Chimeric Anti-CD20 (C2B8)-Mediated Sensitization of B-Cell Lymphoma to Cytotoxic Agents: Role of C2B8 in Regulating Endogenous IL-10 and Oncogenes

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OncologyONCOLOGY Vol 13 No 3
Volume 13
Issue 3

Our studies have shown that unconjugated antibody therapy targeted to the B-cell marker CD20 by the anti-CD20 antibody, C2B8, inhibits the growth of B-cell lymphomas in vitro. We have also demonstrated that B-lymphoma tumor cells can be sensitized to subtoxic doses of therapeutic drugs by the same antibody.

Our studies have shown that unconjugated antibody therapy targeted to the B-cell marker CD20 by the anti-CD20 antibody, C2B8, inhibits the growth of B-cell lymphomas in vitro. We have also demonstrated that B-lymphoma tumor cells can be sensitized to subtoxic doses of therapeutic drugs by the same antibody.

The objective of these studies is to delineate the mechanism by which C2B8 alters B lymphoma cells, leading to inhibition of tumor cell growth and sensitization to chemotherapeutic drugs. This study was designed to examine: (1) whether C2B8 sensitizes the drug- and toxin-resistant 2F7 cell line to tumor necrosis factor-alpha (TNF-alpha), cisplatin (Platinol), fludarabine (Fludara), doxorubicin (Adriamycin and others), and diphtheria toxin (DTX); (2) whether C2B8 regulates interleukin-10 (IL-10) secretion; (3) whether IL-10 is a resistance factor in 2F7; and (4) whether C2B8 sensitization regulates oncogenes and/or tumor-suppressor genes.

We demonstrate that C2B8 sensitizes 2F7 to doxorubicin, fludarabine, TNF-alpha, and DTX-mediated cytotoxicity in a synergistic manner. Furthermore, C2B8-targeted 2F7 downregulates IL-10 expression and secretion after 24 and 72 hours of treatment.

Interleukin-10 has been shown to function as a resistance factor and protects the tumor cells from the cytotoxic effects of therapeutic drugs. We postulate that one method by which CD20 activation reverses drug resistance involves IL-10 autocrine loops, which modulate regulatory apoptotic proteins within the cell. This postulate is verified by demonstrating that the addition of exogenous IL-10 to C2B8-treated 2F7 caused a recovery of the cells, decreasing the ability of C2B8 to sensitize.

We have also shown that C2B8 treatment downregulates the expression of bcl-2 after only 4 hours. Involvement of bcl-2 could explain resistance involved (and reversed) in an array of cytotoxic drugs. Furthermore, C2B8 induces the upregulation of BTG-1 in 2F7 cells. BTG-1 is a member of a family of proteins that induce cell cycle arrest.

CONCLUSION: The present findings demonstrate that the C2B8 antibody exerts many activities on B-cell lymphoma, namely: (1) inhibition of cell growth; (2) downregulation of the secretion of the protective factor IL-10; (3) downregulation of the antiapoptotic Bcl-2 protein; and (4) sensitization of lymphoma to several cytotoxic drugs through IL-10 and Bcl-2 modulation.

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

Articles in this issue

WHO Declares Lymphatic Mapping to Be the Standard of Care for Melanoma
Rituximab: Phase II Retreatment Study in Patients With Low-Grade or Follicular Non-Hodgkin’s Lymphoma
Response Criteria for NHL: Importance of “Normal” Lymph Node Size and Correlations With Response
Chemotherapy Plus Radiation Improves Survival in Patients With Cervical Cancer
A Randomized Trial of Fludarabine, Mitoxantrone (FM) Versus Doxorubicin, Cyclophosphamide, Vindesine, Prednisone (CHEP) as First Line Treatment in Patients With Advanced Low-Grade Non-Hodgkin's Lymphoma: A Multicenter Study by GOELAMS Group
Navelbine Increased Elderly Lung Cancer Patients’ Survival
Fludarabine Versus Conventional CVP Chemotherapy in Newly C Diagnosed Patients With Stages III and IV Low-Grade Malignant Non-Hodgkin’s Lymphoma: Preliminary Results From a Prospective, Randomized Phase III Clinical Trial in 381 Patients
Multicenter, Phase III Study of Iodine-131 Tositumomab (Anti-B1 Antibody) for Chemotherapy-Refractory Low-Grade or Transformed Low-Grade Non-Hodgkin’s Lymphoma
T-Cell–Depleted Allogeneic Bone Marrow Transplant From HLA-Matched Sibling Donors for Non-Hodgkin’s Lymphoma
Consensus Statement on Prevention and Early Diagnosis of Lung Cancer
In Vivo Purging and Adjuvant Immunotherapy With Rituximab During PBSC Transplant For NHL
Fludarabine and Cyclophosphamide: A Highly Active and Well-Tolerated Regimen for Patients With Previously Untreated Indolent Lymphomas
Campath-1H Monoclonal Antibody in Therapy for Advanced Low-Grade Non-Hodgkin’s Lymphomas: A Phase II Study
AIDS Drugs Effective Against Most Common HIV Strain
Rituximab Therapy in Previously Treated Waldenström’s Macroglobulinemia: Preliminary Evidence of Activity
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