Long event-free survival after anti-BCMA CAR-T cell treatment for relapsed and refractory multiple myeloma patients: Two case reports

Introduction:Chimeric antigen receptor T (CAR-T) cells targeting B-cell maturation antigen (BCMA) have been used in the treatment of relapsed and refractory multiple myeloma (RRMM). The response rate and the depth of responses induced by anti-BCMA CAR-T cells are impressive. However, despite this, remissions are not sustained, and the majority of patients eventually relapse.Patient concerns:Two patients with multiple myeloma (MM) were selected to enroll in a phase I study involving anti-BCMA CAR-T cells (ChiCTR-OPC-16009113) because they did not have the good effect after traditional treatment. One is a 48-year-old male patient who received a diagnosis of IgG lambda MM in June 2015, he has received 4 cycles of cyclophosphamide, bortezomib, and dexamethasone (CyBorD) and obtained a complete response (CR). Approximately 11 months later, the disease progressed. Subsequent treatment included regimens incorporating liposomal doxorubicin, bortezomib, and dexamethasone (3 cycles); the response was poor, and the disease kept progressing. Another 65-year-old female patient received a diagnosis of IgG lambda MM in September 2016, she has received induction therapy with 1 cycle of bortezomib and dexamethasone (VD) and 4 cycles of lenalidomide and dexamethasone, the response was poor.Diagnosis:Both patients were diagnosed with RRMM according to the International Myeloma Working Group criteria.Interventions:Both patients received infusions of anti-BCMA CAR-T cells following an induction chemotherapy regimen of cyclophosphamide and fludarabine.Outcomes:Both of them achieved a stringent CR at the 30th day with minimal residual disease-negative bone marrow by flow cytometry and serum monoclonal protein was undetectable at 4 and 10 months after cell transfusion. The CR has persisted in the 2 patients for >36 months.Conclusions:Our findings demonstrate the anti-BCMA CAR-T cell treatment is a feasible therapeutic option for patients with RRMM. Fewer early lines of treatment may be beneficial to maintain the efficacy of CAR-T cells.Trial registration:ChiCTR-OPC-16009113.     

南京地区2型糖尿病患者解偶联蛋白2基因-866G/A多态性与胰岛功能相关性研究

目的研究南京地区汉族人群2型糖尿病解偶联蛋白2(UCP2)基因启动子区-866G/A多态性与胰岛功能的相关性。方法对2006年1～9月在南京大学医学院附属鼓楼医院收集的229例2型糖尿病患者以及196例正常对照者UCP2基因-866G/A位点进行基因分型,并行口服葡萄糖耐量加同步胰岛素释放试验检测胰岛B细胞分泌功能及胰岛素敏感性。结果UCP2基因-866G/A位点的基因型频率和等位基因频率在2型糖尿病与对照组中分布差异有显著性意义(分别为χ2=6.555,P=0.038;χ2=6.363,P=0.012),2型糖尿病组中A/A基因型和A等位基因频率显著高于正常对照(分别为OR=1.99,OR=1.42,均P<0.05);2型糖尿病组中G/A、A/A基因型携带者的早期相胰岛素分泌均低于G/G基因型携带者[1.55(0.77,2.40)对2.46(1.44,4.70),1.23(0.43,2.71)对2.46(1.44,4.70),均P<0.01]。结论UCP2基因启动子区-866G/A多态性与南京地区汉族人群2型糖尿病及胰岛功能存在相关性,UCP2基因可能是2型糖尿病的易患基因之一。     

Recombinant interferon gamma in hairy cell leukemia, multiple myeloma, and Waldenstrom's macroglobulinemia

Fifteen patients with multiple myeloma, five with hairy cell leukemia, and five with Waldenstrom's macroglobulinemia were treated with recombinant interferon gamma (rINF-gamma) to determine the antitumor activity of this agent. The rIFN-gamma was administered by daily intramuscular injection at doses ranging from 0.125 to 0.5 mg/m2. No responses were observed in patients with multiple myeloma, although in one patient the disease has remained stable for over 16 months. Minimal improvement in some hematologic indexes were observed in three of five patients with hairy cell leukemia. One partial remission and one minor response were documented in two of the five patients with Waldenstrom's macroglobulinemia. In five patients, an increase in normal serum immunoglobulins was observed. These results suggest that there is only minimal activity of rIFN-gamma as a single agent in neoplasms of B-cell origin.     

Prognostic significance of tumour-infiltrating T lymphocytes and T-cell subsets in de novo diffuse large B-cell lymphoma: a multiparameter flow cytometry study

Tumour-infiltrating T lymphocytes (TIL-T) have been implicated in playing a role in controlling tumour growth. We evaluated TIL-T in 55 cases of de novo diffuse large B-cell lymphoma (DLBCL) using three- or four-colour flow cytometric immunophenotyping (FCI). The percentage of TIL-T varied from 3% to 72% of total viable cellular events (mean 32 +/- 20%). The CD4:CD8 ratio varied from 0.17 to 13 (mean 2.3 +/- 2.2). Cases with >/= 20% T cells and those with CD4:CD8 ratios > or = 2.0 showed a significantly better overall survival (P = 0.017 and P = 0.034 respectively). These findings were independent of clinical stage at diagnosis. The T-cell percentage and CD4:CD8 ratio were moderately correlated (Spearman correlation coefficient = 0.47, P = 0.001) and multivariate analysis revealed that the association of the two factors with prognosis was mutually dependent. The T cells in 23 cases were studied for CD45RO. The mean percentage of total T cells expressing CD45RO was 86 +/- 10%. There was a trend towards better survival for those patients with a higher percentage of CD45RO+ T cells (P = 0.06). These results suggest that TIL-T, particularly CD4+ T cells, may play a role in the control of DLBCL, and measurement of T-cell percentage and T-cell subsets using FCI may be useful in predicting the clinical behaviour of DLBCL.     

Tumoral non-amyloidotic monoclonal immunoglobulin light chain deposits ('aggregoma'): presenting feature of B-cell dyscrasia in three cases with immunohistochemical and biochemical analyses

Tumoral monoclonal immunoglobulin (Ig) light chain non-fibrillar deposits ('aggregomas'), which can be considered analogous to solitary light chain amyloidomas, are a rare presenting feature of B-cell dyscrasias. It is not certain if they are truly localized or if in reality they represent an initial expression of a silent systemic non-amyloid light chain deposition disease (LCDD). This report describes three patients, two of whom presented with cervical masses and the third with a solitary lung nodule, each comprising granular aggregates of monoclonal kappa light chain. Extracted deposits from the lymph node of one patient were shown by N-terminal amino acid sequence analysis to belong to the variable-region kappa I (Vkappa I) light chain subgroup, the first reported kappa-LCDD protein encoded by the L9 gene and the first report of an expressed protein related to this gene. Extracted deposits from the lung nodule of the second patient belonged to the Vkappa IV light chain subgroup encoded by the B3 germ line gene. The N-terminal amino acid sequences of the light chains from the aggregomas were compared with the related germ line sequences and to the N-terminal amino acid sequences of the nine other known kappa-LCDD light chains reported thus far from patients with systemic LCDD.     

Pancreatic B-cell function in relation to diabetic retinopathy in Asian Indian NIDDM patients

Summary Pancreatic B-cell function in relation to diabetic retinopathy was studied in 195 NIDDM patients with long-standing diabetes. Background diabetic retinopathy (BDR) was present in 95 (48.7%) and proliferative retinopathy (PDR) in 17 (8.7%) of the subjects. There was no significant difference between the BDR, PDR, and non-retinopathy groups with respect to age, age at diagnosis of diabetes and HbA₁ values. Mean duration of diabetes was higher in the PDR group (p<0.05). Serum C-peptide values showed no correlation with the presence of retinopathy or with the duration of diabetes. The C-peptide values were widely scattered in patients with BDR and PDR showing no association between pancreatic B-cell reserve and occurrence or severity of retinopathy in NIDDM patients. Thus, decreased pancreatic B-cell reserve does not appear to be a risk factor for diabetic retinopathy in NIDDM patients.     

Anaplastic large-cell lymphomas of B-cell phenotype are anaplastic lymphoma kinase (ALK) negative and belong to the spectrum of diffuse large B-cell lymphomas

There is controversy in the literature as to whether anaplastic large-cell lymphoma of B-cell phenotype is related to the t(2;5)-positive T- or 'null' cell lymphoma of the same morphology. We report a study of 24 lymphomas with morphological features of anaplastic large-cell lymphoma which expressed one or more B-cell markers and lacked T-lineage markers. Clinical features were more in keeping with large B-cell lymphoma than with classical t(2;5)-positive anaplastic large-cell lymphoma, and immunostaining for anaplastic lymphoma kinase (ALK) protein provided no evidence for the (2;5) translocation (or one of its variants). The staining patterns for CD20 and CD79 were typical of diffuse large B-cell lymphoma, CD30 expression was variable, and most cases (15/22) lacked epithelial membrane antigen (EMA). These findings support the view that 'B-cell anaplastic large-cell lymphoma' is unrelated to t(2;5)-positive (ALK-positive) lymphoma, and that it represents a morphological pattern occasionally encountered among diffuse large B-cell lymphomas. By the same reasoning, most tumours diagnosed as 'ALK-negative anaplastic large-cell lymphoma of T-cell or null phenotype' probably belong to the spectrum of peripheral T-cell lymphomas.     

Modulation of anti-idiotypic immune response by immunization with the autologous M-component protein in multiple myeloma patients

Multiple myeloma is characterized by a proliferation of clonal B lymphocytes and plasma cells. The idiotypic structure of clonal immunoglobulin (Ig) expressed on the tumour B-cell surface can be regarded as a tumour-specific antigen and, as such, a potential target for anti-idiotypic T and B cells in an immune regulation of the tumour-cell clone. Active immunization using the autologous monoclonal Ig as a 'vaccine' was shown to induce tumour-specific immunity in murine B-cell tumours and in human B-cell lymphoma. With the aim to induce or amplify an anti-idiotypic response in multiple myeloma, five stage I–III patients were repeatedly immunized with the autologous monoclonal IgG. Induction of idiotype-specific cellular immunity was analysed in vitro by an enzyme-linked immunospot assay (interferon-γ and interleukin-4 secreting cells). B cells secreting anti-idiotypic IgM antibodies were also analysed. An anti-idiotypic T-cell response was amplified 1.9–5-fold in three of the five patients during immunization. The number of B cells secreting anti-idiotypic antibodies also increased in these three patients. In two of the patients induction of idiotype-specific immunity was associated with a gradual decrease of blood CD19⁺ B cells. The induced T-cell response was eliminated during repeated immunization. Further studies are warranted to optimize the immunization schedule in order to achieve a long-lasting T-cell immunity against idiotypic determinants on the tumour clone. A role for immunity in controlling the tumour clone remains to be established.     

Identification and characterization of human B-cell epitopes in recombinant antigens of Leishmania aethiopica

Recombinant DNA fragments from Leishmania aethiopica that code for epitopes which react with human antibodies have been characterized by cross-hybridization studies and DNA sequence analysis. Twenty clones could be grouped into seven different groups (I–VII), probably representing seven different L. aethiopica antigens. The DNA sequences of representative clones from the seven groups have been obtained and the amino acid sequence of the respective recombinant antigens established. The recombinant antigens have been analysed by epitope scanning with patient sera, and octapeptides that contain potential B-cell epitopes have been identified in all seven recombinant antigens. These octapeptides have further been tested with additional patient sera and control sera, and three octapeptides (HAFCHEEG, YHSSVVHD and SYAPCSLK) were found to contain major epitopes recognizing specific antibodies in nine, seven and four, respectively, of the twenty sera tested. Fifteen of the twenty sera reacted with one or more of these three octapeptides.