Hodgkin lymphoma therapy with interleukin-4 receptor-directed cytotoxin in an infiltrating animal model

Laboratory of Molecular Tumor Biology, Division of Cellular and Gene Therapeutics, Center for Biologics Evaluation and Research, Food and Drug Administration, NIH Bldg 29B/2E08, Bethesda, MD 20892, USA.
Blood (Impact Factor: 10.45). 06/2005; 105(9):3707-13. DOI: 10.1182/blood-2004-08-3216
Source: PubMed


Hodgkin lymphoma represents unique clinicopathologic features because Hodgkin and Reed-Sternberg (H-RS) cells produce a variety of cytokines, express a variety of cytokine receptors, and are surrounded by numerous nonmalignant immunoreactive cells. We found that receptors for interleukin-4 (IL-4R) are highly expressed in H-RS cells. To target interleukin-4 receptor (IL-4R), we used a recombinant protein fusing circularly permuted human IL-4 and Pseudomonas exotoxin termed IL4(38-37)-PE38KDEL, or IL-4 cytotoxin. The cytotoxic effect of IL-4 cytotoxin on H-RS cell lines was determined to be moderate to high in vitro. We developed an infiltrating model of Hodgkin disease (HD) by injecting an adherent population of HD-MyZ cells subcutaneously into the flanks of beige/nude/X-linked immunodeficient mice. The animal model exhibited spontaneous metastasis of H-RS cells to lymph nodes and dissemination to vital organs, including the lungs. Intraperitoneal or intratumoral treatment of these mice with IL-4 cytotoxin resulted in regression of the primary tumor mass and a decrease in the incidence of lymph node metastasis. Mice injected with HD-MyZ cells demonstrated 203% prolonged survival (mean survival, 63 days) compared with control (mean survival, 31 days) when they received systemic IL-4 cytotoxin treatment. Because numerous H-RS cell lines express receptors for IL-4, IL-4 cytotoxin may be a unique agent for the treatment of Hodgkin lymphoma.

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Available from: Raj Puri, Oct 06, 2015
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    • "Furthermore, in HRS cells, activation of various signaling molecules such as Notch1, several tyrosine kinase receptors, the PI3K and MEK/ERK pathways, and the transcription factors NFjB, STAT, AP-1, ATF-5, ATBF1, p21SNFT besides the potential oncogenes, such as rhoC, L-myc, and PTP4A, have been implicated in the etiology of HL [7] [8]. As a whole, it has been proved that HL cells are derived from a compartment of germinal cancer B cells [9]. HL is a malignancy that involves immune system and weakens the immune responses. "
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    ABSTRACT: Hodgkin’s Lymphoma (HL) as a prevalent hematolymphoid malignancy begins in cells of immune system and is characterized by the specific histologic, clinical properties. Abnormality in apoptosis has been recognized as a crucial pathway in its progression. Nowadays, 35-40% of patients in stages III and IV show disease relapse or symptoms of refractory to first-line chemotherapy; therefore, novel treatment strategies are required. As apoptosis inducing is an important mechanism in cancer treatments, novel anticancer molecules to induce programmed cell death are required. The authors present a novel therapeutic approach for HL, with regard to anti-tumoral and immunomodulatory effects of the mda-7/IL-24. This gene, located in human chromosome 1q32-33, has shown tumor suppressor activity in various human malignant cells in, in vitro, in vivo, and even in clinical trial studies. Our hypothesis was designed to evaluate anti- tumoral effects of mda-7/IL-24 in SCID mice model using the adenovirus-based vector. mda-7/IL-24 interestingly has antiangiogenic, immunomodulatory, and bystander antitumoral activities. mda-7/IL-24 can suppress anti-apoptotic Bcl-2 family proteins, and induces GADD family, Bak, Bax, and other pro-apoptosis proteins. This hypothesis suggests that adenovirus vectors expressing mda-7/IL-24 may help for effective immunotherapies of HL.
    Iranian Journal of Medical Hypotheses and Ideas 05/2014; 9(1). DOI:10.1016/j.jmhi.2014.05.002
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    • "The binding of IL1R1 to its agonist activates NFKB, which is constitutively expressed in HL cells (Stylianou and Saklatvala 1998). IL4R has been found to be highly expressed in Hodgkin-Reed Sternberg cells and is being studied as a molecular target for drug development in HL (Kawakami, et al 2005). "
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    ABSTRACT: Familial aggregation, linkage and case-control studies support the role of germline genes in the aetiology of lymphoid malignancies. To further examine the role of genetic variation underlying susceptibility, we analysed 1536 single nucleotide polymorphisms in 152 genes involved in apoptosis, DNA repair, immune response and oxidative stress pathways among a unique sample of 165 unrelated familial cases including patients with chronic lymphocytic leukaemia (CLL), Waldenström macroglobulinaemia (WM) and Hodgkin lymphoma (HL), and 107 spouse controls. We confirmed previous studies showing a polymorphism in the IL10 promoter (rs1800890/-3575T>A) to be associated with non-Hodgkin lymphoma, as this allele was found to be associated with both CLL and WM. We also confirmed the role of IL6 variation to be associated with HL. Polymorphisms in TNFSF10 were associated with both CLL and WM. Future replication and functional studies are needed to clarify the role of these genetic variants. Finally, our data further support the close association of WM and CLL.
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    ABSTRACT: SV40 vectors packaged in vitro (pseudovirions) are an efficient delivery system for plasmids up to 17.7 kb, with or without SV40 sequences. A truncated Pseudomonas exotoxin gene (PE38) was delivered into various human cells (HeLa, KB-3-1, human lymphoblastoids, and erythroleukemia cells), in vitro using pseudovirions. The number of viable cells was reduced significantly in the PE38-transduced cells. Human KB adenocarcinomas growing in mice were treated with intratumoral injection of PE38 packaged in vitro, and tumor size decreased significantly. Intraperitoneal treatments were as effective in reducing tumor size as intratumoral treatments. To check the viability of mock- or PE38-treated mice, every 4 days they were weighed, their blood was tested, and various tissues were screened for pathology. All parameters showed that the in vitro-packaged vectors, injected into tumors or intraperitoneally, caused no abnormalities in mice. The combined treatment of doxorubicin with in vitro-packaged PE38 reduced tumor size slightly more than each of the treatments separately. However, the combined treatment did not cause the weight loss seen with doxorubicin alone. These results indicate that SV40 in vitro packaging is an effective system for cancer gene delivery using two different routes of injection and in combination with chemotherapy.
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