scholarly journals Effective therapy for a murine model of human anaplastic large-cell lymphoma with the anti-CD30 monoclonal antibody, HeFi-1, does not require activating Fc receptors

Blood ◽  
2006 ◽  
Vol 108 (2) ◽  
pp. 705-710 ◽  
Author(s):  
Meili Zhang ◽  
Zhengsheng Yao ◽  
Zhuo Zhang ◽  
Kayhan Garmestani ◽  
Carolyn K. Goldman ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Murine Model ◽  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Tumor Growth Inhibition ◽  
Wild Type ◽  
Large Cell Lymphoma

CD30 is a member of the tumor necrosis factor receptor family. Overexpression of CD30 on some neoplasms versus its limited expression on normal tissues makes this receptor a promising target for antibody-based therapy. Anaplastic large-cell lymphoma (ALCL) represents a heterogeneous group of aggressive non-Hodgkin lymphomas characterized by the strong expression of CD30. We investigated the therapeutic efficacy of HeFi-1, a mouse IgG1 monoclonal antibody, which recognizes the ligand-binding site on CD30, and humanized anti-Tac antibody (daclizumab), which recognizes CD25, in a murine model of human ALCL. The ALCL model was established by intravenous injection of karpas299 cells into nonobese diabetic/severe combined immuno-deficient (SCID/NOD) wild-type or SCID/NOD Fc receptor common γ chain–deficient (FcRγ–/–) mice. HeFi-1, given at a dose of 100 μg weekly for 4 weeks, significantly prolonged survival of the ALCL-bearing SCID/NOD wild-type and SCID/NOD FcRγ–/– mice (P < .01) as compared with the control groups. In vitro studies showed that HeFi-1 inhibited the proliferation of karpas299 cells, whereas daclizumab did not inhibit cell proliferation. We demonstrated that the expression of FcRγ on polymorphonuclear leukocytes and monocytes was not required for HeFi-1–mediated tumor growth inhibition in vivo, although it was required for daclizumab.

scholarly journals Synergistic Drug Combinations Prevent Resistance in ALK+ Anaplastic Large Cell Lymphoma

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4422
Author(s):  
Giulia Arosio ◽  
Geeta G. Sharma ◽  
Matteo Villa ◽  
Mario Mauri ◽  
Ilaria Crespiatico ◽  
...  
Keyword(s):  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Drug Combinations ◽  
Tumor Growth Inhibition ◽  
Anaplastic Lymphoma ◽  
Alk Inhibitor ◽  
Large Cell Lymphoma

Anaplastic lymphoma kinase-positive (ALK+) anaplastic large-cell lymphoma (ALCL) is a subtype of non-Hodgkin lymphoma characterized by expression of the oncogenic NPM/ALK fusion protein. When resistant or relapsed to front-line chemotherapy, ALK+ ALCL prognosis is very poor. In these patients, the ALK inhibitor crizotinib achieves high response rates, however 30–40% of them develop further resistance to crizotinib monotherapy, indicating that new therapeutic approaches are needed in this population. We here investigated the efficacy of upfront rational drug combinations to prevent the rise of resistant ALCL, in vitro and in vivo. Different combinations of crizotinib with CHOP chemotherapy, decitabine and trametinib, or with second-generation ALK inhibitors, were investigated. We found that in most cases combined treatments completely suppressed the emergence of resistant cells and were more effective than single drugs in the long-term control of lymphoma cells expansion, by inducing deeper inhibition of oncogenic signaling and higher rates of apoptosis. Combinations showed strong synergism in different ALK-dependent cell lines and better tumor growth inhibition in mice. We propose that drug combinations that include an ALK inhibitor should be considered for first-line treatments in ALK+ ALCL.

scholarly journals Super-enhancer-based identification of a BATF3/IL-2R−module reveals vulnerabilities in anaplastic large cell lymphoma

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Huan-Chang Liang ◽  
Mariantonia Costanza ◽  
Nicole Prutsch ◽  
Mark W. Zimmerman ◽  
Elisabeth Gurnhofer ◽  
...  
Keyword(s):  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
Breast Implant ◽  
Large Cell ◽  
Antibody Drug Conjugate ◽  
Anaplastic Lymphoma ◽  
Super Enhancer ◽  
Large Cell Lymphoma

AbstractAnaplastic large cell lymphoma (ALCL), an aggressive CD30-positive T-cell lymphoma, comprises systemic anaplastic lymphoma kinase (ALK)-positive, and ALK-negative, primary cutaneous and breast implant-associated ALCL. Prognosis of some ALCL subgroups is still unsatisfactory, and already in second line effective treatment options are lacking. To identify genes defining ALCL cell state and dependencies, we here characterize super-enhancer regions by genome-wide H3K27ac ChIP-seq. In addition to known ALCL key regulators, the AP-1-member BATF3 and IL-2 receptor (IL2R)-components are among the top hits. Specific and high-level IL2R expression in ALCL correlates with BATF3 expression. Confirming a regulatory link, IL-2R-expression decreases following BATF3 knockout, and BATF3 is recruited to IL2R regulatory regions. Functionally, IL-2, IL-15 and Neo-2/15, a hyper-stable IL-2/IL-15 mimic, accelerate ALCL growth and activate STAT1, STAT5 and ERK1/2. In line, strong IL-2Rα-expression in ALCL patients is linked to more aggressive clinical presentation. Finally, an IL-2Rα-targeting antibody-drug conjugate efficiently kills ALCL cells in vitro and in vivo. Our results highlight the importance of the BATF3/IL-2R-module for ALCL biology and identify IL-2Rα-targeting as a promising treatment strategy for ALCL.

scholarly journals Pathobiology of ALK+ anaplastic large-cell lymphoma

Blood ◽  
2007 ◽  
Vol 110 (7) ◽  
pp. 2259-2267 ◽  
Author(s):  
Hesham M. Amin ◽  
Raymond Lai
Keyword(s):  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
Clinical Manifestations ◽  
Large Cell ◽  
Experimental Models ◽  
Lymphoid Cells ◽  
Anaplastic Lymphoma ◽  
Large Cell Lymphoma

Anaplastic large-cell lymphoma (ALCL) was initially recognized on the basis of morphologic features and the consistent expression of CD30. It then became evident that the majority of these tumors are derived from lymphoid cells of T or null immunophenotype. The subsequent finding that t(2;5)(p23;q35) occurs in 40% to 60% of ALCL patients established a distinct clinicopathologic entity. This chromosomal translocation induces the formation of the chimeric protein nucleophosmin–anaplastic lymphoma kinase (NPM-ALK), which possesses significant oncogenic potential resulting from the constitutive activation of the tyrosine kinase ALK. In addition to its specific pathophysiologic events, NPM-ALK–expressing lymphoma presents with consistent clinical manifestations. Only 13 years after the identification of NPM-ALK, tremendous progress has been made in our understanding of this molecule because of the relentless efforts of multiple investigators who have dissected its biologic roles using in vitro and in vivo experimental models. Several upstream modulators, cross-reacting oncogenes, and downstream effectors of NPM-ALK have been identified and characterized. Understanding these interacting oncogenic systems is expected to facilitate the design of new therapeutic strategies and agents. In this review, we briefly discuss ALCL and focus on NPM-ALK.

Cytogenetic characteristics of a murine in vitro model for the human anaplastic large cell lymphoma (ALCL)

2006 ◽  
Vol 114 (3-4) ◽  
pp. 292-295 ◽  
Author(s):  
C. Rudolph ◽  
C. Bittner ◽  
A.C. Feller ◽  
H. Merz ◽  
B. Schlegelberger
Keyword(s):  
Anaplastic Large Cell Lymphoma ◽  
In Vitro Model ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Large Cell Lymphoma ◽  
Vitro Model

scholarly journals The ALK inhibitor ASP3026 eradicates NPM-ALK+ T-cell anaplastic large-cell lymphoma in vitro and in a systemic xenograft lymphoma model

Oncotarget ◽  
2014 ◽  
Vol 5 (14) ◽  
pp. 5750-5763 ◽  
Author(s):  
Suraj Konnath George ◽  
Deeksha Vishwamitra ◽  
Roxsan Manshouri ◽  
Ping Shi ◽  
Hesham M. Amin
Keyword(s):  
T Cell ◽  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Alk Inhibitor ◽  
Large Cell Lymphoma

SGN-30 (Anti-CD30 Monoclonal Antibody) Is Active and Well Tolerated in Patients with Refractory or Recurrent Systemic Anaplastic Large Cell Lymphoma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2637-2637 ◽  
Author(s):  
Andres Forero-Torres ◽  
Steven Bernstein ◽  
Ajay Gopal ◽  
Francine Foss ◽  
John Leonard ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Chest Wall ◽  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large Cell ◽  
In Vivo Models ◽  
Early Results ◽  
Large Cell Lymphoma

Abstract SGN-30 is a chimeric mAb which recognizes the CD30 antigen found on tumor cells from patients (pts) with Hodgkin’s disease (HD) and anaplastic large cell lymphoma (ALCL). In preclinical experiments, SGN-30 was shown to have antitumor activity in both in vitro and in vivo models of HD and ALCL. The results of a multi-dose phase I study showed minimal toxicity associated with doses of 2–12 mg/kg as six weekly IV infusions. One complete response (CR) was seen in the three non-Hodgkin’s lymphoma patients (2 ALCL, 1 diffuse large B-cell lymphoma) accrued to the study and two patients demonstrated stable disease (SD) over time. A phase II multi-dose study was initiated to further evaluate the safety, antitumor activity and pharmacokinetics of six weekly IV infusions of 6 mg/kg of SGN-30 in pts with relapsed or refractory HD or systemic ALCL (sALCL). Five patients (2M, 3F) with ALCL have been enrolled, with a median age of 52 (range 33–75) and 3 median prior therapies (range 2–5). Multiple doses of SGN-30 have been well tolerated in all of the pts. Drug-related adverse events have been typically mild and consistent with mAb administration. No drug-related grade 3/4 events have been observed. Two patients have had objective responses with one patient achieving a CR. The patient’s baseline CT scan showed a 5.1 x 2.0 cm chest wall mass in the lower left anterior lateral chest wall representing local lymphoma recurrence. After six doses of SGN-30 the mass disappeared completely with some edema in the chest wall but no obvious residual mass. The duration of response is pending at this time, and it will be presented in the meeting. Another patient experienced a partial response. The patient, who entered the study with constitutional symptoms and extensive cutaneous and nodal disease, had resolution of all skin lesions, significant reduction in adenopathy and improvement in constitutional symptoms after completion of her SGN-30 therapy. The patient progressed after discontinuation of therapy. Of the other three patients, one had SD and two progressed. These early results are promising and accrual to the trial continues.

miR-135b mediates NPM-ALK–driven oncogenicity and renders IL-17–producing immunophenotype to anaplastic large cell lymphoma

Blood ◽  
2011 ◽  
Vol 118 (26) ◽  
pp. 6881-6892 ◽  
Author(s):  
Hironori Matsuyama ◽  
Hiroshi I. Suzuki ◽  
Hikaru Nishimori ◽  
Masaaki Noguchi ◽  
Takashi Yao ◽  
...  
Keyword(s):  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Jurkat Cells ◽  
Unique Contribution ◽  
Anaplastic Lymphoma ◽  
Transformed Lymphoma ◽  
Immune Phenotypes ◽  
Large Cell Lymphoma

Abstract Many transformed lymphoma cells show immune-phenotypes resembling the corresponding normal lymphocytes; thus, they provide a guide for proper diagnosis and present promising routes to improve their pathophysiologic understanding and to identify novel therapeutic targets. However, the underlying molecular mechanism(s) of these aberrant immune-phenotypes is largely unknown. Here, we report that microRNA-135b (miR-135b) mediates nucleophosmin-anaplastic lymphoma kinase (NPM-ALK)–driven oncogenicity and empowers IL-17–producing immunophenotype in anaplastic large cell lymphoma (ALCL). NPM-ALK oncogene strongly promoted the expression of miR-135b and its host gene LEMD1 through activation of signal transducer and activator of transcription (STAT) 3. In turn, elevated miR-135b targeted FOXO1 in ALCL cells. miR-135b introduction also decreased chemosensitivity in Jurkat cells, suggesting its contribution to oncogenic activities of NPM-ALK. Interestingly, miR-135b suppressed T-helper (Th) 2 master regulators STAT6 and GATA3, and miR-135b blockade attenuated IL-17 production and paracrine inflammatory response by ALCL cells, indicating that miR-135b–mediated Th2 suppression may lead to the skewing to ALCL immunophenotype overlapping with Th17 cells. Furthermore, antisense-based miR-135b inhibition reduced tumor angiogenesis and growth in vivo, demonstrating significance of this “Th17 mimic” pathway as a therapeutic target. These results collectively illuminated unique contribution of oncogenic kinase-linked microRNA to tumorigenesis through modulation of tumor immune-phenotype and microenvironment.

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