Pilot study of subcutaneous recombinant human interleukin 12 in metastatic melanoma.

The aim of this study was to evaluate the safety profile of s.c. administered recombinant human interleukin 12 (rHuIL-12). Pharmacokinetics and pharmacodynamics of rHuIL-12 and any evidence of antitumor effect were also considered. Ten pretreated patients with progressive metastatic melanoma were enrolled in this pilot study. Patients received a fixed dose of rHuIL-12 (0.5 microgram/kg) for two identical 28-day cycles, with injections given on days 1, 8, and 15 of each cycle. In case of any evidence of response or disease stabilization, the treatment was continued for two further 28-day cycles. Toxicity mainly consisted of a flu-like syndrome. Transient increases in transaminasemia (6 of 10 patients) and triglyceridemia (8 of 10 patients) were observed. Peak serum IL-12 levels were reached 8-12 h after the first injection in all patients; no serum IL-12 was detectable in 6 of 9 evaluable patients after the last injection of the second cycle. No antibody response to rHuIL-12 could be detected in any of the patients. A marked, transient reduction in circulating CD8+ and CD16+ lymphocytes and neutrophils was observed after the first administration and high levels of serum IFN-gamma and IL-10 were detected in all patients within 24-48 h. Tumor shrinkage, not reaching partial or complete remission, involved the regression of s.c. nodules (2 of 3 patients), superficial adenopathies (1 of 3 patients), and hepatic metastases (1 of 3 patients); regressions were detected after the first cycle of treatment and were maintained in spite of progression at different sites. s.c. rHuIL-12 treatment was well tolerated and had marked effects on immune parameters and potential antitumor activity.

[1]  M. Atkins,et al.  Phase I evaluation of intravenous recombinant human interleukin 12 in patients with advanced malignancies. , 1997, Clinical cancer research : an official journal of the American Association for Cancer Research.

[2]  J. Kirkwood,et al.  Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. , 1996, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  M. Colombo,et al.  Immunotherapy of experimental metastases by vaccination with interleukin gene-transduced adenocarcinoma cells sharing tumor-associated antigens. Comparison between IL-12 and IL-2 gene-transduced tumor cell vaccines. , 1996, Journal of immunology.

[4]  A. Wellstein,et al.  Melanoma angiogenesis and metastasis modulated by ribozyme targeting of the secreted growth factor pleiotrophin. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[5]  H. Yang,et al.  A functional interleukin 12 receptor complex is composed of two beta-type cytokine receptor subunits. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[6]  H. Bear,et al.  Biologic therapy of melanoma with cytokines and lymphocytes. , 1996, Seminars in surgical oncology.

[7]  G S Kansas,et al.  Selectins and their ligands: current concepts and controversies. , 1996, Blood.

[8]  R. Gelber,et al.  Quality-of-life-adjusted survival analysis of interferon alfa-2b adjuvant treatment of high-risk resected cutaneous melanoma: an Eastern Cooperative Oncology Group study. , 1996, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  M. Vora,et al.  Interleukin-10 induces E-selectin on small and large blood vessel endothelial cells , 1996, The Journal of experimental medicine.

[10]  D. E. Anderson,et al.  IL-12 induces human T cells secreting IL-10 with IFN-gamma. , 1996, Journal of immunology.

[11]  M. Lotze,et al.  Systemic administration of cellular IL-10 induces an effective, specific, and long-lived immune response against established tumors in mice. , 1996, Journal of immunology.

[12]  H. Fujiwara,et al.  Molecular mechanisms underlying IFN-γ-mediated tumor growth inhibition induced during tumor growth inhibition induced during tumor immunotherapy with rIL-12 , 1996 .

[13]  L. Zitvogel,et al.  Interleukin‐12 and B7.1 co‐stimulation cooperate in the induction of effective antitumor immunity and therapy of established tumors , 1996, European journal of immunology.

[14]  M. Colombo,et al.  Amount of interleukin 12 available at the tumor site is critical for tumor regression. , 1996, Cancer research.

[15]  S. Jabłońska,et al.  Interleukin-12 inhibits angiogenesis induced by human tumor cell lines in vivo. , 1996, The Journal of investigative dermatology.

[16]  K. Takeda,et al.  Liver NK1.1+ CD4+ alpha beta T cells activated by IL-12 as a major effector in inhibition of experimental tumor metastasis. , 1996, Journal of immunology.

[17]  A. Kopf,et al.  The incidence of malignant melanoma in the United States: issues as we approach the 21st century. , 1996, Journal of the American Academy of Dermatology.

[18]  F. Miedema,et al.  IL-12-induced IL-10 production by human T cells as a negative feedback for IL-12-induced immune responses. , 1996, Journal of immunology.

[19]  D. Taub,et al.  Human interferon-inducible protein-10 induces mononuclear cell infiltration in mice and promotes the migration of human T lymphocytes into the peripheral tissues and human peripheral blood lymphocytes-SCID mice. , 1996, Blood.

[20]  H. Fujiwara,et al.  Molecular mechanisms underlying IFN-gamma-mediated tumor growth inhibition induced during tumor immunotherapy with rIL-12. , 1996, International immunology.

[21]  E. Manseau,et al.  Expression of vascular permeability factor/vascular endothelial growth factor by melanoma cells increases tumor growth, angiogenesis, and experimental metastasis. , 1996, Cancer research.

[22]  G. Parmiani,et al.  Analysis of TCR usage in human tumors: a new tool for assessing tumor-specific immune responses. , 1995, Immunology today.

[23]  H. Fujiwara,et al.  Administration of recombinant interleukin 12 prevents outgrowth of tumor cells metastasizing spontaneously to lung and lymph nodes. , 1995, Cancer research.

[24]  Y. Koh,et al.  Memory T lymphocytes' adherence to interferon gamma-activated human dermal microvascular endothelial cells via E-selectin. , 1995, Journal of dermatological science.

[25]  H. Fujiwara,et al.  Systemic administration of rIL-12 induces complete tumor regression and protective immunity: response is correlated with a striking reversal of suppressed IFN-gamma production by anti-tumor T cells. , 1995, International immunology.

[26]  D. Taub,et al.  Human Interferon-inducible Protein 10 Is a Potent Inhibitor of Angiogenesis in Vivo , 1995 .

[27]  J. Renauld,et al.  Genes Coding for Tumor Antigens Recognized by Cytolytic T Lymphocytes , 1995, Immunological reviews.

[28]  R. D'Amato,et al.  Inhibition of angiogenesis in vivo by interleukin 12. , 1995, Journal of the National Cancer Institute.

[29]  Judith E. Cartwright,et al.  The expression and release of adhesion molecules by human endothelial cell lines and their consequent binding of lymphocytes. , 1995, Experimental cell research.

[30]  M. Gately,et al.  Biologic effects of recombinant human interleukin-12 in squirrel monkeys (Sciureus saimiri). , 1994, Laboratory investigation; a journal of technical methods and pathology.

[31]  P. Allavena,et al.  Interleukin-12 is chemotactic for natural killer cells and stimulates their interaction with vascular endothelium. , 1994, Blood.

[32]  R. Schreiber,et al.  Recombinant IL-12 administration induces tumor regression in association with IFN-gamma production. , 1994, Journal of immunology.

[33]  S. Rosenberg,et al.  Treatment of patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and interleukin 2. , 1994, Journal of the National Cancer Institute.

[34]  P. Queirolo,et al.  Multicenter randomized trial of dacarbazine alone or in combination with two different doses and schedules of interferon alfa-2a in the treatment of advanced melanoma. , 1994, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[35]  D. Carvajal,et al.  Administration of recombinant IL-12 to normal mice enhances cytolytic lymphocyte activity and induces production of IFN-gamma in vivo. , 1994, International immunology.

[36]  L. Luistro,et al.  Antitumor and antimetastatic activity of interleukin 12 against murine tumors , 1993, The Journal of experimental medicine.

[37]  P. Scott.  IL-12: initiation cytokine for cell-mediated immunity. , 1993, Science.

[38]  M. Gately,et al.  IL-12 receptor. II. Distribution and regulation of receptor expression. , 1992, Journal of immunology.

[39]  C. la Vecchia,et al.  The epidemiology of cutaneous malignant melanoma: aetiology and European data. , 1991, European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation.

[40]  Ina Ruck,et al.  USA , 1969, The Lancet.

[41]  W. M. Linehan,et al.  A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. , 1987, The New England journal of medicine.

[42]  C. Nathan,et al.  Phase I trial of recombinant interferon gamma in cancer patients. , 1986, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.