines were detected to inhibit neuroinflammatory responses. The present results propose that LDS has potential as an anti-neuroinflammatory agent against microglia-mediated neuroinflammatory disorders.

Targeting TREM2 on tumor-associated macrophages enhances immunotherapy.

Converting checkpoint inhibitor (CPI)-resistant individuals to being responsive requires identifying suppressive mechanisms. We identify TREM2+ tumor-associated macrophages (TAMs) as being correlated with exhausted CD8+ tumor-infiltrating lymphocytes (TILs) in mouse syngeneic tumor models and human solid tumors of multiple histological types. Fc domain-enhanced anti-TREM2 monoclonal antibody (mAb) therapy promotes anti-tumor immunity by elimination and modulation of TAM populations, which leads to enhanced CD8+ TIL infiltration and effector function. TREM2+ TAMs are most enriched in individuals with ovarian cancer, where TREM2 expression corresponds to disease grade accompanied by worse recurrence-free survival. In an aggressive orthotopic ovarian cancer model, anti-TREM2 mAb therapy drives potent anti-tumor immunity. These results highlight TREM2 as a highly attractive target for immunotherapy modulation in individuals who are refractory to CPI therapy and likely have a TAM-rich tumor microenvironment.

Comparison of monoclonal antibodies targeting CD38, SLAMF7 and PD-1/PD-L1 in combination with Bortezomib/Immunomodulators plus dexamethasone/prednisone for the treatment of multiple myeloma: an indirect-comparison Meta-analysis of randomised controlled trials.

BACKGROUND: Many clinical trials have assessed the effect and safety of monoclonal antibodies (MAbs) in combination with proteasome inhibitors or immunomodulators plus dexamethasone/prednisone for the treatment of multiple myeloma (MM). The treatment outcomes of comparing different MAbs in combination with the above-mentioned agents remained unclear. We performed the meta-analysis to indirectly compare the effect and safety of MAbs targeting CD38, SLAMF7, and PD-1/PD-L1 in combination with bortezomib/immunomodulators plus dexamethasone/prednisone for patients with MM. METHODS: We searched thoroughly in the databases for randomised controlled trials (RCTs) in which at least one of the three MAbs were included. We included eleven eligible RCTs with 5367 patients in the meta-analysis. Statistical analysis was carried out using StataMP14 and Indirect Treatment Comparisons software. RESULTS: We calculated hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) and relative risk (RR) for overall response rate, complete response (CR) or better, very good partial response (VGPR) or better, VGPR, partial response, stable disease, and grade 3 or higher adverse events among the three groups. The HRs for PFS of the CD38 group vs SLAMF7 group, CD38 group vs PD-1/PD-L1 group, and SLAMF7 group vs PD-1/PD-L1 group were 0.662 (95%CI 0.543-0.806), 0.317 (95%CI 0.221-0.454), and 0.479 (95%CI 0.328-0.699), respectively. The HR for OS of the CD38 group vs SLAMF7 group was 0.812 (95%CI 0.584-1.127). The RR for CR or better in the CD38 group vs SLAMF7 group was 2.253 (95%CI 1.284-3.955). The RR for neutropenia of the CD38 group vs SLAMF7 group was 1.818 (95%CI 1.41-2.344). CONCLUSIONS: Treatment with the CD38 group had longer PFS and better treatment response than that with the SLAMF7 or PD-1/PD-L1 group. In addition, the SLAMF7 group prolonged PFS compared with the PD-1/PD-L1 group and was associated with a lower incidence of grade 3 or higher neutropenia than the CD38 and PD-1/PD-L1 group. In conclusion, MAbs targeting CD38 are the best, followed by those targeting SLAMF7; MAbs targeting PD-1/PD-L1 are the worst when in combination with bortezomib/immunomodulators plus dexamethasone/prednisone for the treatment of MM.

Critical Role of Astrocyte NAD+ Glycohydrolase in Myelin Injury and Regeneration.

Western-style diets cause disruptions in myelinating cells and astrocytes within the mouse CNS. Increased CD38 expression is present in the cuprizone and experimental autoimmune encephalomyelitis models of demyelination and CD38 is the main nicotinamide adenine dinucleotide (NAD+)-depleting enzyme in the CNS. Altered NAD+ metabolism is linked to both high fat consumption and multiple sclerosis (MS). Here, we identify increased CD38 expression in the male mouse spinal cord following chronic high fat consumption, after focal toxin [lysolecithin (LL)]-mediated demyelinating injury, and in reactive astrocytes within active MS lesions. We demonstrate that CD38 catalytically inactive mice are substantially protected from high fat-induced NAD+ depletion, oligodendrocyte loss, oxidative damage, and astrogliosis. A CD38 inhibitor, 78c, increased NAD+ and attenuated neuroinflammatory changes induced by saturated fat applied to astrocyte cultures. Conditioned media from saturated fat-exposed astrocytes applied to oligodendrocyte cultures impaired myelin protein production, suggesting astrocyte-driven indirect mechanisms of oligodendrogliopathy. In cerebellar organotypic slice cultures subject to LL-demyelination, saturated fat impaired signs of remyelination effects that were mitigated by concomitant 78c treatment. Significantly, oral 78c increased counts of oligodendrocytes and remyelinated axons after focal LL-induced spinal cord demyelination. Using a RiboTag approach, we identified a unique in vivo brain astrocyte translatome profile induced by 78c-mediated CD38 inhibition in mice, including decreased expression of proinflammatory astrocyte markers and increased growth factors. Our findings suggest that a high-fat diet impairs oligodendrocyte survival and differentiation through astrocyte-linked mechanisms mediated by the NAD+ase CD38 and highlights CD38 inhibitors as potential therapeutic candidates to improve myelin regeneration.SIGNIFICANCE STATEMENT Myelin disturbances and oligodendrocyte loss can leave axons vulnerable, leading to permanent neurologic deficits. The results of this study suggest that metabolic disturbances, triggered by consumption of a diet high in fat, promote oligodendrogliopathy and impair myelin regeneration through astrocyte-linked indirect nicotinamide adenine dinucleotide (NAD+)-dependent mechanisms. We demonstrate that restoring NAD+ levels via genetic inactivation of CD38 can overcome these effects. Moreover, we show that therapeutic inactivation of CD38 can enhance myelin regeneration. Together, these findings point to a new metabolic targeting strategy positioned to improve disease course in multiple sclerosis and other conditions in which the integrity of myelin is a key concern.

Discovery of the Next-Generation Pan-TRK Kinase Inhibitors for the Treatment of Cancer.

The neurotrophic receptor tyrosine kinase (NTRK) genes including NTRK1, NTRK2, and NTRK3 encode the tropomyosin receptor kinase (Trk) proteins TrkA, TrkB, and TrkC, respectively. So far, two TRK inhibitors, larotrectinib sulfate (LOXO-101 sulfate) and entrectinib (NMS-E628, RXDX-101), have been approved for clinical use in 2018 and 2019, respectively. To overcome acquired resistance, next-generation Trk inhibitors such as selitrectinib (LOXO-195) and repotrectinib (TPX-0005) have been developed and exhibit effectiveness to induce remission in patients with larotrectinib treatment failure. Herein, we report the identification and optimization of a series of macrocyclic compounds as potent pan-Trk (WT and MT) inhibitors that exhibited excellent physiochemical properties and good oral pharmacokinetics. Compound 10 was identified via optimization from the aspects of chemistry and pharmacokinetic properties, which showed good activity against wild and mutant TrkA/TrkC in in vitro and in vivo studies.

Prevention of streptozotocin­induced Neuro­2a cell death by C8­B4 microglia transformed with repetitive low­dose lipopolysaccharide.

Diabetes­associated neuronal dysfunction (DAND) is one of the serious complications of diabetes, but there is currently no remedy for it. Streptozotocin [2­deoxy­2­(3­methy1­3­nitrosoureido) D­glucopyranose; STZ] is one of the most well­established diabetes inducers and has been used in vivo and in vitro DAND models. The aim of the present study was to demonstrate that C8­B4 microglia transformed by the stimulus of repetitive low­dose lipopolysaccharide (LPSx3­microglia) prevent STZ­induced Neuro­2a neuronal cell death in vitro. The ELISA results showed that neurotrophin­4/5 (NT­4/5) secretion was promoted in LPSx3­microglia and the cell viability assay with trypan blue staining revealed that the culture supernatant of LPSx3­microglia prevented STZ­induced neuronal cell death. In addition, reverse transcription­quantitative PCR showed that neurons treated with the culture supernatant of LPSx3­microglia promoted the gene expression of B­cell lymphoma­extra large and glucose­dependent insulinotropic polypeptide receptor. Furthermore, the inhibition of tyrosine kinase receptor B, a receptor of NT­4/5, suppressed the neuroprotective effect of LPSx3­microglia. Taken together, the present study demonstrated that LPSx3­microglia prevent STZ­induced neuronal death and that NT­4/5 may be involved in the neuroprotective mechanism of LPSx3­microglia.