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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    • "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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