Interferon-Gamma Induces CD20 Expression on Multiple Myeloma Cells via Induction of Pu.1 and Augments Rituximab Binding to Myeloma Cells

OncologyONCOLOGY Vol 14 No 3
Volume 14
Issue 3

Rituximab (Rituxan) therapy is successfully used to treat many B-cell malignancies. Absent or diminished CD20 expression on certain B-cell tumors may limit the efficacy of CD20-directed serotherapies

Rituximab (Rituxan) therapy is successfully used to treat many B-cell malignancies. Absent or diminished CD20 expression on certain B-cell tumors may limit the efficacy of CD20-directed serotherapies.

We attempted to identify agents that could induce CD20 expression on these B-cell tumors. We first screened RPMI 8226 multiple myeloma cells with agents known to modulate lymphoid-cell surface receptors, and identified interferon-gamma (IFN-gamma [Actimmnue]) as an inducer of CD20 expression.

We subsequently cultured multiple myeloma patient plasma cells (N = 20), multiple myeloma patient B cells (N = 9), chronic lymphocytic leukemia (CLL) patient B cells (N = 5), non-Hodgkin’s lymphoma (NHL) B cells (N = 3), normal donor B cells

(N = 11), normal donor plasma cells (N = 3), and normal donor CD34-positive hematopoietic progenitor cells (N = 5) without and with IFN-gamma (1 to 100 U/mL) for 48 hours, and evaluated changes in CD20 expression with multicolor flow cytometry. Rituximab binding to RPMI 8226 multiple myeloma cells and multiple myeloma patient plasma cells was also determined before and after IFN-gamma treatment.

These studies demonstrated that IFN-gamma induced CD20 expression (increased mean intensity, and percentage of cells expressing CD20) on multiple myeloma plasma cells, multiple myeloma B cells, and normal donor plasma cells. In contrast, CD20 expression on CLL, NHL (CD20low), and normal donor B cells, as well as on normal donor progenitor cells, was unaffected by IFN-gamma.

The levels of IFN-gamma receptor expression alone did not explain the above differences, since a comparable percentage of multiple myeloma (82% ± 6%) and CLL B cells (88% ± 9%) expressed the IFN-gamma receptor. However, IFN-gamma receptor expression was lower on normal donor (26% ± 6%) vs multiple myeloma and CLL B cells (P < .001). Rituximab binding to RPMI 8226 cells and to multiple myeloma patient plasma cells increased following culture with pharmacologically attainable levels of IFN-gamma (1 to 100 U/mL).

Changes in Pu.1 expression, a transactivator of CD20 expression that is downregulated with plasma cell differentiation, were also examined to discern the means by which IFN-gamma induces CD20 on plasma cells. Western blot analysis and im-munofluorescence staining of RPMI 8226 plasma cells treated with IFN-gamma for 0 to 48 hours showed that Pu.1 was induced at 6 hours, and coincided with CD20 upregulation.

CONCLUSION: IFN-gamma induces CD20 on multiple myeloma plasma cells and multiple myeloma B cells and augments rituximab binding to multiple myeloma plasma cells. These findings provide the rationale for use of rituximab with CD20-directed serotherapies for multiple myeloma.

Click here for Dr. Bruce Cheson’s commentary on this abstract.

Articles in this issue

Comparative Economic Analysis of the Treatment of Relapsed Low-Grade B-Cell Non-Hodgkin’s Lymphoma (NHL) in France Using CHOP, Fludarabine, or Rituximab
FHIT Gene, Smoking, and Cervical Cancer
Final Report on the Safety and Efficacy of Retreatment With Rituximab for Patients With Non-Hodgkins Lymphoma
Prospective, Randomized, Controlled Study of Zevalin Radioimmunotherapy Compared to Rituximab Immunotherapy for B-Cell, Non-Hodgkins Lymphoma: Interim Results
IOM Medical Error Estimates Questioned, But Legislation Considered
Less Toxic Therapies for Hodgkin’s Disease May Reduce Secondary Cancers
Preserving Fertility in Young Women With Ovarian Cancer Does Not Decrease Survival
Iodine-131 Tositumomab for Patients With Transformed, Low-Grade Non-Hodgkin’s Lymphoma: Overall Clinical Trial Experience
Survival Rates Significantly Worse For African-Americans With Endometrial Cancer
Rituximab Has Significant Activity in Patients With Chronic Lymphocytic Leukemia
Responders to Rituximab Show Continued Tumor Regression Over Time and a Progression-Free Survival That Correlates With Response Classification
PhRMA Criticizes FDA’s Proposed Rule on Antibiotic Approvals
Phase II Study of Rituximab in Combination With CHOP in Patients With Previously Untreated Intermediate- or High-Grade Non-Hodgkin’s Lymphoma
New Antibiotic Effective in Treating Gram-Positive Bacteremia
Reduced-Dose Zevalin Radioimmunotherapy for Relapsed or Refractory B-Cell Non-Hodgkin&#146;s Lymphoma Patients With Preexisting Thrombocytopenia: Report of Interim Results of a Phase II Trial
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