Hiroyoshi Ichihara

CD138-negative clonogenic cells are plasma cells but not B cells in some multiple myeloma patients

Clonogenic multiple myeloma (MM) cells reportedly lacked expression of plasma cell marker CD138. It was also shown that CD19+ clonotypic B cells can serve as MM progenitor cells in some patients. However, it is unclear whether CD138-negative clonogenic MM plasma cells are identical to clonotypic CD19+ B cells. We found that in vitro MM colony-forming cells were enriched in CD138−CD19−CD38++ plasma cells, while CD19+ B cells never formed MM colonies in 16 samples examined in this study. We next used the SCID-rab model, which enables engraftment of human MM in vivo. CD138−CD19−CD38++ plasma cells engrafted in this model rapidly propagated MM in 3 out of 9 cases, while no engraftment of CD19+ B cells was detected. In 4 out of 9 cases, CD138+ plasma cells propagated MM, although more slowly than CD138− cells. Finally, we transplanted CD19+ B cells from 13 MM patients into NOD/SCID IL2Rγc−/− mice, but MM did not develop. These results suggest that at least in some MM patients CD138-negative clonogenic cells are plasma cells rather than B cells, and that MM plasma cells including CD138− and CD138+ cells have the potential to propagate MM clones in vivo in the absence of CD19+ B cells.

Immunoglobulin Prophylaxis Against Cytomegalovirus Infection in Patients at High Risk of Infection Following Allogeneic Hematopoietic Cell Transplantation

Reports on the efficacy of intravenous immunoglobulin (IVIG) prophylaxis against cytomegalovirus (CMV) infection after allogeneic hematopoietic cell transplantation (HCT) have often sparked controversy. In addition, we are not aware of any study that has examined whether prophylaxis with IVIG affects the incidence of CMV infection in high-risk patients--those who are elderly or have received human leukocyte antigen (HLA) mismatched HCT. In the present open-label, phase II study, we addressed this question. We enrolled 106 patients in the study. The cumulative incidences of CMV infection at 100 days after HCT were similar in the intervention and the control groups (68% and 64%, P=.89; 89% and 87%, P=.79, respectively, for patients 55 years or older and those who received HLA-mismatched HCT). In those who received HLA-mismatched HCT, 1-year overall survival after HCT was 46% in the intervention group and 40% in the control group (P=.31); for age≥55 years, the corresponding values were 46% and 40% (P=.27). Our data showed that prophylaxis with regular polyvalent IVIG did not affect the incidence of CMV infections or survival among older patients or those who receive HLA-mismatched HCT.

The activated conformation of integrin β7 is a novel multiple myeloma-specific target for CAR T cell therapy

Cancer-specific cell-surface antigens are ideal targets for monoclonal antibody (mAb)-based immunotherapy but are likely to have previously been identified in transcriptome or proteome analyses. Here, we show that the active conformer of an integrin can serve as a specific therapeutic target for multiple myeloma (MM). We screened >10,000 anti-MM mAb clones and identified MMG49 as an MM-specific mAb specifically recognizing a subset of integrin β7 molecules. The MMG49 epitope, in the N-terminal region of the β7 chain, is predicted to be inaccessible in the resting integrin conformer but exposed in the active conformation. Elevated expression and constitutive activation of integrin β7 conferred high MMG49 reactivity on MM cells, whereas MMG49 binding was scarcely detectable in other cell types including normal integrin β7+ lymphocytes. T cells transduced with MMG49-derived chimeric antigen receptor (CAR) exerted anti-MM effects without damaging normal hematopoietic cells. Thus, MMG49 CAR T cell therapy is promising for MM, and a receptor protein with a rare but physiologically relevant conformation can serve as a cancer immunotherapy target.

Wilms Tumor 1 (WT1) mRNA Expression Level at Diagnosis Is a Significant Prognostic Marker in Elderly Patients with Myelodysplastic Syndrome

Background/Aims: A high expression of Wilms tumor 1 (WT1) mRNA occurs in most cases of acute leukemia and myelodysplastic syndrome (MDS). Although there are many reports suggesting that acute myeloid leukemia patients with high expression levels of WT1 mRNA have a relatively poor long-term survival, there are few reports addressing the relationship between WT1 levels and prognosis in MDS. Methods: We retrospectively analyzed 42 elderly patients with MDS whose WT1 levels at diagnosis were available, and we assessed the relationships between WT1 levels in peripheral blood and preexisting prognostic factors such as World Health Organization prognostic scores and Revised International Prognostic Scoring System risk categories, bone marrow blast percentages, and chromosomal abnormalities linked to a poor prognosis. We also evaluated the relationship between WT1 levels and prognosis. Results:WT1 levels were significantly different between high- and low-risk MDS patients (p < 0.05). There was a trend towards a significant difference between those with and those without poor prognostic chromosomal rearrangements (p = 0.051). Moreover, the overall survival and progression-free survival were significantly worse in elderly patients with higher levels of WT1 (p = 0.00039 and p = 0.00077, respectively). Conclusions: The WT1 mRNA expression level at diagnosis may be a significant independent prognostic marker for elderly patients with MDS.

Pulmonary Involvement of Acute Myeloid Leukemia Mimicking Transfusion-related Acute Lung Injury

Transfusion-related acute lung injury (TRALI) is defined as a new episode of acute lung injury (ALI) occurring during transfusion or within 6 hours of transfusion completion. A 66-year-old man suffering from acute myeloid leukemia developed acute respiratory distress syndrome after platelet transfusion. TRALI was diagnosed clinically, but an autopsy showed leukemic cells in diffuse pulmonary edema. Anti-human neutrophil antigen (HNA)-3a antibodies were detected in the donor serum, and the HNA-3 genotype of the patient was identified as a/a. This case was considered to represent pulmonary involvement of acute myeloid leukemia, rather than TRALI. A revision of the definition of TRALI accounting for hematological malignancies should therefore be considered.