Yanchen Li

Toll-Like Receptor 4 Is Required for the Cytotoxicity of Cytokine-Induced Killer Cells

Cytokine-induced killer (CIK) cells are heterogeneous effector T cells with diverse T-cell receptor specificities with non-major histocompatibility complex-restricted cytolytic activities against tumor cells and are considered a promising therapeutic approach against hematologic malignancy. Recently, it has been reported that IL-15-activated CIK cells are superior to cells generated according to the standard protocol; however, the underlying mechanism remains to be elucidated. In the present study, we found that in IL-15-stimulated CIK cells, Toll-like receptor 4 (TLR4) expression was upregulated. Upon knockdown of TLR4, the cytolytic activity was considerably compromised. Re-expression of TLR4 in CIK cells restored their function, confirming the essential role of TLR4 in CIK cell cytotoxicity. Collectively, our study demonstrated that TLR4 was essential for the cytotoxicity of CIK cells against tumor cells, which might provide a novel approach to promote the therapeutic efficacy of CIK cells against hematologic malignancy.

Retrospective analysis of 264 multiple myeloma patients

Multiple myeloma (MM) is the second most common hematological malignancy in China. However, there are only a small number of large cohort studies demonstrating the clinical features of newly diagnosed MM. In the present study, 264 newly diagnosed MM patients from the Beijing Chaoyang Hospital were retrospectively analyzed. The median patient age was 59 years (range, 28–84) and the most common monoclonal protein (42%) was the IgG subtype. Of the 49 patients detected by FISH, 10.2, 2.0 and 12.2% demonstrated del(17p), t(14;16) and t(4;14), respectively. In total, 228 (86%) patients achieved either a complete response (CR), a very good partial response (VGPR) or a partial response (PR). The overall response rate (ORR) in non-autologous stem cell transplantation (non-ASCT) patients was 83.0%, with 48 (18.2%), 7 (2.7%) and 121 (45.8%) patients achieving CR, VGPR and PR, respectively. ASCT patients achieved at least a PR prior to ASCT, and ASCT was not able to increase the ORR (P=0.55). Non-ASCT patients who received bortezomib-based regimens demonstrated an improved ORR compared with those who received regimens that did not contain bortezomib (92.3% vs. 75.8%; P<0.05). With a median follow-up time of 20 months, the estimated median progression-free survival (PFS) and overall survival (OS) times were 27.6 and 61.0 months, respectively. The OS time of patients with high-risk cytogenetic abnormality, del(17p), t(14;16) and t(4;14), was shorter compared with that of other patients (30.2 months vs. not reached, P=0.029). Patients who achieved a CR/VGPR in the ASCT group demonstrated a greater OS time compared with non-ASCT patients (P=0.031). Relapsed patients who received bortezomib-based regimens did not demonstrate a longer survival time post-relapse compared with those who received non-bortezomib-based regimens (26.5 months vs. 10.5 months; P=0.271). The current study presented the clinical characteristics of MM patients who were initially treated at the Beijing Chaoyang Hospital. Bortezomib-based regimens and ASCT were able to improve the OS of MM patients.

Arsenic trioxide potentiates sensitivity of multiple myeloma cells to lenalidomide by upregulating cereblon expression levels

The mechanism of the anti-myeloma effect of the immunomodulatory drug lenalidomide relies upon the binding of lenalidomide or an analogue to cereblon (CRBN) ubiquitin ligase, which inhibits it and results in the degradation of Ikaros-family zinc finger proteins 1 and 3 (IKZF1 and IKZF3). To determine whether the traditional Chinese medicine arsenic trioxide, could potentiate sensitivity of multiple myeloma (MM) cells to lenalidomide and identify the mechanism by which this happens, the present study investigated how arsenic trioxide affected CRBN on MM cell lines and examined the anti-myeloma effect and mechanism in the combination of arsenic trioxide and lenalidomide. The present study revealed that arsenic trioxide upregulates the transcription and protein levels of CRBN, the anti-myeloma target of lenalidomide, thus potentiating the sensitivity of multiple myeloma cells to lenalidomide and enhancing the lenalidomide-dependent degradation of IKZF1 and IKZF3. The results of the present study indicate that clinical trials of this combination therapy could take place within the near future, with the aim of improving MM patient outcome.

Multiple myeloma with extramedullary plasmacytoma invading the skin and eyeballs following autologous stem cell transplantation: A case report

In this study, the case of a 60-year-old female patient who presented with a subcutaneous mass in the lower right limb is described. The mass was confirmed as a plasmacytoma. The patient was diagnosed with multiple myeloma (MM) λ type stage III international stage system (ISS) and received three cycles of a therapeutic PDT regimen (bortezomib, dexamethasone and thalidomide) and complete remission was achieved. Following a further two cycles of the PDT regimen, the patient proceeded to received a high-dose cyclophosphamide regimen combined with granulocyte-colony stimulating factor (G-CSF) for stem cell mobilization. Fourteen months later, the patient received a high-dose therapy supported by autologous stem cell transplantation (auto-SCT). After six months, a subcutaneous mass was identified in the left side of the patient’s neck and the mass gradually increased in size. The patient exhibited exophthalmos and loss of sight one month later. The masses in the neck and right eyelid of the patient were diagnosed as plasmacytomas. These results, combined with the results of bone marrow (BM) aspiration and protein electrophoresis with immunofixation electrophoresis revealed that the disease had relapsed. The patient received two cycles of a therapeutic CPADT regimen (cyclophosphamide, bortezomib, pharmorubicin, dexamethasone and thalidomide). The patient subsequently achieved complete remission again. The patient refused to continue receiving bortezomib and pharmorubicin for therapy and instead received four cycles of the therapeutic CTD regimen (cyclophosphamide, dexamethasone and thalidomide). Subsequently the patient received local radiotherapy for the masses in the eyes and neck. The patient remained stable after treatment following the initial relapse with a progression-free survival (PFS) time of eight months.

Autoantibodies against β1-adrenergic receptor: response to induction therapy with bortezomib-containing regimens for multiple myeloma patients

Abstract This study aims to investigate the predictive value of pre-chemotherapy β1R-AABs by evaluating the response of newly diagnosed symptomatic multiple myeloma (MM) patients to their treatment with a bortezomib-containing regimen. Forty-five de novo MM patients and 50 normal controls (NCs) were prospectively enrolled in this study. Serum titers of β1R-AABs were detected by ELISA. These 45 MM patients were divided into two groups (positive and negative groups) according to their β1R-AABs. Follow-up examinations were performed on these patients during chemotherapy induction. The final analysis covered all 45 MM patients, including 19 patients who were positive for MM and 26 patients who were negative for MM. Multivariate analysis revealed that pre-chemotherapy β1R-AABs are possibly independent predictors for less than very good partial response (VGPR) after the bortezomib-containing regimen treatment (odds ratio: 5.967, 95% confidence interval: 1.513–23.531; p = .011). This study demonstrates for the first time that the presence of β1R-AABs is associated with MM. Pre-chemotherapy β1R-AABs are independent predictors for less than VGPR in de novo MM patients after the bortezomib-containing regimen was administrated. Bortezomib might not significantly give rise to cardiac impairment in MM patients.

A Report of 134 Newly Diagnosed Multiple Myeloma Patients with Renal Impairment

To analyze the effects of bortezomib on the prognosis of the newly diagnosed multiple myeloma patients with renal impairment, we assessed the outcomes of 134 multiple myeloma patients with renal impairment (serum creatinine ≥178 μmol/l) who were treated at Beijing Chaoyang Hospital. The patients were divided into two groups: bortezomib (n = 83) and nonbortezomib (n = 51). The overall response rate of the bortezomib group was higher than that of the nonbortezomib group. There was no significant difference in the time to restore renal function, but the complete renal response ratio was significantly higher in the bortezomib group. The 2-year overall survival (OS) rate of the bortezomib group was significantly greater than the nonbortezomib group, as was the 3-year OS rate. Kaplan-Meier analysis revealed significantly better survival for the bortezomib group. The main side effects in the bortezomib group were thrombocytopenia, peripheral neuropathy, infection, and herpes zoster, and there was a low incidence of grades 3 and 4 adverse events. Our findings indicate that bortezomib-based combination chemotherapy can improve the prognosis of the newly diagnosed multiple myeloma patients with renal impairment and should be considered as a first-line therapy.

Comparable outcome of stem cell transplant versus bortezomib-based consolidation in myeloma patients after major response to induction

Abstract High-dose therapy with autologous stem cell transplant (ASCT) has been established as standard treatment for eligible patients with myeloma. However, whether this approach is still beneficial with new therapy is yet to be determined. Consolidation of effective therapy may be an alternative to ASCT following major response to initial induction. This retrospective case-series analysis included a total of 48 patients with newly diagnosed myeloma. All these patients achieved complete response or very good partial response to bortezomib-based induction and were eligible for ASCT; 24 of these patients proceeded with ASCT, and other 24 patients opted out of ASCT and received two additional cycles of bortezomib therapy as consolidation. With a median follow-up of 28.5 months in ASCT group and 29 months in non-ASCT group, no significant difference was seen in progression-free survival, 39 versus 32 months, P = 0.82. Median overall survival had not been reached, and the estimated 3-year overall survival rates were 87.5 and 67.5% in ASCT and non-ASCT, respectively, P = 0.97. This study provides an initial assessment of survival outcome of ASCT in comparison with non-ASCT consolidation. The additional study is required to establish the efficacy of non-ASCT consolidation.

Immunoparesis in symptomatic multiple myeloma at diagnosis affects PFS with bortezomib-containing induction therapy, but not ASCT consolidation

In novel agent era, the impact of immunoparesis at diagnosis on outcomes in symptomatic multiple myeloma (MM) remains unclear. We reviewed medical records of 147 MM patients at Beijing Chao Yang hospital. Most patients exhibited immunoparesis at diagnosis (84%). After a median follow-up of 27 months (range 1–78 months), in the group with immunoparesis at diagnosis, there was a very significantly shorter progression-free survival (PFS) than in the group without immunoparesis (estimated PFS of not reached vs 25 months, P = 0.001). Patients with suppressed Immunoglobulins (Igs) had the tendency to have a shorter OS than patients without suppression (estimated OS of not reached vs 38 months, P = 0.06). In multivariate analysis, the negative impact of immunoparesis on PFS was confirmed. In addition, achievement of both at least VGPR and at least CR was significantly higher in patients with preserved uninvolved Igs than in those with suppression of at least one uninvolved Ig. However, the negative impact of immunoparesis on response was not confirmed in a multivariate analysis. These results suggest immunoparesis in patients with symptomatic MM at diagnosis is an independent poor prognostic factor for upfront bortezomib-containing regimen.

Recombinant human thrombopoietin improves the efficacy of intermediate-dose cyclophosphamide plus granulocyte colony-stimulating factor in mobilizing peripheral blood stem cells in patients with multiple myeloma: A cohort study

Abstract The combination of intermediate-dose cyclophosphamide (ID-CTX) and granulocyte colony-stimulating factor (G-CSF) fails to mobilize peripheral blood stem cells (PBSCs) in approximately 20% of treated patients with multiple myeloma (MM). In this cohort study, patients with MM underwent PBSC mobilization with either an ID-CTX plus G-CSF plus recombinant human thrombopoietin (rhTPO) regimen (72 patients; TPO group), or an ID-CTX plus G-CSF regimen (70 patients; non-TPO group). In the TPO group, the median CD34+ harvest was 5.36 × 106 per kg of body weight (0.50–22.39 × 106 per kg of body weight), with a harvest success rate of 91.7% (66/72), and an excellence rate of 55.6% (40/72). In the non-TPO group, the median CD34+ harvest was 3.30 × 106 per kg of body weight (0.20–21.14 × 106 per kg of body weight), with a harvest success rate of 75.7% (53/70), and an excellence rate of 25.7% (18/70). The median count of the CD34+ cells collected, success rate of collection, and excellence rate of collection were significantly higher in the TPO group than in the non-TPO group (P=.0001, P=.01, and P = .0001, respectively). Time to granulocyte and platelet engraftment was faster among patients in the TPO group than that in those from the non-TPO group. No platelet engraftment delay (>21 days) was observed among patients in the TPO group, while 3 patients in the non-TPO group displayed delayed platelet engraftment. Adding rhTPO to the ID-CTX chemotherapy plus G-CSF regimen improved treatment efficacy in mobilizing PBSCs for autologous hematopoietic stem cell transplantation.

Differential Protein Expression Profile Between CD20 Positive and Negative Cells of the NCI-H929 Cell Line

At present, multiple myeloma (MM) remains an incurable disease and cologenic cells may be responsible for disease relapse. It has been proposed that CD20+/CD138- NCI-H929 cells could be hallmarks of MM clonogenic cells. Here, the immunology phenotype of NCI-H929 cells is described. Only a small population of CD20+/CD138- cells (<1%) was found in the NCI-H929 cell line, but CD20+/CD138- cells were not detected. We found that CD20+/CD138+ cells were able to exhibit cologenic capacity by colony formation assay and continuous passage culture. Proteins were analyzed by 1D-SDS-PAGE and TMT based quantitative differential liquid chromatography tandem mass spectrometry (LC-MS/MS). 1,082 non-redundant proteins were identified, 658 of which were differentially expressed with at least a 1.5-fold difference. 205 proteins in CD20+ cells were expressed at higher levels and 453 proteins were at lower levels compared with CD20- cells. Most proteins had catalytic and binding activity and mainly participated in metabolic processes, cell communication and molecular transport. These results proved that there are different biological features and protein expression profile between CD20+ and CD20- cells in the NCI-H929 cell line.