A new multi‐parameter flow cytometric assay for monitoring lymphoma growth and spread in a pre‐clinical murine model for human lymphoma

Neeson, Paul J.; Paterson, Yvonne

doi:10.1002/cyto.a.20023

Cited by 7 publications

(5 citation statements)

References 55 publications

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“…For our initial in vivo studies, we chose the 38C13-huCD20 model, a syngeneic human CD20-expressing murine B-cell lymphoma grown in immunocompetent C3H mice. 39 The 38C13 lymphoma is a highly aggressive tumor model in which mice develop micrometastases in the spleen, lymph nodes, and bone marrow within 6 to 9 days of subcutaneous tumor inoculation, 46 thus representing a stringent setting in which to evaluate novel therapeutics. This setting not only allows recruitment of the full range of host innate and adaptive immune effector mechanisms, but also assessment of IFN␣ toxicity.…”

Section: Discussionmentioning

confidence: 99%

Targeted delivery of interferon-alpha via fusion to anti-CD20 results in potent antitumor activity against B-cell lymphoma

Xuan

Steward

Timmerman

et al. 2010

Blood

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The anti-CD20 antibody rituximab has substantially improved outcomes in patients with B-cell non-Hodgkin lymphomas. However, many patients are not cured by rituximab-based therapies, and overcoming de novo or acquired rituximab resistance remains an important challenge to successful treatment of Bcell malignancies. Interferon-alpha (IFN␣) has potent immunostimulatory properties and antiproliferative effects against some B-cell cancers, but its clinical utility is limited by systemic toxicity. To improve the efficacy of CD20-targeted therapy, we constructed fusion proteins consisting of anti-CD20 and murine or human IFN␣. Fusion proteins had reduced IFN␣ activity in vitro compared with native IFN␣, but CD20 targeting permitted efficient antiproliferative and proapoptotic effects against an aggressive rituximab-insensitive human CD20 ؉ murine lymphoma (38C13-huCD20) and a human B-cell lymphoma (Daudi). In vivo efficacy was demonstrated against established 38C13-huCD20 grown in syngeneic immunocom- IntroductionThe anti-CD20 antibody rituximab (C2B8/Rituxan; Genentech/ Biogen-IDEC) has substantially improved treatment outcomes in B-cell non-Hodgkin lymphomas (NHLs), achieving high response rates in low-grade B-cell lymphomas, 1 and improving survival in both indolent and aggressive lymphomas in combination with chemotherapy. 2,3 However, many tumors do not respond to or relapse after rituximab-based therapies. 4 Thus, new approaches are needed to improve anti-CD20 efficacy and overcome rituximab resistance.The in vivo antilymphoma effects of rituximab are believed to be mediated by antibody dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), induction of apoptosis in tumor cells, and recruitment of T cells responding to tumor antigens released upon antibody-mediated tumor lysis. [5][6][7] Clinical studies have suggested that ADCC plays a dominant role in rituximab action in humans. 8,9 Thus, attempts have been made to boost rituximab-mediated ADCC by activation of Fc receptorbearing natural killer (NK) cells, monocytes/macrophages, or granulocytes via systemic administration of cytokines such as interleukin-2, interleukin-12, or granulocyte-macrophage colonystimulating factor, 10-12 with limited efficacy. None of these trials involving systemic administration of cytokines offered a clear advantage over the expected efficacy of rituximab alone, likely due to the inability of systemically administered agents to achieve high concentrations within the tumor bed.Interferon-alpha (IFN␣), a member of the type I interferon family (␣, ␤, ), is a pleiotropic cytokine with attractive features for combination with rituximab in treating NHL. 13,14 Beneficial properties of IFN␣ against NHL and other cancers include direct antiproliferative and proapoptotic effects, 15-17 blockade of autocrine growth factor loops, 18 repression of c-myc oncogene expression, 19 down-regulation of telomerase activity, 20 and inhibition of angiogenesis. 21 Favorable immunologic effects of IFN␣ for lymphoma treatment...

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Section: Discussionmentioning

confidence: 99%

Targeted delivery of interferon-alpha via fusion to anti-CD20 results in potent antitumor activity against B-cell lymphoma

Xuan

Steward

Timmerman

et al. 2010

Blood

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“…38 Subcutaneously administered tumor rapidly metastasizes to spleen, lymph nodes, and bone marrow, within 6 to 9 days, resulting in a systemic tumor burden. 39 38C13 as well as 38C13-V2, the idiotype negative variant of 38C13, 40,41 were maintained in RPMI-1640 medium supplemented with 10% heatinactivated fetal calf serum (FCS), 2 mM L-glutamine, 100 U/mL penicillin, 100 g/mL streptomycin, and 50 M 2-mercaptoethanol (cRPMI). The spontaneously arising, C3H-derived fibrosarcoma AG104A 42 (kindly provided by Dr Hans Schreiber, University of Chicago, IL) was also grown in cRPMI.…”

Section: Mice and Cell Linesmentioning

confidence: 99%

Dendritic cells loaded with apoptotic antibody-coated tumor cells provide protective immunity against B-cell lymphoma in vivo

Franki¹,

Steward

Betting³

et al. 2008

Blood

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IntroductionAmong human cancers, B-cell lymphomas appear among the most susceptible to immunotherapeutic strategies, because of their high rate of response to monoclonal antibodies (mAbs) targeting the B-cell differentiation antigen CD20 and encouraging results from early phase clinical trials of tumor-specific therapeutic vaccines. 1 The availability of both passive and active immunotherapeutic agents against B-cell lymphomas has made them an important testing ground for the development of clinically effective immunotherapies in humans. [1][2][3] The best characterized target for active immunotherapy of B-cell lymphoma is tumor-specific immunoglobulin (idiotype, Id). 4 Immunization of patients with Id protein derived from their own tumors can elicit humoral and T cell-mediated immune responses associated with improvements in survival and tumor burden. [5][6][7][8] Traditional Id vaccines consist of Id protein chemically conjugated to the highly immunogenic carrier protein keyhole limpet hemocyanin (KLH) and injected together with an immunologic adjuvant. 1 Because of their potent antigenpresenting properties, 9 dendritic cells (DCs) have been used to augment lymphoma vaccine effectiveness, and durable tumor regressions have been observed after immunization with Id-loaded DCs. 10,11 Granulocytemacrophage colony-stimulating factor (GM-CSF), a DC growth and maturation factor, has also been used as an effective adjuvant in Id-KLH vaccines. 4,7,12 However, despite the elegant nature of the Id vaccine approach, shortcomings of this strategy include the requirement of producing a custom-made protein for each patient and limitation of the antitumor response to a single antigen. In contrast, vaccines using whole tumor cells offer the opportunity to elicit immunity against the entire collection of antigens expressed by the tumor. Pulsed DC vaccination using apoptotic tumor cells or lysates has emerged as a popular strategy for immunization against tumors in a variety of preclinical and human studies. While killed tumor cells in the form of apoptotic bodies or freeze-thaw lysates alone display limited immunogenicity, DCs loaded with these preparations have been found to elicit antitumor immunity in a variety of preclinical models [13][14][15][16] and early clinical trials. [17][18][19][20][21] Other strategies using DCs to present the full repertoire of tumor antigens expressed by tumor cells include fusion with tumor cells 22 or pulsing with tumorderived RNA. 23 The goal of these approaches is to achieve processing and presentation of exogenous cell-derived antigenic peptides by professional antigen-presenting cells (ie, "crosspresentation"), thereby evoking a CD8 ϩ T-cell antitumor response. 24 One attractive strategy for increasing tumor antigen crosspresentation is the targeting of IgG-complexed antigens into DCs via Fc␥ receptors. 25 Antigen-antibody complexes internalized via Fc␥ receptors at the DC surface efficiently enter both the MHC class I 26-28 and class II 29,30 antigen-presentation pathways. Several investi...

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“…Although many mouse-specific antibodies are commercially available for IHC in frozen tissue, cryostat sections are inferior in quality when compared to paraffin sections. During the last 20 years, pathologists engaged in the pathology of mice have been making efforts to apply immunohistochemistry in the diagnosis of mouse hematopoietic diseases (Fredrickson et al, 1985(Fredrickson et al, ,1999Frith et al, 1993;Ward et al, 1993;Qi et al 1998Qi et al , 2000Sabourin et al, 2000;Morse et al, 2001;Eason et al, 2003;Lange et al, 2003;Utsuyama and Hirokawa, 2003;Canela et al, 2004;Huang et al, 2004;Miyakawa et al, 2004;Neeson and Paterson, 2004).…”

Section: Introductionmentioning

confidence: 99%

A Comprehensive Antibody Panel for Immunohistochemical Analysis of Formalin-Fixed, Paraffin-Embedded Hematopoietic Neoplasms of Mice: Analysis of Mouse Specific and Human Antibodies Cross-Reactive with Murine Tissue

et al. 2007

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Immunohistochemistry is an indispensable tool in human pathology enabling immunophenotypic characterization of tumor cells. Immunohistochemical analyses of mouse models of human hematopoietic neoplasias have become an important aspect for comparison of murine entities with their human counterparts. The aim of this study was to establish a diagnostic antibody panel for analysis of murine lymphomas/leukemias, useful in formalin-fixed/paraffin-embedded tissue. Overall, 48 antibodies (4 rabbit monoclonal, 12 rabbit polyclonal, 2 goat polyclonal, 11 rat, and 19 mouse monoclonal), which were either mouse-specific (14) or cross-reactive with murine tissue (34) were tested for staining quality and diagnostic value in 468 murine hematopoietic neoplasms. Specific staining was achieved with 29 antibodies, of which 18 were human antibodies cross-reactive with murine tissue. Only 23 (B220, BCL-2, BCL-6, CD117, CD138 (2×), CD3 (2×), CD43, CD45, CD5, CD79αcy, cyclin D1, Ki-67 (2×), Mac-3, Mac-2, lysozyme, mast cell tryptase, MPO, Pax-5, TdT, and TER-119) were regarded as valuable for diagnostic evaluation. Immunohistochemistry was also established in an automated immunostainer for high throughput analysis. The antibody panel developed is useful for the classification of murine lymphomas and leukemias analyzed, and a valuable tool for human and veterinary pathologists involved in the diagnostic interpretation of murine models of hematopoietic neoplasias.

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A new multi‐parameter flow cytometric assay for monitoring lymphoma growth and spread in a pre‐clinical murine model for human lymphoma

Cited by 7 publications

References 55 publications

Targeted delivery of interferon-alpha via fusion to anti-CD20 results in potent antitumor activity against B-cell lymphoma

Targeted delivery of interferon-alpha via fusion to anti-CD20 results in potent antitumor activity against B-cell lymphoma

Dendritic cells loaded with apoptotic antibody-coated tumor cells provide protective immunity against B-cell lymphoma in vivo

A Comprehensive Antibody Panel for Immunohistochemical Analysis of Formalin-Fixed, Paraffin-Embedded Hematopoietic Neoplasms of Mice: Analysis of Mouse Specific and Human Antibodies Cross-Reactive with Murine Tissue

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