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NEOPLASIA
From the Division of Hematology-Oncology, The
Ohio State University, Columbus; Division of Hematologic Malignancies,
Johns Hopkins Oncology Center, Baltimore, MD; and Burnham Institute,
Cancer Research Center, La Jolla, CA.
Rituximab is a chimeric monoclonal antibody directed at CD20 with
significant activity in non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). A variety of pathways of tumor cytotoxicity different from cytotoxic chemotherapy have been proposed for this therapeutic antibody including antibody-dependent cellular cytotoxicity and complement-mediated cell lysis. This report describes that a
proportion of patients with CLL receiving rituximab treatment have in
vivo activation of caspase-9, caspase-3, and poly(ADP-ribose) polymerase (PARP) cleavage in blood leukemia cells immediately following infusion of rituximab. This suggests that apoptosis using a
pathway similar to fludarabine and other chemotherapeutic agents is
intricately involved in the blood elimination of tumor cells after
rituximab treatment. Patients having caspase-3 activation and PARP
cleavage in vivo had a significantly lower blood leukemia cell count
after treatment as compared to those without caspase activation.
Significant down-modulation of the antiapoptotic proteins XIAP and
Mcl-1 was also noted, possibly explaining in part how rituximab
sensitizes CLL cells to the cytotoxic effect of chemotherapy in
vivo. These findings suggest that the therapeutic benefit of antibody-based therapy in vivo for patients with CLL depends in part on
induction of apoptosis and provides another area of focus for studying
mechanisms of antibody-resistance in neoplastic cells.
(Blood. 2002;99:1038-1043) Since the initial introduction of serotherapy with
a murine antibody in 1980,1 a variety of novel therapies
for the treatment of low-grade non-Hodgkin lymphoma (NHL) and B-cell
chronic lymphocytic leukemia (CLL) have been introduced.2
One of those is rituximab, a chimeric antibody directed against CD20.
Studies have demonstrated that rituximab is quite effective in the
treatment of both relapsed NHL at lower doses3-7 and CLL at
higher doses.8,9 Unlike many other therapies used in both
NHL and CLL, rituximab has tumor selectivity and hence is not
associated with morbidity commonly experienced with standard cytotoxic chemotherapy.
One of the attractive features of immunotherapy with monoclonal
antibodies, including rituximab, is a mechanism of cell clearance that
is proposed to be different than that of cytotoxic chemotherapy. Specifically, it is believed that monoclonal antibodies eliminate tumor
cells by both complement-mediated cell lysis and antibody-dependent cellular cytotoxicity.10 A recent report by Clynes et
al11 demonstrated the importance of specific Fc receptors
in mediating the cytotoxic effects of rituximab against NHL in vivo in
a severe combined immunodeficiency (SCID) mouse model. Specifically,
this study demonstrated that deficiency of Fc A major limitation of in vitro and in vivo animal model studies
involving tumor cell lines for exploring mechanisms of tumor elimination by novel agents is that data derived from such sources are
not reflective of what actually occurs in a patient. Specifically, it
remains uncertain if apoptosis contributes to the cytotoxic effects of
monoclonal antibodies used in the treatment of patients with CLL, NHL,
or other related malignancies whose biology is quite different from
dividing immortalized tumor cell lines. In addition, the specific
pathway of apoptosis used bears great relevance to what mechanisms of
resistance develop, making these therapies ineffective. Unlike most
human tumors, patients with CLL have easily assessable neoplastic cells
in the blood, making serial in vivo sampling during treatment quite
feasible. We therefore sought to study the in vivo contribution of
apoptotic pathways to the clinical response observed in patients with
CLL receiving treatment with rituximab.
Clinical study
Therapy was administered with close monitoring as outlined
previously.9 Briefly, for the first treatment, 100 mg
rituximab was administered over 4 hours. Infusions were then
administered on a 3-times-a-week schedule for 4 weeks with the full
dose (cohort 1, 250 mg/m2 or cohorts 2 and 3, 375 mg/m2) assigned specific to this cohort. Cohort 2 differed
from cohort 3 by the rate rituximab was administered after the second
infusion. Patients were assessed for disease response at the completion of therapy.
Sample processing
Assessment of B-cell depletion after rituximab therapy The CLL cells immediately before treatment with rituximab and immediately after treatment were washed with PBS and then incubated with an anti-CD19 phycoerythrin (PE)-labeled antibody (Becton Dickinson, San Jose, CA) and an anti-CD5 fluorescein isothiocyanate (FITC)-labeled antibody (Becton Dickinson) for 10 minutes. The cells were washed with PBS and were then analyzed on a FACScan (Becton Dickinson) illuminated at 488 nm and measuring green fluorescence (detecting FITC levels) at 530 nm and red fluorescence (measuring PE content of the cells) at more than 600 nm on an exponential scale. CD19- and CD5-coexpressing cells before treatment were compared to similar coexpression immediately after treatment. These studies showed the median pretreatment percentage of CD19/CD5+ cells was 86.9% (95% CI ± 5.3), whereas the posttreatment percentage was 72.3% (95% CI ± 11.8). The overlapping 95% CIs between these time points provide support for examining changes before and after therapy in whole-cell lysate protein levels.Western blotting Immunoblot assays were performed as described in detail elsewhere, using the multiple antigen detection (MAD) immunoblotting method that has been previously described.15 Protein was quantified in each supernatant by the bicin choninic acid (BCA) method (Pierce, Rockford, IL). Each sample was normalized for total protein content (12.5 µg/lane) and subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE; 12% gel), followed by transfer to nitrocellulose filters. The primary antibodies used represented rabbit polyclonal antisera raised either against synthetic peptides (Bcl-2, Bax, Mcl-1) or recombinant protein produced in bacteria (caspase-3, caspase-8, and caspase-9).16-20 Other primary antibodies included murine monoclonal antibodies specific for -actin (Sigma Immunochemicals), XIAP (Tranduction
Laboratories, Lexington, KY), and poly(ADP-ribose) polymerase
(PARP; a kind gift from N. A. Berger). Secondary antibodies
consisted of horseradish peroxidase (HRP)-conjugated goat anti-rabbit
IgG or goat anti-mouse IgG (Bio-Rad Laboratories, Richmond, CA).
Detection was performed by an enhanced chemiluminescence (ECL) method
(Amersham, Arlington Heights, IL), followed by colorimetric detection,
using SG substrate (Vector Laboratories, Burlingame, CA). For
verification of equivalence in protein loading, the blot was probed
with anti--actin antibody, showing equivalence in protein loading.
Protein bands were quantified by laser densitometry.
Statistical analysis Groups of data were compared using Student paired t test with SPSS software (version 9.0, SPSS, Chicago, IL) or Quatropro software (Novell, Orem, Utah). All P values are 2-sided.
Rituximab induces caspase-3 activation in CLL cells in vivo Based on observations noted in cell lines,12 we hypothesized that the clinical response observed in patients with CLL receiving rituximab may in part be mediated through induction of apoptosis. In the context of a clinical trial of rituximab in the treatment of CLL that included 33 patients, we performed pretreatment and posttreatment sampling (approximately 4 hours after initiation of therapy) of peripheral blood leukemia cells from 10 patients with CLL on days 1 and 3 of treatment. Patients who were not included either had a low lymphocyte count at the beginning of therapy or had rapid decrease in lymphocyte count after the first treatment. In these patients, we were unable to assess the status of caspase activation or expression of various apoptosis-regulating proteins.Caspase-3 serves as an effector caspase, causing cleavage of a variety
of important cellular proteins including PARP. Therefore, expression
and proteolytic processing of caspase-3 and PARP were examined in all
patients for whom pretreatment and posttreatment cellular lysates were
obtained. The results of the studies performed on all 10 patients
studied are summarized in Table 1, with
representative examples shown in Figure
1. In 3 patients, we were able to
demonstrate that rituximab induces cleavage of caspase-3 with
subsequent appearance of the 17-kd cleavage product corresponding to
the large subunit of the catalytically active protease. Concurrent with
these changes, we also detected cleavage of PARP, a known caspase
substrate. These data suggest that at least part of the clinical
effectiveness of rituximab in vivo may be explained by apoptosis
induction in the leukemia cells.
Evidence of caspase-9 involvement in rituximab-induced apoptosis of CLL cells Caspase-3 can be activated through a variety of mechanisms (for a review, see Reed21) including pathways involving caspase-9 (mitochondrial pathway) and caspase-8 (tumor necrosis factor [TNF]-family death receptor pathway). To further characterize the pathway of in vivo apoptosis used by rituximab, we performed additional studies to examine if levels of the proforms of either caspase-8 or caspase-9 decreased after treatment, an indication that these proteases have undergone proteolytic processing and activation. The results of these studies for each patient are shown in Table 1. In all 10 patients studied, no decrease in caspase-8 zymogen was noted. Of the 3 patients having activation of caspase-3 following rituximab treatment, 2 also had a notable decline in caspase-9 zymogen protein. Three additional patients had evidence of a decline in caspase-9 zymogen without caspase-3 activation or PARP cleavage. Figure 1 shows a representative CLL specimen, demonstrating that the proform of caspase-9 decreased after treatment, whereas no change in procaspase-8 levels was noted. These findings suggest that rituximab induces apoptosis in vivo through a caspase-9 pathway, although triggering of this pathway in vivo does not always result in demonstrable activation of effector caspases such as caspase-3 and subsequent cleavage of PARP.Rituximab favorably modulates Mcl-1 and XIAP in vivo in human CLL cells Relative overexpression of antiapoptotic proteins Bcl-2 and Mcl-1 and altered ratio of Bcl-2 to proapoptotic protein Bax have been reported to be associated with lower response rates to chemotherapy regimens in CLL.22-30 To date, both preclinical and clinical trials in CLL and NHL have documented that rituximab can chemosensitize neoplastic cells to cytotoxic therapy.31-33 We hypothesized therefore that rituximab may alter expression of one or more of these apoptosis-regulating proteins in CLL cells, thus offering a plausible explanation for these clinically observed phenomena. Expression of Bcl-2, Bax, Mcl-1, and XIAP proteins was examined in pretreatment and posttreatment samples from CLL patients receiving rituximab therapy. These studies demonstrated that neither Bcl-2 nor Bax protein changed following treatment with rituximab (data not shown). In contrast, relative levels of both XIAP and Mcl-1 protein were diminished on day 3 after treatment with rituximab in 10 and 9 of the patients, respectively. Representative examples are presented in Figures 1 and 2 showing rituximab induces changes in Mcl-1 and XIAP in vivo in circulating CLL cells. Indeed, expression of XIAP declined significantly in all patients examined after rituximab treatment on day 1 (P = .008) and day 3 (P = .03). A similar significant decline was noted with Mcl-1 protein expression in 9 of the 10 patients examined on day 1 (P = .012) and day 3 (P = .01). These data suggest in vivo treatment with rituximab reduces expression of certain antiapoptotic proteins and may explain why rituximab appears to chemosensitize cells even in the absence of primary induction of apoptosis in vivo.
Rituximab modulates Mcl-1 and XIAP in vitro in some patients' CLL cells Because we have demonstrated that rituximab modulates Mcl-1 and XIAP in vivo in a subset of patients treated with rituximab, we sought to determine if this also occurred in vitro following treatment with rituximab. Similar to data presented by others using B-cell lymphoma cell lines,12 rituximab as a single agent did not induce in vitro apoptosis in human CLL cells (data not shown). Figure 3 demonstrates the paired in vitro evaluation of CLL cells derived from 7 patients incubated with or without rituximab (10 µg/mL). Levels of both Mcl-1 and XIAP decreased in 4 of the 7 patients. The median changes in Mcl-1 and XIAP relative to baseline were 85% (range, 56%-314%) and 98% (range, 34%-318%). These data provide further evidence that treatment with rituximab reduces expression of certain antiapoptotic proteins without concurrently inducing apoptosis.
Rituximab-induced apoptosis in vivo correlates with favorable clinical outcome To determine if the in vivo laboratory documentation of caspase-3 activation and PARP cleavage was clinically relevant, we correlated this occurrence with clinical end points. As assessment of apoptosis activation occurred in the blood compartment, we compared both pretreatment and posttreatment absolute blood lymphocyte counts between patients with and without caspase-3 activation. As demonstrated in Figure 4, the mean lymphocyte count before treatment was similar in patients demonstrating versus not demonstrating caspase activation (mean, 98.3 × 109/L; 95% CI ± 73.6 versus 115.5 × 109/L; 95% CI ± 20.9). In contrast, the posttreatment absolute blood lymphocyte numbers from patients demonstrating caspase activation were significantly lower than those not having caspase activation (mean, 6.1 × 109/L; 95% CI ± 6.33 versus 52.2 × 109/L; 95% CI ± 40; P = .04). Furthermore, all 3 of the patients with caspase-3 and PARP cleavage experienced clinical benefit of rituximab treatment with 2 displaying partial responses (as defined by modified NCI criteria)13 and 1 having stable disease with improvement. Rituximab-induced decreases in Mcl-1 were noted in all 3 of these patients (30.7% baseline patient 1, partial response; 37.2% baseline patient 17, partial response; 61.1% baseline patient 25, stable disease with improvement). Also, the CLL cells of 2 patients with partial responses (patients 1 and 17) in whom caspase-3 proteolytic processing and PARP cleavage were observed exhibited similar decreases (64% and 86% of baseline) in XIAP, whereas the patient demonstrating stable disease with improvement had a slight increase in XIAP over baseline (26%).
To our knowledge, this report represents the first study to provide evidence that a therapeutic monoclonal antibody induces apoptosis in vivo in humans. Although preliminary, these data suggest that rituximab exerts its cytotoxic effects in vivo against human CLL cells at least in part through induction of apoptosis via a caspase-9 (mitochondrial) pathway, without evidence of concomitant activation of the caspase-8 pathway. Induction of apoptosis in vivo was associated with clinical benefit as measured by a significant decline of tumor cells in the compartment measured (ie, blood). Furthermore, 2 of the patients described herein having demonstrable caspase-3 activation also attained a partial response to therapy, and the third patient demonstrated signs of clinical benefit. These data provide clinical support for the potential significance of a known in vitro mechanism for antibody cytotoxicity. In addition, our findings also point to potential pathways that might explain resistance to antibody-based therapy. To date, the apoptotic pathway by which rituximab induces apoptosis in CLL cells or lymphoma cells in vitro has been poorly characterized. Work by Shen and colleagues12 demonstrated in lymphoma cell lines that anti-CD20 antibody-induced apoptosis appeared to be partially dependent on increases in intracellular calcium, as demonstrated by inhibition of apoptosis by intracellular and extracellular calcium chelators. A follow-up study by this group34 showed rituximab to be the most effective of several CD20 antibodies in vitro and documented caspase-3 activation concurrent with induction of apoptosis. Similar in vitro activation of caspase-3 was demonstrated by 2 other groups.35,36 Our study is the first to demonstrate that caspase-3 activation occurs in vivo in human tumor cells concurrent with cleavage of PARP, a known caspase-3 substrate. Furthermore, activation of this effector caspase appears to be associated in rituximab-treated CLL cells with activation of caspase-9. Typically, caspase-9 is activated by a mitochondria-dependent pathway involving release of cytochrome c from the organelles and activation of Apaf-1, which binds and activates procaspase-9 (for a review, see Reed37) The mitochondrial pathway is commonly activated by cytotoxic agents active in CLL such as fludarabine38 and other cytotoxic anticancer drugs.39 In contrast, caspase-8 was not processed in any patient samples examined. This initiator caspase is typically activated by TNF/FAS-family cytokine receptors and is often used by immune effector cells that mediate antibody-dependent cellular cytotoxicity.40 This observation does not diminish the importance of in vivo Fc receptor interaction recently shown to be important with rituximab in NHL cell line xenograft murine experiments,11 but it remains to be determined whether the antitumor mechanisms that depend on Fc receptors also trigger a caspase-9-dependent pathway. Given the anomalous results in some patients demonstrating clinical benefit in the absence of caspase processing, it is quite likely that alternative mechanisms including antibody-mediated cellular cytotoxicity and complement-mediated cell lysis also have an impact on clinical benefit observed with rituximab. It is of interest that some CLL specimens derived from patients on rituximab therapy demonstrated evidence of capase-9 activation in the absence of concomitant caspase-3 or PARP cleavage (Table 1). This observation suggests that some CLL cells possess a block in the caspase cascade at or between the point of activation of caspase-3 and caspase-9. Multiple mechanisms could potentially account for such impairments in this step of the mitochondrial pathway of apoptosis including phosphorylation of caspase-3 by protein kinase B (AKT), overexpression of Hsp70, and overexpression of the IAP family member proteins (for a review, see Deveraux et al41). Several studies have reported an association of elevated levels of antiapoptotic proteins Bcl-2 and Mcl-1 or altered ratios of antiapoptotic and proapoptotic proteins (Bcl-2:Bax) of the Bcl-2 family with a lower clinical response rates to fludarabine-based regimens in CLL.22-28 Similarly, elevated levels of XIAP, an IAP family member that inhibits caspases,29,30,41 have been associated with less durable responses to cytarabine-containing regimens in acute myeloid leukemia, though its relevance to CLL has not yet been explored.42 To date, both preclinical and clinical trials in CLL and NHL have documented that rituximab chemosensitizes tumor cells to the effects of cytotoxic therapy.31-33 This formed the basis for the hypothesis that rituximab may alter expression of one or more apoptosis regulatory proteins in CLL cells and thus offer a plausible explanation for this clinically observed phenomenon. Serial studies of a variety of antiapoptotic proteins in vivo demonstrated that both Mcl-1 and XIAP were significantly modulated in virtually all patients examined. Similar findings were observed in a proportion of different patients following in vitro incubation with rituximab. Although preliminary, this finding suggests that such modulation of antiapoptosis signals in vivo may in part explain why rituximab has been observed to sensitize neoplastic cells (including CLL cells) to the effects of cytotoxic chemotherapy. Indeed, preliminary observations suggest that more complete responses are obtained when rituximab is combined with fludarabine33 in previously untreated patients with CLL. Future studies directed at serial in vivo quantification of these proteins in the context of clinical trials combining rituximab with fludarabine or other CLL therapies may provide the opportunity to test this hypothesis. In addition, studies examining resistance mechanisms of rituximab and potential cross-resistance of apoptosis between this agent and chemotherapy should be considered.
The authors wish to thank the patients who participated in this trial and to acknowledge the research team (Kathy Park, Margaret Lucas, and Amy Goodrich) that assisted in coordinating the clinical trial; Robin Howard, for statistical input; and Drs Michael Grever and Joseph Drabick, for reviewing the manuscript. Additional thanks are provided to the National Institutes of Health, the Leukemia and Lymphoma Society of America, the D. Warren Brown Foundation, and Sidney Kimmel Cancer Research Foundation for support.
Submitted January 24, 2001; accepted October 1, 2001.
The clinical trial was supported in part by a grant from Genentech and IDEC Pharmaceuticals. This work was supported by the National Cancer Institute (P01 CA81534-02 and CA98099), the Sidney Kimmel Cancer Research Foundation, the D. Warren Brown Foundation, and the Leukemia and Lymphoma Society of America.
J.C.B. and S.K. contributed equally to the production of this work.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: John C. Byrd, B302 Starling Loving Hall, The Ohio State University, 320 W 10th Ave, Columbus, OH 43210; e-mail: byrd-3{at}medctr.osu.edu.
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 X. Zhou, W. Hu, and X. Qin The Role of Complement in the Mechanism of Action of Rituximab for B-Cell Lymphoma: Implications for Therapy Oncologist, September 1, 2008; 13(9): 954 - 966. [Abstract] [Full Text] [PDF]
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 P. V. Beum, M. A. Lindorfer, F. Beurskens, P. T. Stukenberg, H. M. Lokhorst, A. W. Pawluczkowycz, P. W. H. I. Parren, J. G. J. van de Winkel, and R. P. Taylor Complement Activation on B Lymphocytes Opsonized with Rituximab or Ofatumumab Produces Substantial Changes in Membrane Structure Preceding Cell Lysis J. Immunol., July 1, 2008; 181(1): 822 - 832. [Abstract] [Full Text] [PDF]
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 C. A. Walshe, S. A. Beers, R. R. French, C. H. T. Chan, P. W. Johnson, G. K. Packham, M. J. Glennie, and M. S. Cragg Induction of Cytosolic Calcium Flux by CD20 Is Dependent upon B Cell Antigen Receptor Signaling J. Biol. Chem., June 20, 2008; 283(25): 16971 - 16984. [Abstract] [Full Text] [PDF]
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N. I. Pathan, P. Chu, K. Hariharan, C. Cheney, A. Molina, and J. Byrd Mediation of apoptosis by and antitumor activity of lumiliximab in chronic lymphocytic leukemia cells and CD23+ lymphoma cell lines Blood, February 1, 2008; 111(3): 1594 - 1602. [Abstract] [Full Text] [PDF]
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E. Bremer, B. ten Cate, D. F. Samplonius, N. Mueller, H. Wajant, A. J. Stel, M. Chamuleau, A. A. van de Loosdrecht, J. Stieglmaier, G. H. Fey, et al. Superior Activity of Fusion Protein scFvRit:sFasL over Cotreatment with Rituximab and Fas Agonists Cancer Res., January 15, 2008; 68(2): 597 - 604. [Abstract] [Full Text] [PDF]
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P. Macor, C. Tripodo, S. Zorzet, E. Piovan, F. Bossi, R. Marzari, A. Amadori, and F. Tedesco In vivo Targeting of Human Neutralizing Antibodies against CD55 and CD59 to Lymphoma Cells Increases the Antitumor Activity of Rituximab Cancer Res., November 1, 2007; 67(21): 10556 - 10563. [Abstract] [Full Text] [PDF]
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A. P. Kater, M. H. J. van Oers, and T. J. Kipps Cellular immune therapy for chronic lymphocytic leukemia Blood, October 15, 2007; 110(8): 2811 - 2818. [Abstract] [Full Text] [PDF]
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X. Zhao, R. Lapalombella, T. Joshi, C. Cheney, A. Gowda, M. S. Hayden-Ledbetter, P. R. Baum, T. S. Lin, D. Jarjoura, A. Lehman, et al. Targeting CD37-positive lymphoid malignancies with a novel engineered small modular immunopharmaceutical Blood, October 1, 2007; 110(7): 2569 - 2577. [Abstract] [Full Text] [PDF]
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S.-R. A. Hussain, C. M. Cheney, A. J. Johnson, T. S. Lin, M. R. Grever, M. A. Caligiuri, D. M. Lucas, and J. C. Byrd Mcl-1 Is a Relevant Therapeutic Target in Acute and Chronic Lymphoid Malignancies: Down-Regulation Enhances Rituximab-Mediated Apoptosis and Complement-Dependent Cytotoxicity Clin. Cancer Res., April 1, 2007; 13(7): 2144 - 2150. [Abstract] [Full Text] [PDF]
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R. Nimmanapalli, M.-A. Lyu, M. Du, M. J. Keating, M. G. Rosenblum, and V. Gandhi The growth factor fusion construct containing B-lymphocyte stimulator (BLyS) and the toxin rGel induces apoptosis specifically in BAFF-R-positive CLL cells Blood, March 15, 2007; 109(6): 2557 - 2564. [Abstract] [Full Text] [PDF]
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A. J. Stel, B. ten Cate, S. Jacobs, J. W. Kok, D. C. J. Spierings, M. Dondorff, W. Helfrich, H. C. Kluin-Nelemans, L. F. M. H. de Leij, S. Withoff, et al. Fas Receptor Clustering and Involvement of the Death Receptor Pathway in Rituximab-Mediated Apoptosis with Concomitant Sensitization of Lymphoma B Cells to Fas-Induced Apoptosis J. Immunol., February 15, 2007; 178(4): 2287 - 2295. [Abstract] [Full Text] [PDF]
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K. D. Khan, C. Emmanouilides, D. M. Benson Jr., D. Hurst, P. Garcia, G. Michelson, S. Milan, A. K. Ferketich, L. Piro, J. P. Leonard, et al. A Phase 2 Study of Rituximab in Combination with Recombinant Interleukin-2 for Rituximab-Refractory Indolent Non-Hodgkin's Lymphoma Clin. Cancer Res., December 1, 2006; 12(23): 7046 - 7053. [Abstract] [Full Text] [PDF]
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J. A. Bowles, S.-Y. Wang, B. K. Link, B. Allan, G. Beuerlein, M.-A. Campbell, D. Marquis, B. Ondek, J. E. Wooldridge, B. J. Smith, et al. Anti-CD20 monoclonal antibody with enhanced affinity for CD16 activates NK cells at lower concentrations and more effectively than rituximab Blood, October 15, 2006; 108(8): 2648 - 2654. [Abstract] [Full Text] [PDF]
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J. L. Teeling, W. J. M. Mackus, L. J. J. M. Wiegman, J. H. N. van den Brakel, S. A. Beers, R. R. French, T. van Meerten, S. Ebeling, T. Vink, J. W. Slootstra, et al. The Biological Activity of Human CD20 Monoclonal Antibodies Is Linked to Unique Epitopes on CD20 J. Immunol., July 1, 2006; 177(1): 362 - 371. [Abstract] [Full Text] [PDF]
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 M. Alfonso-Perez, S. Lopez-Giral, N. E. Quintana, J. Loscertales, P. Martin-Jimenez, and C. Munoz Anti-CCR7 monoclonal antibodies as a novel tool for the treatment of chronic lymphocyte leukemia J. Leukoc. Biol., June 1, 2006; 79(6): 1157 - 1165. [Abstract] [Full Text] [PDF]
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 B. F. Israel, M. Gulley, S. Elmore, S. Ferrini, W.-h. Feng, and S. C. Kenney Anti-CD70 antibodies: a potential treatment for EBV+ CD70-expressing lymphomas Mol. Cancer Ther., December 1, 2005; 4(12): 2037 - 2044. [Abstract] [Full Text] [PDF]
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 E A Clark and J A Ledbetter How does B cell depletion therapy work, and how can it be improved? Ann Rheum Dis, November 1, 2005; 64(suppl_4): iv77 - iv80. [Abstract] [Full Text] [PDF]
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A. P. Kater, F. Dicker, M. Mangiola, K. Welsh, R. Houghten, J. Ostresh, A. Nefzi, J. C. Reed, C. Pinilla, and T. J. Kipps Inhibitors of XIAP sensitize CD40-activated chronic lymphocytic leukemia cells to CD95-mediated apoptosis Blood, September 1, 2005; 106(5): 1742 - 1748. [Abstract] [Full Text] [PDF]
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N. Zhang, L. A. Khawli, P. Hu, and A. L. Epstein Generation of Rituximab Polymer May Cause Hyper-Cross-linking-Induced Apoptosis in Non-Hodgkin's Lymphomas Clin. Cancer Res., August 15, 2005; 11(16): 5971 - 5980. [Abstract] [Full Text] [PDF]
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J. M. Pagel, C. Laugen, L. Bonham, R. C. Hackman, D. M. Hockenbery, R. Bhatt, D. Hollenback, H. Carew, J. W. Singer, and O. W. Press Induction of Apoptosis Using Inhibitors of Lysophosphatidic Acid Acyltransferase-{beta} and Anti-CD20 Monoclonal Antibodies for Treatment of Human Non-Hodgkin's Lymphomas Clin. Cancer Res., July 1, 2005; 11(13): 4857 - 4866. [Abstract] [Full Text] [PDF]
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K. Balakrishnan, C. M. Stellrecht, D. Genini, M. Ayres, W. G. Wierda, M. J. Keating, L. M. Leoni, and V. Gandhi Cell death of bioenergetically compromised and transcriptionally challenged CLL lymphocytes by chlorinated ATP Blood, June 1, 2005; 105(11): 4455 - 4462. [Abstract] [Full Text] [PDF]
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O. Berezovskaya, A. D. Schimmer, A. B. Glinskii, C. Pinilla, R. M. Hoffman, J. C. Reed, and G. V. Glinsky Increased Expression of Apoptosis Inhibitor Protein XIAP Contributes to Anoikis Resistance of Circulating Human Prostate Cancer Metastasis Precursor Cells Cancer Res., March 15, 2005; 65(6): 2378 - 2386. [Abstract] [Full Text] [PDF]
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M.S. Czuczman, A. Koryzna, A. Mohr, C. Stewart, K. Donohue, L. Blumenson, Z.P. Bernstein, P. McCarthy, A. Alam, F. Hernandez-Ilizaliturri, et al. Rituximab in Combination With Fludarabine Chemotherapy in Low-Grade or Follicular Lymphoma J. Clin. Oncol., February 1, 2005; 23(4): 694 - 704. [Abstract] [Full Text] [PDF]
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M. L. Palomba, W. K. Roberts, T. Dao, G. Manukian, J. A. Guevara-Patino, J. D. Wolchok, D. A. Scheinberg, and A. N. Houghton CD8+ T-Cell-Dependent Immunity Following Xenogeneic DNA Immunization against CD20 in a Tumor Challenge Model of B-Cell Lymphoma Clin. Cancer Res., January 1, 2005; 11(1): 370 - 379. [Abstract] [Full Text] [PDF]
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J. W. Friedberg Unique Toxicities and Resistance Mechanisms Associated with Monoclonal Antibody Therapy Hematology, January 1, 2005; 2005(1): 329 - 334. [Abstract] [Full Text] [PDF]
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J. P. Leonard Targeting CD20 in Follicular NHL: Novel Anti-CD20 Therapies, Antibody Engineering, and the Use of Radioimmunoconjugates Hematology, January 1, 2005; 2005(1): 335 - 339. [Abstract] [Full Text] [PDF]
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M. R. Smith, F. Jin, and I. Joshi Enhanced efficacy of therapy with antisense BCL-2 oligonucleotides plus anti-CD20 monoclonal antibody in scid mouse/human lymphoma xenografts Mol. Cancer Ther., December 1, 2004; 3(12): 1693 - 1699. [Abstract] [Full Text] [PDF]
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G. Cartron, H. Watier, J. Golay, and P. Solal-Celigny From the bench to the bedside: ways to improve rituximab efficacy Blood, November 1, 2004; 104(9): 2635 - 2642. [Abstract] [Full Text] [PDF]
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M. S. Cragg, M. B. Bayne, A. L. Tutt, R. R. French, S. Beers, M. J. Glennie, and T. M. Illidge A new anti-idiotype antibody capable of binding rituximab on the surface of lymphoma cells Blood, October 15, 2004; 104(8): 2540 - 2542. [Abstract] [Full Text] [PDF]
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C. F. Eisenbeis, A. Grainger, B. Fischer, R. A. Baiocchi, L. Carrodeguas, S. Roychowdhury, L. Chen, A. L. Banks, T. Davis, D. Young, et al. Combination Immunotherapy of B-Cell Non-Hodgkin's Lymphoma with Rituximab and Interleukin-2: A Preclinical and Phase I Study Clin. Cancer Res., September 15, 2004; 10(18): 6101 - 6110. [Abstract] [Full Text] [PDF]
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J. L. Teeling, R. R. French, M. S. Cragg, J. van den Brakel, M. Pluyter, H. Huang, C. Chan, P. W. H. I. Parren, C. E. Hack, M. Dechant, et al. Characterization of new human CD20 monoclonal antibodies with potent cytolytic activity against non-Hodgkin lymphomas Blood, September 15, 2004; 104(6): 1793 - 1800. [Abstract] [Full Text] [PDF]
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Y. K. Lee, N. D. Bone, A. K. Strege, T. D. Shanafelt, D. F. Jelinek, and N. E. Kay VEGF receptor phosphorylation status and apoptosis is modulated by a green tea component, epigallocatechin-3-gallate (EGCG), in B-cell chronic lymphocytic leukemia Blood, August 1, 2004; 104(3): 788 - 794. [Abstract] [Full Text] [PDF]
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A. K. Gopal, J. M. Pagel, N. Hedin, and O. W. Press Fenretinide enhances rituximab-induced cytotoxicity against B-cell lymphoma xenografts through a caspase-dependent mechanism Blood, May 1, 2004; 103(9): 3516 - 3520. [Abstract] [Full Text] [PDF]
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M. S. Cragg and M. J. Glennie Antibody specificity controls in vivo effector mechanisms of anti-CD20 reagents Blood, April 1, 2004; 103(7): 2738 - 2743. [Abstract] [Full Text] [PDF]
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A. D. Kennedy, P. V. Beum, M. D. Solga, D. J. DiLillo, M. A. Lindorfer, C. E. Hess, J. J. Densmore, M. E. Williams, and R. P. Taylor Rituximab Infusion Promotes Rapid Complement Depletion and Acute CD20 Loss in Chronic Lymphocytic Leukemia J. Immunol., March 1, 2004; 172(5): 3280 - 3288. [Abstract] [Full Text] [PDF]
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A. P. Mone, P. Huang, H. Pelicano, C. M. Cheney, J. M. Green, J. Y. Tso, A. J. Johnson, S. Jefferson, T. S. Lin, and J. C. Byrd Hu1D10 induces apoptosis concurrent with activation of the AKT survival pathway in human chronic lymphocytic leukemia cells Blood, March 1, 2004; 103(5): 1846 - 1854. [Abstract] [Full Text] [PDF]
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S. S. Farag, I. W. Flinn, R. Modali, T. A. Lehman, D. Young, and J. C. Byrd Fc{gamma}RIIIa and Fc{gamma}RIIa polymorphisms do not predict response to rituximab in B-cell chronic lymphocytic leukemia Blood, February 15, 2004; 103(4): 1472 - 1474. [Abstract] [Full Text] [PDF]
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A. R. Jazirehi and B. Bonavida Resveratrol modifies the expression of apoptotic regulatory proteins and sensitizes non-Hodgkin's lymphoma and multiple myeloma cell lines to paclitaxel-induced apoptosis Mol. Cancer Ther., January 1, 2004; 3(1): 71 - 84. [Abstract] [Full Text]
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C. F. Eisenbeis, M. A. Caligiuri, and J. C. Byrd Rituximab: Converging Mechanisms of Action in Non-Hodgkin's Lymphoma? Clin. Cancer Res., December 1, 2003; 9(16): 5810 - 5812. [Full Text] [PDF]
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W.-K. Weng and R. Levy Two Immunoglobulin G Fragment C Receptor Polymorphisms Independently Predict Response to Rituximab in Patients With Follicular Lymphoma J. Clin. Oncol., November 1, 2003; 21(21): 3940 - 3947. [Abstract] [Full Text] [PDF]
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H. T. C. Chan, D. Hughes, R. R. French, A. L. Tutt, C. A. Walshe, J. L. Teeling, M. J. Glennie, and M. S. Cragg CD20-induced Lymphoma Cell Death Is Independent of Both Caspases and Its Redistribution into Triton X-100 Insoluble Membrane Rafts Cancer Res., September 1, 2003; 63(17): 5480 - 5489. [Abstract] [Full Text] [PDF]
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M. Coleman, D. M. Goldenberg, A. B. Siegel, J. C. Ketas, M. Ashe, J. M. Fiore, and J. P. Leonard Epratuzumab: Targeting B-Cell Malignancies through CD22 Clin. Cancer Res., September 1, 2003; 9(10): 3991S - 3994. [Abstract] [Full Text] [PDF]
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N. Di Gaetano, E. Cittera, R. Nota, A. Vecchi, V. Grieco, E. Scanziani, M. Botto, M. Introna, and J. Golay Complement Activation Determines the Therapeutic Activity of Rituximab In Vivo J. Immunol., August 1, 2003; 171(3): 1581 - 1587. [Abstract] [Full Text] [PDF]
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J. L. Aron, M. R. Parthun, G. Marcucci, S. Kitada, A. P. Mone, M. E. Davis, T. Shen, T. Murphy, J. Wickham, C. Kanakry, et al. Depsipeptide (FR901228) induces histone acetylation and inhibition of histone deacetylase in chronic lymphocytic leukemia cells concurrent with activation of caspase 8-mediated apoptosis and down-regulation of c-FLIP protein Blood, July 15, 2003; 102(2): 652 - 658. [Abstract] [Full Text] [PDF]
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R. Bannerji, S. Kitada, I. W. Flinn, M. Pearson, D. Young, J. C. Reed, and J. C. Byrd Apoptotic-Regulatory and Complement-Protecting Protein Expression in Chronic Lymphocytic Leukemia: Relationship to In Vivo Rituximab Resistance J. Clin. Oncol., April 15, 2003; 21(8): 1466 - 1471. [Abstract] [Full Text] [PDF]
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F. Ravandi, M. Talpaz, and Z. Estrov Modulation of Cellular Signaling Pathways: Prospects for Targeted Therapy in Hematological Malignancies Clin. Cancer Res., February 1, 2003; 9(2): 535 - 550. [Abstract] [Full Text] [PDF]
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A. D. Kennedy, M. D. Solga, T. A. Schuman, A. W. Chi, M. A. Lindorfer, W. M. Sutherland, P. L. Foley, and R. P. Taylor An anti-C3b(i) mAb enhances complement activation, C3b(i) deposition, and killing of CD20+ cells by rituximab Blood, February 1, 2003; 101(3): 1071 - 1079. [Abstract] [Full Text] [PDF]
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J. C. Byrd, L. Smith, M. L. Hackbarth, I. W. Flinn, D. Young, J. H. Proffitt, and N. A. Heerema Interphase Cytogenetic Abnormalities in Chronic Lymphocytic Leukemia May Predict Response to Rituximab Cancer Res., January 1, 2003; 63(1): 36 - 38. [Abstract] [Full Text] [PDF]
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W. L. Carroll, D. Bhojwani, D.-J. Min, E. Raetz, M. Relling, S. Davies, J. R. Downing, C. L. Willman, and J. C. Reed Pediatric Acute Lymphoblastic Leukemia Hematology, January 1, 2003; 2003(1): 102 - 131. [Abstract] [Full Text] [PDF]
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J. C. Byrd, B. L. Peterson, V. A. Morrison, K. Park, R. Jacobson, E. Hoke, J. W. Vardiman, K. Rai, C. A. Schiffer, and R. A. Larson Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712) Blood, January 1, 2003; 101(1): 6 - 14. [Abstract] [Full Text] [PDF]
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I. M. Pedersen, S. Kitada, L. M. Leoni, J. M. Zapata, J. G. Karras, N. Tsukada, T. J. Kipps, Y. S. Choi, F. Bennett, and J. C. Reed Protection of CLL B cells by a follicular dendritic cell line is dependent on induction of Mcl-1 Blood, August 13, 2002; 100(5): 1795 - 1801. [Abstract] [Full Text] [PDF]
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N. E. Kay, T. J. Hamblin, D. F. Jelinek, G. W. Dewald, J. C. Byrd, S. Farag, M. Lucas, and T. Lin Chronic Lymphocytic Leukemia Hematology, January 1, 2002; 2002(1): 193 - 213. [Abstract] [Full Text]
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Top
Abstract
Introduction
III receptors or use of
altered antibodies that prevented binding to the Fc receptor resulted in diminished in vivo response to the rituximab therapy. Such
findings strongly implicate the importance of the Fc receptor in
mediating the in vivo effect of rituximab. Another study demonstrated that murine anti-CD20 antibodies can inhibit cell growth but more importantly induce apoptosis on Fc receptor cross-linking in vitro in
human lymphoma cell lines.
80°C. Studies
examining in vitro modulation of antiapoptosis proteins in vitro were
performed from CLL cells obtained from patients with CLL as part of an
IRB-approved protocol. Similar methods for lysate preparation were
applied to CLL cells incubated in vitro with rituximab (10 µg/mL) and media for 4 hours.
) and posttreatment (
) lymphocyte count
(× 109/L) for patients with and without caspase-3
activation.
can't live without it.
Cell.
1997;91:559-562