Subcutaneous interleukin-4 (IL-4) for relapsed and resistant non-Hodgkin lymphoma: A phase II trial in the North Central Cancer Treatment Group, NCCTG 91-78-51

Interleukin-4 (IL-4), a pleiotropic cytokine, has in vitro activity against non-Hodgkin lymphoma (NHL). This phase II study was conducted to learn the efficacy and toxicity of IL-4 in patients with NHL. Patients with relapsed or refractory indolent or aggressive NHL were eligible to receive 2.5 or 5.0 mcg/kg of subcutaneous IL-4 for 28 days of a 42-day cycle. Patients with response and acceptable toxicity after two cycles were eligible to continue treatment for six cycles. The target overall response rate (ORR) was 20%. Forty-one patients were enrolled and assessable for toxicity; two were ineligible after histology review. The ORR was 13% (5/39) with one complete and four partial responses. All responders were treated with 5.0 mcg/kg; the median time to progression was 84 days, the median duration of response for responders was 8.3 months. The most common toxicities of any grade in all patients were edema (66%), malaise (56%), and elevated liver function tests (56%). Grade 3 and 4 toxicities were more common at 5.0 mcg/kg, leading to a reduction in the starting dose. Although the study observed anti-tumor activity with IL-4, the ORR goal of the study was not achieved. Agents that target the IL-4 receptor can potentially benefit patients with NHL; however, alternative schedules using IL-4 in shorter duration and in combination with other agents would be required to overcome toxicities observed in this study.

[1]  G. Saglio,et al.  Molecular pathogenesis of diffuse large B-cell lymphoma , 2009 .

[2]  Xiaocheng Wu,et al.  Annual report to the nation on the status of cancer, 1975–2003, featuring cancer among U.S. Hispanic/Latino populations , 2006, Cancer.

[3]  M. Schiller,et al.  Interleukin‐4 supports interleukin‐12‐induced proliferation and interferon‐γ secretion in human activated lymphoblasts and T helper type 1 cells , 2006, Immunology.

[4]  Randy D Gascoyne,et al.  Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[5]  S. Galli,et al.  Interleukin‐4‐triggered, STAT6‐dependent production of a factor that induces mouse mast cell apoptosis , 2006, European journal of immunology.

[6]  L. Ricci-Vitiani,et al.  Autocrine production of interleukin-4 and interleukin-10 is required for survival and growth of thyroid cancer cells. , 2006, Cancer research.

[7]  I. Soubeyran,et al.  Aggressive non-Hodgkin's lymphoma: Concomitant evaluation of interleukin-2, soluble interleukin-2 receptor, interleukin-4, interleukin-6, interleukin-10 and correlation with outcome , 2006, Leukemia & lymphoma.

[8]  R. Puri,et al.  A recombinant IL-4-Pseudomonas exotoxin inhibits protein synthesis and overcomes apoptosis resistance in human CLL B cells. , 2005, Leukemia research.

[9]  Ash A. Alizadeh,et al.  Distinct IL-4-induced gene expression, proliferation, and intracellular signaling in germinal center B-cell-like and activated B-cell-like diffuse large-cell lymphomas. , 2005, Blood.

[10]  R. Marcus,et al.  CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. , 2005, Blood.

[11]  I. Lossos,et al.  IL-4 Affects Proliferation, Chemosensitivity-and Rituximab Sensitivity of Germinal Center B-Cell like (GCB) and Activated B-Cell like (ABC) Diffuse Large B-Cell Lymphoma Differently. , 2004 .

[12]  Yusuke Nakamura,et al.  Identification of the interleukin 4 receptor alpha gene as a direct target for p73. , 2003, Cancer research.

[13]  Robert Tibshirani,et al.  HGAL is a novel interleukin-4-inducible gene that strongly predicts survival in diffuse large B-cell lymphoma. , 2003, Blood.

[14]  B. E. C. Oiffier,et al.  CHOP Chemotherapy plus Rituximab Compared with CHOP Alone in Elderly Patients with Diffuse Large-B-Cell Lymphoma , 2002 .

[15]  I. Pastan,et al.  IL-4 receptors on human medulloblastoma tumours serve as a sensitive target for a circular permuted IL-4-Pseudomonas exotoxin fusion protein , 2002, British Journal of Cancer.

[16]  J. Bertoglio,et al.  Induction of the IL-13 receptor α2-chain by IL-4 and IL-13 in human keratinocytes: involvement of STAT6, ERK and p38 MAPK pathways , 2001, Oncogene.

[17]  H M Rosenberg,et al.  Annual report to the nation on the status of cancer (1973 through 1998), featuring cancers with recent increasing trends. , 2001, Journal of the National Cancer Institute.

[18]  R. Fisher,et al.  Phase II evaluation of interleukin-4 in patients with non-Hodgkin's lymphoma: a Southwest Oncology Group Trial , 2000, Anti-cancer drugs.

[19]  P. Rothman,et al.  IL-4/IL-13 signaling beyond JAK/STAT. , 2000, The Journal of allergy and clinical immunology.

[20]  I. Pastan,et al.  Interleukin-4 receptor-directed cytotoxin therapy of AIDS-associated Kaposi's sarcoma tumors in xenograft model , 1999, Nature Medicine.

[21]  J. Ritz,et al.  The functional synergy between IL-12 and IL-2 involves p38 mitogen-activated protein kinase and is associated with the augmentation of STAT serine phosphorylation. , 1999, Journal of immunology.

[22]  J. Gustafsson,et al.  Extracellular signal-regulated kinase (ERK) interacts with signal transducer and activator of transcription (STAT) 5a. , 1999, Molecular endocrinology.

[23]  A. Al-Shami,et al.  Granulocyte-Macrophage Colony-stimulating Factor-activated Signaling Pathways in Human Neutrophils , 1999, The Journal of Biological Chemistry.

[24]  D. Yee,et al.  Interleukin 4 inhibits growth and induces apoptosis in human breast cancer cells. , 1998, Cancer research.

[25]  R. Puri,et al.  Interleukin-13 Receptor α′ But Not α Chain: A Functional Component of Interleukin-4 Receptors , 1998 .

[26]  D. Yee,et al.  Insulin Receptor Substrate-1 is the Predominant Signaling Molecule Activated by Insulin-like Growth Factor-I, Insulin, and Interleukin-4 in Estrogen Receptor-positive Human Breast Cancer Cells* , 1998, The Journal of Biological Chemistry.

[27]  M. Kaplan,et al.  Stat Proteins Control Lymphocyte Proliferation by Regulating p27Kip1 Expression , 1998, Molecular and Cellular Biology.

[28]  B. Ryffel,et al.  Growth inhibition signalled through the interleukin-4/interleukin-13 receptor complex is associated with tyrosine phosphorylation of insulin receptor substrate-1. , 1996, The Biochemical journal.

[29]  E. Thiel,et al.  Antiproliferative effect of human interleukin-4 in human cancer cell lines: studies on the mechanism. , 1995, Leukemia & lymphoma.

[30]  S. Narula,et al.  Interleukin 4 retards dissemination of a human B-cell lymphoma in severe combined immunodeficient mice. , 1995, Cancer research.

[31]  E. Thiel,et al.  Recombinant human interleukin 4 has antiproliferative activity on human tumor cell lines derived from epithelial and nonepithelial histologies. , 1995, Cancer research.

[32]  R. Puri,et al.  Receptor for Interleukin 13 , 1995, The Journal of Biological Chemistry.

[33]  B. Ryffel,et al.  Growth inhibition of human colorectal‐carcinoma cells by interleukin‐4 and expression of functional interleukin‐4 receptors , 1994, International journal of cancer.

[34]  F. Behm,et al.  Interleukin-4 induces programmed cell death (apoptosis) in cases of high-risk acute lymphoblastic leukemia. , 1994, Blood.

[35]  J. Rossi,et al.  Antiproliferative effects of interleukin-4 on freshly isolated non-Hodgkin malignant B-lymphoma cells. , 1992, Blood.

[36]  M. Toi,et al.  Inhibition of colon and breast carcinoma cell growth by interleukin-4. , 1992, Cancer research.

[37]  P. Leder,et al.  Murine interleukin-4 displays potent anti-tumor activity in vivo , 1989, Cell.

[38]  S. Rosenberg,et al.  Interleukin 4 (B cell stimulatory factor 1) can mediate the induction of lymphokine-activated killer cell activity directed against fresh tumor cells , 1987, The Journal of experimental medicine.

[39]  W. Paul,et al.  B cell stimulatory factor-1 (interleukin 4) activates macrophages for increased tumoricidal activity and expression of Ia antigens. , 1987, Journal of immunology.

[40]  D. Yee,et al.  STAT6 mediates interleukin-4 growth inhibition in human breast cancer cells. , 2002, Neoplasia.

[41]  Pierre Morel,et al.  CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. , 2002, The New England journal of medicine.

[42]  R. Puri,et al.  Overexpressed cell surface interleukin-4 receptor molecules can be successfully targeted for antitumor cytotoxin therapy. , 2001, Critical reviews in immunology.

[43]  W. Paul,et al.  The IL-4 receptor: signaling mechanisms and biologic functions. , 1999, Annual review of immunology.

[44]  R. Puri,et al.  Interleukin-13 receptor alpha' but not alpha chain: a functional component of interleukin-4 receptors. , 1998, Blood.

[45]  W. Leonard,et al.  Sharing of a common gamma chain, gamma c, by the IL-2, IL-4, and IL-7 receptors: implications for X-linked severe combined immunodeficiency (XSCID). , 1994, Advances in experimental medicine and biology.

[46]  G. Haas,et al.  Expression of high affinity interleukin-4 receptors on human renal cell carcinoma cells and inhibition of tumor cell growth in vitro by interleukin-4. , 1993, The Journal of clinical investigation.

[47]  T. Grogan,et al.  Effects of interleukin-4 on the in vitro growth of human lymphoid and plasma cell neoplasms. , 1990, Blood.