Hao Xi

A multicenter, open-label phase II study of recombinant CPT (Circularly Permuted TRAIL) plus thalidomide in patients with relapsed and refractory multiple myeloma

Circularly permuted TRAIL (CPT), a recombinant mutant of human Apo2L/TRAIL, is a novel antitumor candidate for multiple myeloma (MM) and other hematologic malignancies. In this phase II study, the safety and efficacy of CPT plus thalidomide was investigated in thalidomide‐resistant MM patients. A total of 43 patients were recruited into three CPT plus thalidomide cohorts based on CPT dosage in sequence: 5 mg/kg (n = 11), 8 mg/kg (n = 17), and 10 mg/kg (n = 15). CPT was administered via intravenous infusion on days 1–5, and thalidomide was given orally at 100 mg once daily in each 21‐day cycle. The overall response rate (ORR) of 41 efficacy‐evaluable patients was 22.0% (2 complete response, 3 near complete response, and 4 partial response). No significant difference in the ORR was observed among the three dose cohorts; however, the ORR tended to be higher with the higher‐dose regimen. Median progression‐free survival and median duration of response were 6.6 months and 6.1 months, respectively. The most common treatment‐related adverse events (TRAEs) were neutropenia (46.5%), leukopenia (41.9%), fever (37.2%), elevated AST (32.6%), and elevated ALT (20.9%). TRAEs of Grade 3–4 were mainly neutropenia (18.6%), anemia (9.3%), elevated AST (7.0%), and leukopenia (4.7%). No significant differences were found in the incidence and severity of TRAEs among the three cohorts. In conclusion, CPT plus thalidomide was well tolerated with no occurrence of dose‐limiting toxicities and demonstrated promising antitumor activity in RRMM patients. CPT at 10 mg/kg for 5 days in combination with thalidomide and dexamethason will be studied in the next clinical trial. Am. J. Hematol. 89:1037–1042, 2014.

Human heat shock protein-specific cytotoxic T lymphocytes display potent antitumour immunity in multiple myeloma

Tumour cell–derived heat shock proteins (HSPs) are used as vaccines for immunotherapy of cancer patients. However, it is proposed that the peptide chaperoned on HSPs, not HSPs themselves, elicited a potent immune response. Given that HSPs are highly expressed by most myeloma cells and vital to myeloma cell survival, we reasoned that HSPs themselves might be an ideal myeloma antigen. In the present study, we explored the feasibility of targeting HSPs themselves for treating multiple myeloma. We identified and chose HLA‐A*0201‐binding peptides from human HSPB1 (HSP27) and HSP90AA1 (HSP90), and confirmed their immunogenicity in HLA‐A*0201 transgenic mice. Dendritic cells pulsed with HSPB1 and HSP90AA1 peptides were used to stimulate peripheral blood mononuclear cells from healthy volunteers and myeloma patients to generate HSP peptide‐specific cytotoxic T lymphocytes (CTLs). HSP peptide‐specific CTLs efficiently lysed HLA‐A*0201+ myeloma cells (established cell lines and primary plasma cells) but not HLA‐A*0201− myeloma cells in vitro, indicating that myeloma cells naturally express HSP peptides in the context of major histocompatibility complex class I molecules. More importantly, HSP peptide‐specific CTLs effectively reduced tumour burden in the xenograft mouse model of myeloma. Our study clearly demonstrated that HSPs might be novel tumour antigens for immunotherapy of myeloma.

Clinicopathological implications of nuclear factor κB signal pathway activation in diffuse large B-cell lymphoma.

Although abnormal activation of the nuclear factor κB (NF-κB) signaling pathway plays an important role in the pathogenesis of diffuse large B-cell lymphoma (DLBCL), only a few studies have dealt with the relation of NF-κB activation to clinical outcomes in this disease. We analyzed the clinical characteristics of 147 consecutive DLBCL patients, examined paraffin-embedded tissues from 120 of them to identify the activation of the NF-κB pathway by using immunohistochemical staining, and performed an overall survival (OS) analysis. Expression of P-p65 and p52 was found in 30.0% (n = 36) and 35.8% (n = 43) of the patients, respectively. Coexpression of these factors was found in 16.7% (n = 14) of the cases. Patients were divided into 4 groups according to P-p65 and/or p52 expression: P-p65(+) only, p52(+) only, both P-p65(+) and p52(+), and both P-p65(-) and p52(-). The 3-year OS rates in the 4 groups were 51.3%, 68.3%, 34.6%, and 85.8%, respectively (P = .006). Univariate analysis showed that early stage (P = .032), low International Prognostic Index score (P = .001), less than 2 extranodal metastases (P = .014), complete remission with chemotherapy (P < .0001), germinal-center B-cell-like subtype (P = .049), Ki-67 < 75% (P = .017), and P-p65(-) (P = .002) or p52(-) (P = .031) were associated with longer 3-year OS. Multivariate analysis indicated that P-p65 expression was an independent prognostic factor for shorter OS (P = .032). In conclusion, NF-κB pathway activation markers P-p65 and p52 predict poor survival in DLBCL patients.

Depression in older patients with advanced colorectal cancer is closely connected with immunosuppressive acidic protein

Colorectal cancer (CRC) is one of the most common tumors. CRC patients are susceptible to suffering from depression. Whether the immune system of CRC patients with depression is impaired or stimulated is controversial. Possible reasons for this conflict are the involvement of confounding factors, such as the age of the patient, the stage of the CRC and the types of treatment in previous studies. To demonstrate clearly the relationship between depression and the immune system in the context of CRC, the present study included only older patients with advanced CRC who received only chemotherapy, and the study adopted immunosuppressive acidic protein (IAP) as an immune parameter for the first time. A total of 56 older patients with advanced CRC completed the Zung Self-Rating Depression Scale (SDS) and were divided into two groups according to SDS scores. The patients exhibiting depression were treated with fluoxetine until their symptoms remitted. The serum levels of IAP and the percentages of CD3-positive (CD3+), CD4+, CD8+ T lymphocytes and CD56+ natural killer (NK) cells and Neutrophil-lymphocyte ratio (NLR) were calculated at the time of enrollment and once the symptoms remitted. Correlation analyses revealed that the SDS score was positively associated with serum IAP levels but negatively associated with CD3 and CD4 levels. Among the depressed and non-depressed patients, serum IAP levels and the percentages of CD3 and CD4 cells were dramatically different. After the depression symptoms were treated, the IAP levels dramatically decreased, while the levels of CD3, CD4, CD8 and CD56 were unchanged. All of above suggested that IAP was closely correlated with depression and might be a relatively objective parameter for predicting depression.

Multiple Myeloma Patients at Various Cytogenetic Risks Benefit Differently from Autologous Stem Cell Transplantation as a Consolidation Therapy

Aim. To evaluate whether patients with multiple myeloma at various risks can still benefit the same from autologous stem cell transplantation consolidation in the era of novel agents. We retrospectively analyzed 67 consecutive myeloma patients receiving autologous stem cell transplantation after bortezomib and/or thalidomide based inductions. Totally 17 high-risk, 24 intermediate-risk, and 26 low-risk patients were enrolled, based on fluorescence in situ hybridization and ISS stage. Meanwhile, another 67 risk-, response depth-, and age-matched patients not proceeding to autologous stem cell transplantation were chosen as controls. Our preliminary data indicated that, in the high-risk subgroup, progression-free survival and overall survival were both significantly prolonged after autologous stem cell transplantation (P < 0.001 and P = 0.015) while, in the intermediate-risk subgroup, neither progression-free survival nor overall survival was prolonged significantly after autologous stem cell transplantation (P > 0.05), and in the low-risk subgroup, only progression-free survival was extended significantly (P = 0.012) after autologous stem cell transplantation. Multiple variables analysis further indicated that autologous stem cell transplantation and risk stratification were two independent prognostic factors for overall survival. Our results indicated that myeloma patients at different risks all benefit from autologous stem cell transplantation consolidation even in the era of novel agents.