Immunotherapeutic strategies targeting B cell maturation antigen in multiple myeloma

Multiple myeloma(MM) is the second most common hematologic malignancy, and is characterized by the clonal expansion of malignant plasma cells. Despite the recent improvement in patient outcome due to the use of novel therapeutic agents and stem cell transplantation, all patients eventually relapse due to clone evolution. B cell maturation antigen(BCMA) is highly expressed in and specific for MM cells, and has been implicated in the pathogenesis as well as treatment development for MM. In this review, we will summarize representative anti-BCMA immune therapeutic strategies, including BCMA-targeted vaccines, anti-BCMA antibodies and BCMA-targeted CAR cells. Combination of different immunotherapeutic strategies of targeting BCMA, multi-target immune therapeutic strategies, and adding immune modulatory agents to normalize anti-MM immune system in minimal residual disease(MRD) negative patients, will also be discussed.

Probiotic metabolites from Bacillus coagulans GanedenBC30^(TM) support maturation of antigen-presenting cells in vitro

AIM:To study the effects of probiotic metabolites on maturation stage of antigen-presenting immune cells.METHODS:Ganeden Bacillus coagulans 30(GBC30) bacterial cultures in log phase were used to isolate the secreted metabolite(MET) fraction.A second fraction was made to generate a crude cell-wall-enriched fraction,by centrifugation and lysis,followed by washing.A preparation of MET was subjected to size exclusion centrifugation,generating three fractions:< 3 kDa,3-30 kDa,and 30-200 kDa and activities were tested in comparison to crude MET and cell wall in primary cultures of human peripheral blood mononuclear cell(PBMC) as a source of antigen-presenting mononuclear phagocytes.The maturation status of mononuclear phagocytes was evaluated by staining with monoclonal antibodies towards CD14,CD16,CD80 and CD86 and analyzed by flow cytometry.RESULTS:Treatment of PBMC with MET supported maturation of mononuclear phagocytes toward both macrophage and dendritic cell phenotypes.The biological activity unique to the metabolites included a reduction of CD14+ CD16+ pro-inflammatory cells,and this property was associated with the high molecular weight metabolite fraction.Changes were also seen for the dendritic cell maturation markers CD80 and CD86.On CD14dim cells,an increase in both CD80 and CD86 expression was seen,in contrast to a selective increase in CD86 expression on CD14bright cells.The co-expression of CD80 and CD86 indicates effective antigen presentation to T cells and support of T helper cell differentiation.The selective expression of CD86 in the absence of CD80 points to a role in generating T regulatory cells.CONCLUSION:The data show that a primary mechanism of action of GBC30 metabolites involves support of more mature phenotypes of antigen-presenting cells,important for immunological decision-making.

A key role for PTP1B in dendritic cell maturation, migration, and T cell activation

Dendritic cells(DC)are the major antigen-presenting cells bridging innate and adaptive immunity,a function they perform by converting quiescent DC to active,mature DC with the capacity to activate naı¨ve T cells.They do this by migrating from the tissues to the T cell area of the secondary lymphoid tissues.Here,wedemonstrate thatmyeloid cell-specific genetic deletion of PTP1B(LysM PTP1B)leads to defects in lipopolysaccharide-driven bone marrow-derivedDC(BMDC)activation associated with increased levels of phosphorylated Stat3.We showthatmyeloid cell-specific PTP1Bdeletion also causes decreased migratory capacity of epidermal DC,aswell as reduced CCR7 expression and chemotaxis to CCL19 by BMDC.PTP1B deficiency in BMDC also impairs their migration in vivo.Further,immature LysM PTP1B BMDC display fewer podosomes,increased levels of phosphorylated Src at tyrosine 527,and loss of Src localization to podosome puncta.In co-culture with T cells,LysM PTP1B BMDC establish fewer and shorter contacts than control BMDC.Finally,LysMPTP1BBMDCfail to present antigen to T cells as efficiently as controlBMDC.These data provide first evidence for a key regulatory role for PTP1B in mediating a central DC function of initiating adaptive immune responses in response to innate immune cell activation.

Anti-BCMA CAR-T Cell Therapy in Relapsed or Refractory Multiple Myeloma Patients with Impaired Renal Function

Anti-B cell maturation antigen(BCMA)chimeric antigen receptor(CAR)T-cell therapyis effective and well-tolerated for refractory or relapsed multiple myeloma(RRMM).The purposcof the present study was to analyze efficacy in RRMM patients with renal impairment treated byanti-BCMA CAR-T cell therapy.A total of 59 RRMM patients were selected,and divided intoimpaired renal function(lRF)group[basclinc cstimated giomerular filtration rate(eSFR)<90 m/min/1.73 m^2(n=18)]and normal renal function(NRF)group(baseline eGFR≥90 mL/min/1.73 m,n=41).For patients with IRF,eGFR at the 6th month post-CAR-T cells infusion was significantlyhigher than the baseline(P<0.05).The multivariate analysis showed that light chain type and beta-2 micro-globulin(bcta-2M)were associated factors with the decrease of serum creatinine.Medianprogression-free survival(PFS)in the NRF group and IRF group was 266 days and 181 daysrespectively.Overall survival(OS)in the NRF group and lRF group was 877 days and 238 daysrespectively.There was no significant difference in the objective response rate(ORR)between thelRF group and the NRF group.It is suggested that CAR-T cells therapy could improve the renalfunction during the treatment of RRMM.The renal function could be more significantly improvedin RRMM patients with light chain type than with other types.

Luspatercept enhances hemoglobin levels in a Chinese boy with congenital sideroblastic anemia:A case report

BACKGROUND Congenital sideroblastic anemia(CSA)is a rare and heterogeneous group of genetic disorders.Conventional treatment include pyridoxine(vitamin B6)and allogeneic hematopoietic stem cell transplantation(allo-HSCT),and can alleviate anemia in the majority of cases.Nevertheless,some CSA cases remain unresponsive to pyridoxine or are unable to undergo allo-HSCT.Novel management approaches is necessary to be developed.To explore the response of luspatercept in treating congenital sideroblastic anemia.CASE SUMMARY We share our experience in luspatercept in a 4-year-old male patient with CSA.Luspatercept was administered subcutaneously at doses of 1.0 mg/kg/dose to 1.25 mg/kg/dose every 3 wk,three consecutive doses,evaluating the hematological response.Luspatercept leading to a significant improvement in the patient's anemia.The median hemoglobin during the overall treatment with three doses of luspatercept was 90(75-101)g/L,the median absolute reticulocyte count was 0.0593(0.0277-0.1030)×10^(12)/L,the median serum ferritin was 304.3(234.4-399)ng/mL,and the median lifespan of mature red blood cells was 80(57-92)days.Notably,no adverse reactions,such as headaches,dizziness,vomiting,joint pain,or back pain,were observed during the treatment period.CONCLUSION We believe that luspatercept might emerge as a viable therapeutic option for the maintenance treatment of CSA or as a bridging treatment option before hematopoietic stem cell transplantation.

Host and viral factors contributing to CD8+ T cell failure in hepatitis C virus infection

Virus-specific CD8+ T cells are thought to be the major anti-viral effector cells in hepatitis C virus (HCV) infection. Indeed, viral clearance is associated with vigorous CD8+ T cell responses targeting multiple epitopes. In the chronic phase of infection, HCV-specific CD8+ T cell responses are usually weak, narrowly focused and display often functional defects regarding cytotoxicity, cytokine production, and proliferative capacity. In the last few years, different mechanisms which might contribute to the failure of HCV-specific CD8+ T cells in chronic infection have been identified, including insufficient CD4+ help, deficient CD8+ T cell differentiation, viral escape mutations, suppression by viral factors, inhibitory cytokines, inhibitory ligands, and regulatory T cells. In addition, host genetic factors such as the host’s human leukocyte antigen (HLA) background may play an important role in the efficiency of the HCV- specific CD8+ T cell response and thus outcome of infection. The growing understanding of the mechanisms contributing to T cell failure and persistence of HCV infection will contribute to the development of successful immunotherapeutical and -prophylactical strategies.

In vitro Induction of primary antibody responses to particulate and soluble protein antigens in T cell-replaced murine spleen cell cultures

Specific antibody responses could be induced in serumfree condition.Specific anti-SRBC or anti-SRBC ghost antibody were induced from anti-Thy treated (T-depleted) murine spleen cells in serum-free culture in the presence of Con A conditioned medium.This induction system may facilitate the study of lymphokine functions on antigen triggered B cells. In T cell-replaced cultures,the antibody responses of B cells could be successfully induced when soluble SRBC membrane proteins were used as antigens.It thus indicates that antigen together with lymphokines are sufficient to drive B cells to become antibody secreting cells in the absence of T cells.The T cell-replaced system provides a more stable way for in vitro immunization and may be applied to monoclonal antibody production when in vivo immunization is difficult to be carried out.

Ikaros in B cell development and function

The zinc finger transcription factor, Ikaros, is a central regulator of hematopoiesis. It is required for the development of the earliest B cell progenitors and at later stages for VDJ recombination and B cell receptors expression. Mature B cells rely on Ikaros to set the activation threshold for various stimuli, and to choose the correct antibody isotype during class switch recombination. Thus, Ikaros contributes to nearly every level of B cell differentiation and function.

Male fertility following childhood cancer: current conceptsand future therapies

<abstract>Prepubertal boys treated for cancer may exhibit impaired fertility in later life. A number of chemotherapeu tic agents have been identified as being gonadotoxic, and certain treatment regimens, such as that used for Hodgkin's disease, are particularly associated with subsequent infertility. Radiotherapy may also cause gonadal damage, most notably following direct testicular irradiation or total body irradiation. Because of the varied nature of the cytotoxic insult, it can be difficult to predict the likelihood of infertility in later life. Currently it is not possible to detect gonadal damage early due to the lack of a sensitive marker of gonadal function in the prepubertal age group.Semen cryopreservation is currently the only method of preserving fertility in patients receiving gonadotoxic therapy. This is only applicable to postpubertal patients and can be problematic in the adolescent age group. At present there is no provision for the prepubertal boy, although there are a number of experimental methods currently being investigated. By harvesting testicular tissue prior to gonadotoxic therapy, restoration of fertility could be achieved following treatment, either by germ cell transplantation or by in vitro maturation of the germ cells harvested. Alternatively, rendering the testes quiescent during cytotoxic treatment may protect the germ cells from subsequent damage. In addition to the many scientific and technical issues to be overcome prior to clinical application of these techniques, a number of ethical and legal issues must also be addressed to ensure a safe and realistic prospect for future fertility in these patients.

Surveilling Russell body Helicobacter pylori-negative gastritis: A case report and review of literature

BACKGROUND Russell body gastritis(RBG)is very rare type of chronic inflammation of gastric mucosa.The pathologic hallmark of the disease is Russell bodies(RB)which represent accumulation of eosinophilic cytoplasmic inclusions in endoplasmic reticulum of mature plasma cells(Mott cells).Most published cases are associated with Helicobacter pylori(H.pylori)infection because of correlation between plasma cell activation and antigenic stimulation.There are insufficient data about H.pylori-negative RBG and very little is known about the natural course of the disease.CASE SUMMARY A 51-year-old male patient underwent endoscopic screening for mild iron deficiency anemia.Gastroscopy revealed diffuse hyperemia,edema and nodularity of the fundic and corpus mucosa.Due to non-specific endoscopic findings and iron-deficiency anemia our preliminary diagnosis was diffuse type of gastric carcinoma or gastric lymphoma.Biopsy specimens of gastric mucosa showed inflammatory infiltrate rich in Mott cells,consisting entirely of cytoplasmic RB.Absence of nuclear atypia and mitosis of the plasma cells,polyclonal pattern of the Mott cells and negative staining for cytokeratins favored diagnosis of RBG.The patient was treated with proton-pump inhibitor for 8 wk.Long-term clinical and endoscopic surveillance was scheduled.Albeit,there was no improvement in endoscopic features of the gastric mucosa in three consecutive gastroscopies,histopathological findings demonstrated that the chronic inflammatory infiltrate in the fundic mucosa is less pronounced,rich in plasma cells,with almost absent RB and Mott cells.CONCLUSION The prognosis of this entity is uncertain,that is why these patients are subjects of continuous follow up.

A rare case of intraoral lipoma in a six year-old child:a case report

One type of soft tissue lesions of the oral cavity is lipoma, which is a kind of benign tumor composed of mature lipid cells. Although the lipoma presents as one of the most common mesenchymal neoplasms, most tend to develop on the trunk and proximal portions of the extremities. However, lipomas in the oral and maxillofacial region are much less frequent. Here we present a case of an intraoral lipoma in a six year-old child.

A potential role of karyopherin a2 in the impaired maturation of dendritic cells observed in glioblastoma patients

Aim:Patients with glioblastomas demonstrate well‑documented immunological impairments including decreased numbers of mature dendritic cells(DCs).Recent data identified karyopherin a2(KPNA2),a nucleocytoplasmic shuttling receptor,as diagnostic and prognostic biomarker for gliomas.The aim of this ongoing study is to correlate parameters of immunity and nucleocytoplasmic transport in glioblastoma patients.Methods:We preoperatively collected serum from 17 patients with glioblastomas and determined DC subsets(HLA DR+Lin-,CD34-,CD45+,CD123+,CD11+were analyzed)using a 6‑color flow cytometry panel.Expression levels of KPNA2 and nuclear accumulation of p53 were evaluated semi‑quantitatively by immunohistochemistry.O6‑methylguanine DNA methyltransferase(MGMT)and isocitrate dehydrogenase‑1(IDH‑1)status were assessed by pyrosequencing and immunohistochemistry,respectively.Results:Median expression levels for both KPNA2 and p53 were 5-10%.IDH‑1‑R132H mutation and MGMT promoter hypermethylation was detected in 3/16 and 1/9 patients,respectively.Mean counts of total mature DCs,myeloid DCs and plasmacytoid DCs were 9.6,2.1,3.4 cells/μL.A preliminary analysis suggests an association between low KPNA2 nuclear expression and increased numbers of mature DCs.However,this correlation did not reach statistical significance so far(P=0.077).Conclusion:Our preliminary data may indicate a role of KPNA2 in the impaired maturation of DCs observed in glioblastoma patients.

Lactosylated N-Alkyl polyethylenimine coated iron oxide nanoparticles induced autophagy in mouse dendritic cells

Dendritic cell(DC)-based vaccines have shown promising therapeutic results in cancer and some immune disorders.It is critical to track in vivo migration behaviours of DCs and monitor the whole process dynamically and non-invasively.Superparamagnetic iron oxide(SPIO)nanoparticles are chosen for DC labelling under magnetic resonance imaging(MRI)because of their proven biosafety as contrast agents.However,when used for cell labelling,sensitive biological indicators such as cell autophagy may be helpful to better understand the process and improve the probe design.Here,lactosylated N-Alkyl polyethylenimine coated SPIO nanoparticles are used for DC labelling.This probe shows satisfactory cell labelling efficiency and low cytotoxicity.In this study,autophagy was used as a key factor to understand how DCs react to nanoparticles after labelling.Our results demonstrate that the nanoparticles can induce protective autophagy in DCs,as inhibition of the autophagy flux could lead to cell death.Meanwhile,the nanoparticles induced autophagy could promote DC maturation which is an essential process for its migration and antigen presentation.Autophagy induced DC maturation is known to enhance the vaccine functions of DCs,therefore,our results suggest that beyond the MRI tracking ability,this probe might enhance therapeutic immune activation as well.

Nanomedicine-mediated ubiquitination inhibition boosts antitumor immune response via activation of dendritic cells

Tumor immunotherapy as a promising method for tumor treatment received tremendous attention. However, the problem of low clinical response rate still needs to be solved, especially in the poorly immunogenic tumors. The enhancement of tumor antigens presentation can effectively activate dendritic cells (DCs) and improve the tumor immunotherapy. In this work, TAK-243 as an inhibitor of the ubiquitin activating enzyme (UAE), was fabricated into cationic lipid-assisted nanoparticle (CLANTAK-243). The obtained CLANTAK-243 could act as an effective tumor immunotherapy enhancer to promote the maturation of DCs as well as antigen presentation, which obviously stimulated the T cells activation and proliferation. Such CLANTAK-243 injected intravenously could well trigger immune response to tumor cells in vivo. Importantly, mice treated with CLANTAK-243 could obtain a long immune memory effect to protect themselves from re-challenged tumor cells. Therefore, this work presented an effective immunotherapy strategy for poorly immunogenic tumor.

A rationally designed cancer vaccine based on NIR-II fluorescence image-guided light-triggered remote control of antigen cross-presentation and autophagy

Cancer vaccines represent a promising immunotherapeutic treatment modality.The promotion of cross-presentation of extracellular tumor-associated antigens on the major histocompatibility complex(MHC) class I molecules and dendritic cell maturation at the appropriate time and place is crucial for cancer vaccines to prime cytolytic T cell response with reduced side effects.Current vaccination strategies,however,are not able to achieve the spatiotemporal control of antigen cross-presentation.Here,we report a liposomal vaccine loading the second near-infrared window(NIR-II,1000—1700 nm) fluorophore BPBBT with an efficient photothermal conversion effect that offers an NIR-light-triggered endolysosomal escape under the imaging guidance.The NIR-II image-guided vaccination strategy specifically controls the cytosolic delivery of antigens for cross-presentation in the draining lymph nodes(DLNs).Moreover,the photothermally induced endolysosomal rupture initiates autophagy.We also find that the adjuvant simvastatin acts as an autophagy activator through inhibiting the PI3K/AKT/m TOR pathway.The light-induced autophagy in the DLNs together with simvastatin treatment cooperatively increase MHC class II expression by activating autophagy machinery for dendritic cell maturation.This study presents a paradigm of NIR-II image-guided light-triggered vaccination.The approach for remote control of antigen cross-presentation and autophagy represents a new strategy for vaccine development.