Hyper-interleukin-11 novel designer molecular adjuvant targeting gp130 for whole cell cancer vaccines

Background: Hyper-IL-11 (H11) is a fusion protein comprising IL-11 and soluble IL-11 receptor directly targeting gp130. We evaluated efficacy of H11 as a molecular adjuvant in therapeutic whole tumor cell vaccine formulation. Methods: H11 was tested in ectopic and orthotopic murine renal cell carcinoma (RENCA) models. H11 cDNA was transduced into RENCA cells (RENCA-H11). Mice were immunized with RENCA-H11 or control vaccine (RENCA-IRR) in prophylactic, adjuvant and therapeutic settings. Tumor formation, survival and immune mechanisms activated by H11 were studied. Results: Biologically active H11 was secreted by RENCA-H11 cells. Immunization with RENCA-H11 resulted in mounting specific anti-RENCA response. Treatment of tumor bearing mice in adjuvant setting prevented disease recurrence in therapeutic setting eradicated tumors. In induction phase H11 inhibited T-regulatory cell formation and activated recruitment and maturation of dendritic cells. Downstream of immunization tumors were densely infiltrated by CD8+, CD4+, NK cells, cells expressing CD8+CD69+ and CD4+CD62Llow. Conclusions: H11 is a good candidate for adjuvant of whole tumor cell vaccines. Direct targeting of gp130 leads to induction of specific and long lasting anticancer immune response. Enhancement of tumor antigen presentation, abrogation of immune tolerance, and activation of NK cells and generation of memory cells lead to eradication of existing tumors.

[1]  A. Mackiewicz,et al.  Gene-modified cellular vaccines: technologic aspects and clinical problems. , 2010, Transplantation proceedings.

[2]  P. Kantoff,et al.  Sipuleucel-T immunotherapy for castration-resistant prostate cancer. , 2010, The New England journal of medicine.

[3]  D. Speiser,et al.  Molecularly defined vaccines for cancer immunotherapy, and protective T cell immunity. , 2010, Seminars in immunology.

[4]  S. Reed,et al.  Adjuvants for cancer vaccines. , 2010, Seminars in immunology.

[5]  A. Mackiewicz,et al.  Immunotherapy of cancer and perspectives of its development , 2010 .

[6]  M. Smyth,et al.  Three agonist antibodies in combination with high-dose IL-2 eradicate orthotopic kidney cancer in mice , 2010, Journal of Translational Medicine.

[7]  M. Smyth,et al.  Multiple antitumor mechanisms downstream of prophylactic regulatory T-cell depletion. , 2010, Cancer research.

[8]  J. Malicki,et al.  Gene-modified tumor vaccine secreting a designer cytokine Hyper-Interleukin-6 is an effective therapy in mice bearing orthotopic renal cell cancer , 2010, Cancer Gene Therapy.

[9]  H. Tahara,et al.  Cytokine gene‐mediated immunotherapy: Current status and future perspectives , 2009, Cancer science.

[10]  K. Mills.  Designer adjuvants for enhancing the efficacy of infectious disease and cancer vaccines based on suppression of regulatory T cell induction. , 2009, Immunology letters.

[11]  A. Zlotta,et al.  Synergy Between Dendritic Cells and GM–CSF-secreting Tumor Cells for the Treatment of a Murine Renal Cell Carcinoma , 2009, Journal of immunotherapy.

[12]  H. Hammad,et al.  Mechanism of action of clinically approved adjuvants. , 2009, Current opinion in immunology.

[13]  A. Hauschild,et al.  Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial , 2008, The Lancet.

[14]  A. Mackiewicz,et al.  Interleukin 15 augments antitumor activity of cytokine gene-modified melanoma cell vaccines in a murine model. , 2008, Oncology reports.

[15]  L. Zitvogel,et al.  Regulatory T Cells Control Dendritic Cell/NK Cell Cross-Talk in Lymph Nodes at the Steady State by Inhibiting CD4+ Self-Reactive T Cells , 2008, The Journal of Immunology.

[16]  M. Neurath,et al.  Cutting Edge: Trans-Signaling via the Soluble IL-6R Abrogates the Induction of FoxP3 in Naive CD4+CD25− T Cells1 , 2007, The Journal of Immunology.

[17]  A. Mackiewicz,et al.  Clinical trials of active cancer immunotherapy , 2007, Expert opinion on investigational drugs.

[18]  C. Szczylik,et al.  Recent developments in renal cell cancer immunotherapy , 2007, Expert opinion on biological therapy.

[19]  Hao Wang,et al.  Recent developments in the use of adenoviruses and immunotoxins in cancer gene therapy , 2007, Cancer Gene Therapy.

[20]  J. Chabalgoity,et al.  The relevance of cytokines for development of protective immunity and rational design of vaccines. , 2007, Cytokine & growth factor reviews.

[21]  L. Zitvogel,et al.  The role of regulatory T cells in the control of natural killer cells: relevance during tumor progression , 2006, Immunological reviews.

[22]  W. Suchorska,et al.  Captopril, an Angiotensin-Converting Enzyme Inhibitor, Promotes Growth of Immunogenic Tumors in Mice , 2006, Clinical Cancer Research.

[23]  A. Mackiewicz,et al.  Effect of cyclophosphamide on tumorogenesis of the IL-6 and Hyper-IL-6 gene modified murine melanoma cells , 2004 .

[24]  W. Lehmacher,et al.  Adjuvant autologous renal tumour cell vaccine and risk of tumour progression in patients with renal-cell carcinoma after radical nephrectomy: phase III, randomised controlled trial , 2004, The Lancet.

[25]  J. Prieto,et al.  CD4+/CD25+ Regulatory Cells Inhibit Activation of Tumor-Primed CD4+ T Cells with IFN-γ-Dependent Antiangiogenic Activity, as well as Long-Lasting Tumor Immunity Elicited by Peptide Vaccination 1 , 2003, The Journal of Immunology.

[26]  W. Jongmans,et al.  Targeting of adenovirus to human renal cell carcinoma cells. , 2003, Urology.

[27]  S. Steinberg,et al.  Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[28]  P. Heinrich,et al.  Principles of interleukin (IL)-6-type cytokine signalling and its regulation. , 2003, The Biochemical journal.

[29]  Z. Xiang,et al.  A method that allows easy characterization of tumor-infiltrating lymphocytes. , 2001, Journal of immunological methods.

[30]  Sung-Soo Yoon,et al.  Behavior of Murine Renal Carcinoma Cells Grown in Ectopic or Orthotopic Sites in Syngeneic Mice , 2001, Tumor Biology.

[31]  P. Schirmacher,et al.  The designer cytokine hyper-IL-6 mediates growth inhibition and GM–CSF-dependent rejection of B16 melanoma cells , 2001, Oncogene.

[32]  S. Rose-John,et al.  The gp130-stimulating designer cytokine hyper-IL-6 promotes the expansion of human hematopoietic progenitor cells capable to differentiate into functional dendritic cells. , 2000, Experimental hematology.

[33]  B. Klein,et al.  Interleukin-6 receptor signaling. II. Bio-availability of interleukin-6 in serum. , 1999, European cytokine network.

[34]  P. Heinrich,et al.  A fusion protein of interleukin‐11 and soluble interleukin‐11 receptor acts as a superagonist on cells expressing gp130 , 1999, FEBS letters.

[35]  B. Chain,et al.  In vivo priming of T cells against cryptic determinants by dendritic cells exposed to interleukin 6 and native antigen. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[36]  P. Heinrich,et al.  Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. , 1998, The Biochemical journal.

[37]  C. Begley,et al.  Recombinant Soluble Interleukin-11 (IL-11) Receptor α-Chain Can Act as an IL-11 Antagonist , 1997 .

[38]  D. Williams,et al.  Interleukin-11: review of molecular, cell biology, and clinical use. , 1997, Blood.

[39]  S. Rose-John,et al.  A bioactive designer cytokine for human hematopoietic progenitor cell expansion , 1997, Nature Biotechnology.

[40]  D. Hilton,et al.  Complex of the soluble IL-11 receptor and IL-11 acts as IL-6-type cytokine in hepatic and nonhepatic cells. , 1996, Journal of immunology.

[41]  P. Heinrich,et al.  Complex of soluble human IL-6-receptor/IL-6 up-regulates expression of acute-phase proteins. , 1992, Journal of immunology.

[42]  C. Bucana,et al.  Orthotopic and ectopic organ environments differentially influence the sensitivity of murine colon carcinoma cells to doxorubicin and 5‐fluorouracil , 1992, International journal of cancer.

[43]  G QVIST,et al.  Spontaneous Regression of Cancer , 1963, British medical journal.

[44]  W. Murphy,et al.  Antigen specific memory T cells and their putative need for the generation of sustained anti-tumor responses. , 2010, Advances in experimental medicine and biology.

[45]  B. Baradaran,et al.  Target therapy of cancer: implementation of monoclonal antibodies and nanobodies. , 2009, Human antibodies.

[46]  Robert M. Hoffman,et al.  Orthotopic Metastatic Mouse Models for Anticancer Drug Discovery and Evaluation: a Bridge to the Clinic , 2004, Investigational New Drugs.

[47]  I. Melero,et al.  CD4 /CD25 Regulatory Cells Inhibit Activation of Tumor-Primed CD4 T Cells with IFN- -Dependent Antiangiogenic Activity, as well as Long-Lasting Tumor Immunity Elicited by Peptide Vaccination , 2003 .

[48]  A. Mackiewicz,et al.  IL-11 is a potent anti-melanoma factor. , 2001, Advances in experimental medicine and biology.

[49]  P. Murawa,et al.  Humoral responses to melanoma vaccine, genetically modified with interleukin 6 and soluble interleukin 6 receptor. , 2001, Advances in experimental medicine and biology.

[50]  C. Begley,et al.  Recombinant soluble interleukin-11 (IL-11) receptor alpha-chain can act as an IL-11 antagonist. , 1997, Blood.

[51]  Everson Tc,et al.  Spontaneous regression of cancer. , 1967, Progress in clinical cancer.