Single-Agent Monoclonal Antibody Efficacy in Bulky Non-Hodgkin's Lymphoma: Results of a Phase II Trial of Rituximab

Davis, Thomas A.; White, Christine; Grillo-López, Antonio J; Velasquez, William S.; Link, Brian K.; Maloney, DG; Dillman, Robert O.; Williams, Michael E.; Mohrbacher, Ann; Weaver, Robin; Dowden, Sue; Levy, Ronald

doi:10.1200/jco.1999.17.6.1851

Cited by 263 publications

(140 citation statements)

References 29 publications

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“…Rituximab is commonly used in the treatment of patients with relapsed B-cell non-Hodgkin's lymphoma. [38][39][40] We found that the combination of these two agents decreased the fraction of viable cells after 9 days significantly more than either agent alone. When tested in the same lymphoma xenograft model, the combination of the survivin ASO and rituximab inhibited tumor growth more than the survivin ASO or rituximab alone, and to a greater degree than rituximab in combination with a control oligonucleotide.…”

Section: Discussionmentioning

confidence: 81%

Inhibition of survivin expression suppresses the growth of aggressive non-Hodgkin's lymphoma

et al. 2004

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Survivin is a member of the inhibitor of apoptosis protein (IAP) family and functions both as an apoptosis inhibitor and a regulator of cell division. Survivin overexpression is common in many human tumors and correlates with survival in large cell non-Hodgkin's lymphoma. To evaluate this molecule as a potential therapeutic target in large-cell lymphoma, we evaluated the effect of survivin inhibition both in vitro and in vivo. Using an antisense oligonucleotide (ASO) approach, cell growth was significantly inhibited in the DoHH2, RL and HT lymphoma cell lines. In a lymphoma xenograft model, the development of tumors as well as the growth of established tumors was inhibited in the survivin ASO-treated mice compared to controls. To assess the efficacy of the survivin ASO in combination with other biological agents, we combined the survivin ASO with an anti-CD20 monoclonal antibody, rituximab. The effect of survivin ASO and rituximab in combination was additive in vitro. In vivo, however, suppression of tumor growth with the combination was not significantly superior to controls. We conclude that inhibition of survivin expression is an attractive therapeutic strategy in aggressive non-Hodgkin's lymphomas, and that combining survivin ASO with rituximab may enhance the efficacy of this approach.

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Section: Discussionmentioning

confidence: 81%

Inhibition of survivin expression suppresses the growth of aggressive non-Hodgkin's lymphoma

et al. 2004

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“…6 Thus, apoptosis could indeed be one of the anti-tumor mechanisms of chimeric anti-CD20 mAbs in vivo. In a study in 31 lymphoma patients with bulky disease, 2 it was demonstrated that the number of prior chemotherapy courses, the number of relapses, resistance to chemotherapy, prior aggressive therapy or prior anthracyclin therapy, were not correlated to the response to anti-CD20-therapy. Furthermore, in low grade lymphoma patients treated with chimeric anti-CD20 mAbs, 1 baseline peripheral blood Bcl-2 negativity was correlated with a lower response to CD20 therapy, indicating that Bcl-2-positive tumors were sensitive to CD20 therapy.…”

Section: Figurementioning

confidence: 99%

“…1,2 Its application in other CD20-positive B cell malignancies, eg aggressive lymphomas, 3 post-transplant lymphoma, or chronic lymphocytic leukemia (reviewed in Refs. 4 and 5), is rapidly expanding.…”

Section: Introductionmentioning

confidence: 99%

CD20-induced B cell death can bypass mitochondria and caspase activation

et al. 2002

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The apoptotic pathway activated by chimeric anti-CD20 monoclonal antibodies (rituximab, IDEC.C2B8) was analyzed using the Burkitt lymphoma cell line Ramos. Crosslinking of CD20 (CD20XL) induced apoptosis in Ramos cells, which involved loss of mitochondrial membrane potential (⌬ m ), the release of cytochrome-c (cyt-c), and activation of caspases-9 and -3. Nevertheless, several lines of evidence showed that the apoptotic outcome did not depend on these events. First, under circumstances where Ramos cells display resistance to either CD95-or B cell receptor (BCR)-induced apoptosis, CD20XL-induced apoptosis was not affected, pointing to a distinct pathway. Second, the broad-spectrum caspase inhibitor zVAD-fmk prevented processing of caspase-9, -3 and PARP as well as DNA fragmentation, but did not block apoptosis as measured by annexin V staining, cell size and membrane integrity. Lastly, Bcl-2 overexpression blocked cyt-c release and the decrease in ⌬ m , and completely prevented CD95-or BCR-mediated apoptosis; however, it did not affect CD20XL-induced cell death. We conclude that although CD20XL can initiate the mitochondrial apoptosis pathway, CD20-induced apoptosis does not necessarily require active caspases and cannot be blocked by Bcl-2. Since most chemotherapeutic drugs require the activation of caspases to exert their cytotoxicity, these findings provide an important rationale for the use of CD20 mAbs in chemoresistant malignancies.

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“…[1][2][3] It is composed of human IgG1 and kappa constant regions and variable antigen recognition sites from the murine CD20 mAb IDEC-2B8. 4 Rituximab is directed against the B cell-specific antigen CD20, a nonglycosylated 33 to 37 kDa phosphoprotein, expressed on more than 95% of normal and malignant B cells.…”

Section: Introductionmentioning

confidence: 99%

Analysis of CD20-dependent cellular cytotoxicity by G-CSF-stimulated neutrophils

et al. 2002

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Rituximab, a chimeric CD20 monoclonal antibody (mAb), is widely used in the treatment of patients with low-grade nonHodgkin's lymphoma. Possible anti-tumour mechanisms involve complement-mediated lysis and/or antibody-dependent cellular cytotoxicity (ADCC). Because G-CSF greatly enhances the cytotoxicity of neutrophils (PMN) in ADCC, the clinical efficacy of rituximab might be enhanced by the addition of G-CSF. Therefore, we investigated the neutrophil-mediated CD20-dependent cellular cytotoxicity in B cell lines. In contrast to previous studies by others, we found that G-CSF-primed PMN are capable of functioning as effector cells in CD20-dependent cellular cytotoxicity. However, HLA class II mAbs were far more effective. The differences between HLA class II-and CD20-mediated PMN-ADCC were not due to: (1) the use of chimeric (hIgG1) mAbs vs mIgG2a mAbs; (2) HLA class II-induced apoptosis as an 'ADCC-sensitising' mechanism; (3) CD20-induced inhibition of ADCC; (4) inferior membrane mobility of CD20. Analysis of Fc␥receptor (Fc␥R) involvement showed that although CD20-induced ADCC was mediated mainly via Fc␥RI, for optimal lysis Fc␥RI and Fc␥RII were both required. In contrast, in HLA class II-dependent ADCC both Fc␥RI and II were capable of independently inducing maximum lysis. The mechanism underlying these differences in Fc␥R-binding and activation remains to be elucidated. Leukemia (2002) 16, 693-699.

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Single-Agent Monoclonal Antibody Efficacy in Bulky Non-Hodgkin's Lymphoma: Results of a Phase II Trial of Rituximab

Abstract: Rituximab single-agent outpatient therapy is safe and shows significant clinical activity in patients with bulky relapsed or refractory low-grade or follicular B-cell NHL.

Cited by 263 publications

References 29 publications

Inhibition of survivin expression suppresses the growth of aggressive non-Hodgkin's lymphoma

Inhibition of survivin expression suppresses the growth of aggressive non-Hodgkin's lymphoma

CD20-induced B cell death can bypass mitochondria and caspase activation

Analysis of CD20-dependent cellular cytotoxicity by G-CSF-stimulated neutrophils

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