Chimeric antigen receptor (CAR) T cell therapy has demonstrated proven efficacy in some hematologic cancers. We evaluated the safety and efficacy of LCAR-B38M, a dual epitope-binding CAR T cell ...therapy directed against 2 distinct B cell maturation antigen epitopes, in patients with relapsed/refractory (R/R) multiple myeloma (MM).
This ongoing phase 1, single-arm, open-label, multicenter study enrolled patients (18 to 80 years) with R/R MM. Lymphodepletion was performed using cyclophosphamide 300 mg/m
. LCAR-B38M CAR T cells (median CAR+ T cells, 0.5 × 10
cells/kg range, 0.07 to 2.1 × 10
) were infused in 3 separate infusions. The primary objective is to evaluate the safety of LCAR-B38M CAR T cells; the secondary objective is to evaluate the antimyeloma response of the treatment based on the general guidelines of the International Myeloma Working Group.
At data cutoff, 57 patients had received LCAR-B38M CAR T cells. All patients experienced ≥ 1 adverse events (AEs). Grade ≥ 3 AEs were reported in 37/57 patients (65%); most common were leukopenia (17/57; 30%), thrombocytopenia (13/57; 23%), and aspartate aminotransferase increased (12/57; 21%). Cytokine release syndrome occurred in 51/57 patients (90%); 4/57 (7%) had grade ≥ 3 cases. One patient reported neurotoxicity of grade 1 aphasia, agitation, and seizure-like activity. The overall response rate was 88% (95% confidence interval CI, 76 to 95); 39/57 patients (68%) achieved a complete response, 3/57 (5%) achieved a very good partial response, and 8/57 (14%) achieved a partial response. Minimal residual disease was negative for 36/57 (63%) patients. The median time to response was 1 month (range, 0.4 to 3.5). At a median follow-up of 8 months, median progression-free survival was 15 months (95% CI, 11 to not estimable). Median overall survival for all patients was not reached.
LCAR-B38M CAR T cell therapy displayed a manageable safety profile and demonstrated deep and durable responses in patients with R/R MM.
ClinicalTrials.gov , NCT03090659 ; Registered on March 27, 2017, retrospectively registered.
•We describe the chemokines and their receptors, including CCL2/CCL12-CCR2, CCL3/4/5-CCR5, CCL15-CCR1, CX3CL1/CCL26-CX3CR1, CXCL5/2/1-CXCR2, CXCL8-CXCR1/2, CCL21-CCR7, CXCL13-CXCR5 axes important for ...MDSCs recruitment to the tumor site, and their correlation with tumor growth, metastasis and prognosis.•We discuss underlying signaling pathways and regulatory mechanisms involved in the chemokine control of MDSCs migration to the tumor site.•We examine chemokine and their receptors as a potential targets in cancer immunotherapy, solo or in combination therapy.
Myeloid-derived suppressor cells (MDSCs) expand in tumor-bearing host. They suppress anti-tumor immune response and promote tumor growth. Chemokines play a vital role in recruiting MDSCs into tumor tissue. They can also induce the generation of MDSCs in the bone marrow, maintain their suppressive activity, and promote their proliferation and differentiation. Here, we review CCL2/CCL12-CCR2, CCL3/4/5-CCR5, CCL15-CCR1, CX3CL1/CCL26-CX3CR1, CXCL5/2/1-CXCR2, CXCL8-CXCR1/2, CCL21-CCR7, CXCL13-CXCR5 signaling pathways, their role in MDSCs recruitment to tumor tissue, and their correlation with tumor development, metastasis and prognosis. Targeting chemokines and their receptors may serve as a promising strategy in immunotherapy, especially combined with other strategies such as chemotherapy, cyclin-dependent kinase or immune checkpoints inhibitors.
Psychological stress has great impacts on the immune system, particularly the leukocytes distribution. Although the impacts of acute stress on blood leukocytes distribution are well studied, however, ...it remains unclear how chronic stress affects leukocytes distribution in peripheral circulation. Furthermore, there is no report about the role of spleen in the blood leukocytes distribution induced by stress. Here we show that spleen contributes to the alteration of restraint stress induced blood leukocytes distribution. Our data confirmed that restraint stress induced anxiety-like behavior in mice. Furthermore, we found that restraint stress decreased the CD4/CD8 ratio and elevated the percentages of natural killer cells, monocytes and polymorphonuclear myeloid-derived suppressor cell. We demonstrated that activation of hypothalamic-pituitary-adrenal axis (HPA) and sympathetic nervous system (SNS) contributes to restraint stress induced alteration of blood leukocyte distribution. Interestingly, we found that splenectomy could reverse the change of CD4/CD8 ratio induced by restraint stress. Together, our findings suggest that activation of HPA axis and SNS was responsible for the blood leukocyte subsets changes induced by restraint stress. Spleen, at least in part, contributed to the alteration in peripheral circulation induced by restraint stress.
Parvalbumin‐positive neurons (PVs) are the main class of inhibitory neurons in the mammalian central nervous system. By examining diurnal changes in synaptic and neuronal activity of PVs in the ...supragranular layer of the mouse primary visual cortex (V1), we found that both PV input and output are modulated in a time‐ and sleep‐dependent manner throughout the 24‐h day. We first show that PV‐evoked inhibition is stronger by the end of the light cycle (ZT12) relative to the end of the dark cycle (ZT0), which is in line with the lower inhibitory input of PV neurons at ZT12 than at ZT0. Interestingly, PV inhibitory and excitatory synaptic transmission slowly oscillate in opposite directions during the light/dark cycle. Although excitatory synapses are predominantly regulated by experience, inhibitory synapses are regulated by sleep, via acetylcholine activating M1 receptors. Consistent with synaptic regulation of PVs, we further show in vivo that spontaneous PV activity displays daily rhythm mainly determined by visual experience, which negatively correlates with the activity cycle of surrounding pyramidal neurons and the dorsal lateral geniculate nucleus‐evoked responses in V1. These findings underscore the physiological significance of PV's daily modulation.
Synopsis
Unveiling the modulatory mechanism of cortical parvalbumin‐positive neurons (PVs) in the mature mammalian brain is critical for understanding how cognitive function is regulated in normal and diseased brains. Here the behavior of PVs in area V1 of the mouse visual cortex is investigated ex vivo and in vivo and a circadian output is identified.
The excitatory and inhibitory synaptic transmissions of PV neurons bidirectionally oscillate in opposite directions during the 24‐h day.
Experience and sleep dominate the daily regulation of the excitatory and inhibitory synapses onto PV neurons, respectively.
ACh mediates the daily regulation of PV inhibitory synaptic transmission via targeting the presynaptic M1Rs.
In line with synaptic modulation of PVs, evoked PV output ex vivo and spontaneous PV activity in vivo are both altered at different times of the day.
Functional oscillation of PVs negatively correlates with the spontaneous activity of surrounding pyramidal neurons and dorsal lateral geniculate nucleus‐evoked responses in area V1 of the mouse visual cortex.
Parvalbumin‐positive neurons of the mouse primary visual cortex are found to be rhythmically regulated in a time‐ and sleep‐dependent manner during the circadian light/dark cycle, mediated by acetylcholine activation of M1 receptors.
The coronavirus disease 2019 (COVID-19) outbreak has seriously endangered the health and lives of Chinese people. In this study, we predicted the COVID-19 epidemic trend and estimated the efficacy of ...several intervention strategies in the mainland of China.
According to the COVID-19 epidemic status, we constructed a compartmental model. Based on reported data from the National Health Commission of People's Republic of China during January 10-February 17, 2020, we estimated the model parameters. We then predicted the epidemic trend and transmission risk of COVID-19. Using a sensitivity analysis method, we estimated the efficacy of several intervention strategies.
The cumulative number of confirmed cases in the mainland of China will be 86 763 (95% CI: 86 067-87 460) on May 2, 2020. Up until March 15, 2020, the case fatality rate increased to 6.42% (95% CI: 6.16-6.68%). On February 23, 2020, the existing confirmed cases reached its peak, with 60 890 cases (95% CI: 60 350-61 431). On January 23, 2020, the effective reproduction number was 2.620 (95% CI: 2.567-2.676) and had dropped below 1.0 since February 5, 2020. Due to governmental intervention, the total number of confirmed cases was reduced by 99.85% on May 2, 2020. Had the isolation been relaxed from February 24, 2020, there might have been a second peak of infection. However, relaxing the isolation after March 16, 2020 greatly reduced the number of existing confirmed cases and deaths. The total number of confirmed cases and deaths would increase by 8.72 and 9.44%, respectively, due to a 1-day delayed diagnosis in non-isolated infected patients. Moreover, if the coverage of close contact tracing was increased to 100%, the cumulative number of confirmed cases would be decreased by 88.26% on May 2, 2020.
The quarantine measures adopted by the Chinese government since January 23, 2020 were necessary and effective. Postponing the relaxation of isolation, early diagnosis, patient isolation, broad close-contact tracing, and strict monitoring of infected persons could effectively control the COVID-19 epidemic. April 1, 2020 would be a reasonable date to lift quarantine in Hubei and Wuhan.
Acute pancreatitis(AP)is one of the most common diseases.AP is associated with significant morbidity and mortality,but it lacks specific and effective therapies.Traditional Chinese medicine(TCM)is ...one of the most popular complementary and alternative medicine modalities worldwide for the treatment of AP.The current evidence from basic research and clinical studies has shown that TCM has good therapeutic effects on AP.This review summarizes the widely used formulas,single herbs and monomers that are used to treat AP and the potential underlying mechanisms of TCM.Because of the abundance,low cost,and safety of TCM as well as its ability to target various aspects of the pathogenesis,TCM provides potential clinical benefits and a new avenue with tremendous potential for the future treatment of AP.
Objective
Collectin 11 (CL‐11) is a soluble C‐type lectin, a mediator of innate immunity. Its role in autoimmune disorders is unknown. We undertook this study to determine the role of CL‐11 in a ...mouse model of rheumatoid arthritis (RA).
Methods
A murine collagen‐induced arthritis (CIA) model was used and combined two approaches, including gene deletion of Colec11 and treatment with recombinant CL‐11 (rCL‐11). Joint inflammation and tissue destruction, circulating levels of inflammatory cytokines, and adaptive immune responses were assessed in mice with CIA. Splenic CD11c+ cells were used to examine the influence of CL‐11 on antigen‐presenting cell (APC) function. Serum CL‐11 levels in RA patients were also examined.
Results
Colec11−/− mice developed more severe arthritis than wild‐type mice, as determined by disease incidence, clinical arthritis scores, and histopathology (P < 0.05). Disease severity was associated with significantly enhanced APC activation, Th1/Th17 responses, pathogenic IgG2a production and joint inflammation, as well as elevated circulating levels of inflammatory cytokines. In vitro analysis of CD11c+ cells revealed that CL‐11 is critical for suppression of APC activation and function. Pharmacologic treatment of mice with rCL‐11 reduced the severity of CIA in mice. Analysis of human blood samples revealed that serum CL‐11 levels were lower in RA patients (n = 51) compared to healthy controls (n = 53). Reduction in serum CL‐11 was inversely associated with the Disease Activity Score in 28 joints, erythrocyte sedimentation rate, and C‐reactive protein level (P < 0.05).
Conclusion
Our findings demonstrate a novel role of CL‐11 in protection against RA, suggesting that the underlying mechanism involves suppression of APC activation and subsequent T cell responses.
•PMN-MDSCs were increased and dominant in H22 orthotopic hepatoma mice.•The spleen contributed to the increase of PMN-MDSCs in H22 orthotopic hepatoma mice.•Splenic PMN-MDSCs could be mobilized to ...the peripheral blood by CCL9 or CCL2 in H22 orthotopic hepatoma mice.
Myeloid-derived suppressor cells (MDSCs) are classified into polymorphonuclear (PMN)-MDSCs and monocytic (M)-MDSCs. The predominant subtype of MDSCs in hepatocellular carcinoma (HCC) is still elusive. The spleen is the largest immune organ in the body and is the origin of many cells. It is still unknown whether the spleen is the origin of MDSCs. In this study, we investigated the expression, origin and mobilization of the predominant MDSC subtype in H22 orthotopic hepatoma mice. Compared with M-MDSCs, PMN-MDSCs were increased and dominant in the spleen, peripheral blood and tumor tissues. Splenectomy could decrease the percentages of PMN-MDSCs in the peripheral blood and tumor tissues, increase the frequencies of NK cells in the peripheral blood and CD3+CD4+T, CD3+CD8+T, NK and NKT cells in the tumor tissues, reduce the tumor weight and the amounts of ascites, and prolong survival time in hepatoma mice. The levels of chemokine (CC motif) ligand 9 (CCL9) and chemokine (CC motif) ligand 2 (CCL2) were elevated in the peripheral blood of tumor-bearing (TB) mice, and their receptors CCR1 and CCR2 were expressed on spleen PMN-MDSCs. Migration assay showed that CCL2 and CCL9 could attract spleen PMN-MDSCs in vitro. These results indicate that PMN-MDSCs were increased and dominant in orthotopic H22 hepatoma mice, the spleen contributed to the increase of PMN-MDSCs, and PMN-MDSCs could be mobilized from the spleen to the peripheral blood by CCL9 and CCL2, thus facilitated tumor growth.
Pancreatitis is an increasingly common and sometimes severe disease that lacks a specific therapy.The pathogenesis of pancreatitis is still not well understood.Calcium(Ca2+)is a versatile carrier of ...signals regulating many aspects of cellular activity and plays a central role in controlling digestive enzyme secretion in pancreatic acinar cells.Ca2+overload is a key early event and is crucial in the pathogenesis of many diseases.In pancreatic acinar cells,pathological Ca2+signaling(stimulated by bile,alcohol metabolites and othercauses)is a key contributor to the initiation of cell injury due to prolonged and global Ca2+elevation that results in trypsin activation,vacuolization and necrosis,all of which are crucial in the development of pancreatitis.Increased release of Ca2+from stores in the intracellular endoplasmic reticulum and/or increased Ca2+entry through the plasma membrane are causes of such cell damage.Failed mitochondrial adenosine triphosphate(ATP)production reduces re-uptake and extrusion of Ca2+by the sarco/endoplasmic reticulum Ca2+-activated ATPase and plasma membrane Ca2+-ATPase pumps,which contribute to Ca2+overload.Current findings have provided further insight into the roles and mechanisms of abnormal pancreatic acinar Ca2+signals in pancreatitis.The lack of available specific treatments is therefore an objective of ongoing research.Research is currently underway to establish the mechanisms and interactions of Ca2+signals in the pathogenesis of pancreatitis.
Both the C3a/C3aR and C5a/C5aR1 axes are regarded as important pathways for inducing and regulating inflammatory responses. It is well documented that the C5a/C5aR1 axis is a potent inflammatory ...mediator in the pathogenesis of many clinic disorders. However, our understanding of the role of the C3a/C3aR axis in renal disorders remains limited. Contrary to the C5a/C5aR axis, we now show that the C3a/C3aR axis has a protective role in uropathogenic Escherichia coli (UPEC)–induced renal injury. C3aR-/- mice were found to develop severe renal pathology compared to wild type mice, a pathology characterized by intense tissue damage and an increased bacterial load within the kidney. This was associated with an overwhelming production of pro-inflammatory mediators and increased neutrophil infiltration in the kidney. Bone marrow chimera experiments found that tissue damage and bacterial load were significantly reduced in C3aR-/- mice that received bone marrow from wild type mice, compared with that in mice re-populated with bone marrow from C3aR-/- mice. This supports a critical role for C3aR on myeloid cells in the pathological process. Pharmacological treatment of mice with a C3aR agonist reduced both the extent of tissue injury and bacterial load. Mechanistic analyses indicated that the C3a/C3aR axis downregulates the lipopolysaccharide-induced pro-inflammatory responses in macrophages and facilitates the phagocytosis of UPEC by phagocytes. Thus, our findings clearly demonstrate a protective role of the C3a/C3aR axis in UPEC-induced renal injury, conferred by the suppression of pro-inflammatory responses and enhanced phagocytosis by macrophages.
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