Abstract
Despite novel targeted agents, prognosis of metastatic renal cell cancer (RCC) remains poor, and experimental therapeutic strategies are warranted. Transfection of tumor cells with co-stimulatory molecules and/or cytokines is able to increase immunogenicity. Therefore, in our clinical study, 10 human leukocyte antigen (HLA)-A*0201+ patients with histologically-confirmed progressive metastatic clear cell RCC were immunized repetitively over 22 weeks with 2.5–40 × 106 interleukin (IL)-7/CD80 cotransfected allogeneic HLA-A*0201+ tumor cells (RCC26/IL-7/CD80). Endpoints of the study were feasibility, safety, immunological and clinical responses. Vaccination was feasible and safe. In all, 50% of the patients showed stable disease throughout the study; the median time to progression was 18 weeks. However, vaccination with allogeneic RCC26/IL-7/CD80 tumor cells was not able to induce TH1-polarized immune responses. A TH2 cytokine profile with increasing amounts of antigen-specific IL-10 secretion was observed in most of the responding patients. Interferon-γ secretion by patient lymphocytes upon antigen-specific and non-specific stimulation was substantially impaired, both before and during vaccination, as compared with healthy controls. This is possibly due to profound tumor-induced immunosuppression, which may prevent induction of antitumor immune responses by the gene-modified vaccine. Vaccination in minimal residual disease with concurrent depletion of regulatory cells might be one strategy to overcome this limitation.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Mocellin S, Mandruzzato S, Bronte V, Lise M, Nitti D . Part I: vaccines for solid tumors. Lancet Oncol 2004; 5: 681–689.
De Gruijl TD, van den Eertwegh AJM, Pinedo HM, Scheper RJ . Whole-cell cancer vaccination: from autologous to allogeneic tumor- and dendritic cell-based vaccines. Cancer Immunol Immunother 2008; 57: 1569–1577.
Fournier P, Schirrmacher V . Randomized clinical studies of anti-tumor vaccination: state of the art in 2008. Exper rev Vaccines 2009; 8: 51–66.
Sobol RE . The rationale for prophylactic cancer vaccines and need for a paradigm shift. Cancer Gene Ther 2006; 13: 725–731.
Finn OJ . Cancer vaccines: between the idea and the reality. Nat Rev Immunol 2003; 3: 630–641.
Mach N, Dranoff G . Cytokine-secreting tumor cell vaccines. Curr Opin Immunol 2000; 12: 571–575.
Pardoll DM . Cancer vaccines. Nat Med 1998; 4: 525–531.
Blankenstein T, Cayeux S, Qin Z . Genetic approaches to cancer immunotherapy. Rev Physiol Biochem Pharmacol 1996; 129: 3–49.
Dranoff G, Jaffee E, Lazenby A, Golumbek P, Levitsky H, Brose K et al. Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Nat Acad Sci USA 1993; 90: 3539–3543.
Soiffer R, Hodi FS, Haluska F, Jung K, Gillessen S, Singer S et al. Vaccination with irradiated, autologous melanoma cells engineered to secrete human granulocyte-macrophage colony-stimulating factor by adenoviral-mediated gene transfer augments antitumor immunity in patients with metastatic melanoma. J Clin Oncol 2003; 21: 3343–3350.
Soiffer R, Lynch T, Mihm M, Jung K, Rhuda C, Schmollinger JC et al. Vaccination with irradiated autologous melanoma cells engineered to secrete human granulocyte-macrophage colony-stimulating factor generates potent antitumor immunity in patients with metastatic melanoma. Proc Nat Acad Sci USA 1998; 95: 13141–13146.
Gansbacher B, Zier K, Daniels B, Cronin K, Bannerji R, Gilboa E . Interleukin-2 gene transfer into tumor cells abrogates tumorigenicity and induces protective immunity. J Exp Med 1990; 172: 1217–1224.
Cayeux S, Beck C, Aicher A, Dörken B, Blankenstein T . Tumor cells cotransfected with interleukin-7 and B7.1 genes induce CD25 and CD28 on tumor-infiltrating T lymphocytes and are strong vaccines. Eur J Immunol 1995; 25: 2325–2331.
Schendel DJ, Gansbacher B, Oberneder R, Kriegmair M, Hofstetter A, Riethmüller G et al. Tumor-specific lysis of human renal cell carcinomas by tumor-infiltrating lymphocytes. I. HLA-A2-restricted recognition of autologous and allogeneic tumor lines. J Immunol 1993; 151: 4209–4220.
Pohla H, Frankenberger B, Stadlbauer B, Oberneder R, Hofstetter A, Willimsky G et al. Allogeneic vaccination for renal cell carcinoma: development and monitoring. Bone Marrow Transplant 2000; 25 (Suppl 2): S83–S87.
Frankenberger B, Pohla H, Noessner E, Willimsky G, Papier B, Pezzutto A et al. Influence of CD80, interleukin-2, and interleukin-7 expression in human renal cell carcinoma on the expansion, function, and survival of tumor-specific CTLs. Clin Cancer Res 2005; 11: 1733–1742.
Shen L, Rock KL . Priming of T cells by exogenous antigen cross-presented on MHC class I molecules. Curr Opin Immunol 2006; 18: 85–91.
Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M . Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol 2002; 20: 289–296.
Buchner A, Pohla H, Willimsky G, Frankenberger B, Frank R, Baur-Melnyk A et al. Phase I trial of an allogeneic gene-modified tumor cell vaccine (RCC-26/CD80/IL-2) in patients with metastatic renal cell carcinoma. Hum Gene Ther 2010; 21: 285–297.
Schendel DJ, Frankenberger B, Jantzer P, Cayeux S, Nöbetaner E, Willimsky G et al. Expression of B7.1 (CD80) in a renal cell carcinoma line allows expansion of tumor-associated cytotoxic T lymphocytes in the presence of an alloresponse. Gene Ther 2000; 7: 2007–2014.
Frankenberger B, Regn S, Geiger C, Noessner E, Falk CS, Pohla H et al. Cell-based vaccines for renal cell carcinoma:genetically-engineered tumor cells and monocyte-derived dendritic cells. World J Urol 2005; 23: 166–174.
Motzer RJ, Mazumdar M, Bacik J, Berg W, Amsterdam A, Ferrara J . Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol 1999; 17: 2530–2540.
Frankenberger B, Noessner E, Schendel DJ . Immune suppression in renal cell carcinoma. Semin Cancer Biol 2007; 17: 330–343.
Kang SM, Beverly B, Tran AC, Brorson K, Schwartz RH, Lenardo MJ . Transactivation by AP-1 is a molecular target of T cell clonal anergy. Science 1992; 257: 1134–1138.
Dols A, Smith JW, Meijer SL, Fox BA, Hu HM, Walker E et al. Vaccination of women with metastatic breast cancer, using a costimulatory gene (CD80)-modified, HLA-A2-matched, allogeneic, breast cancer cell line: clinical and immunological results. Hum Gene Ther 2003; 14: 1117–1123.
Michael A, Ball G, Quatan N, Wushishi F, Russell N, Whelan J et al. Delayed disease progression after allogeneic cell vaccination in hormone-resistant prostate cancer and correlation with immunologic variables. Clin Cancer Res 2005; 11: 4469–4478.
Hege KM, Jooss K, Pardoll D . GM-CSF gene-modified cancer cell immunotherapies: of mice and men. Int Rev Immunol 2006; 25: 321–352.
Barrio MM, de Motta PT, Kaplan J, von Euw EM, Bravo AI, Chacón RD et al. A phase I study of an allogeneic cell vaccine (VACCIMEL) with GM-CSF in melanoma patients. J Immunother 2006; 29: 444–454.
Brill TH, Kübler HR, Pohle H, Buchner A, Fend F, Schuster T et al. Therapeutic vaccination with an interleukin-2-interferon-g-secreting allogeneic tumor vaccine in patients with progressive castration-resistant prostate cancer: a phase I/II trial. Hum Gene Ther 2009; 20: 1641–1651.
Simons JW, Jaffee EM, Weber CE, Levitsky HI, Nelson WG, Carducci MA et al. Bioactivity of autologous irradiated renal cell carcinoma vaccines generated by ex vivo granulocyte-macrophage colony-stimulating factor gene transfer. Cancer Res 1997; 57: 1537–1546.
Zhou X, Jun DY, Thomas AM, Huang X, Huang LQ, Mautner J et al. Diverse CD8+ T-cell responses to renal cell carcinoma antigens in patients treated with an autologous granulocyte-macrophage colony-stimulating factor gene-transduced renal tumor cell vaccine. Cancer Res 2005; 65: 1079–1088.
Antonia SJ, Seigne J, Diaz J, Muro-Cacho C, Extermann M, Farmelo MJ et al. Phase I trial of a B7-1 (CD80) gene modified autologous tumor cell vaccine in combination with systemic interleukin-2 in patients with metastatic renal cell carcinoma. J Urol 2002; 167: 1995–2000.
Fishman M, Hunter TB, Soliman H, Thompson P, Dunn M, Smilee R et al. Phase II trial of a B7-1 (CD86) transduced autologous tumor cell vaccine plus subcutaneous interleukin-2 for treatment of stage IV renal cell carcinoma. J Immunother 2008; 31: 72–80.
Willimsky G, Blankenstein T . Sporadic immunogenic tumours avoid destruction by inducing T-cell tolerance. Nature 2005; 437: 141–146.
Willimsky G, Blankenstein T . The adaptive immune response to sporadic cancer. Immunol Rev 2007; 220: 102–112.
Bronte V, Mocellin S . Suppressive influences in the immune response to cancer. J Immunother 2009; 32: 1–11.
Casana GC, De Raffele G, Cohen S, Moroziewicz D, Mitcham J, Stoutenburg J et al. Characterization of CD4+CD25+ regulatory T cells in patients treated with high-dose interleukin-2 for metastatic melanoma or renal cell carcinoma. J Clin Oncol 2006; 24: 1169–1177.
Zhou W . Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev Cancer 2005; 5: 263–274.
Schuster SJ, Neelapu SS, Gause BL, Muggia FM, Gockerman JP, Sotomayor EM et al. Idiotype vaccine therapy (BiovaxID) in follicular lymphoma in first complete remission: Phase III clinical trial results. J Clin Oncol 2009; 27 (Suppl): 5s.
Kantoff PW, Schuetz T, Blumenstein BA, Glode MM, Bilhartz D, Wyand M et al. Overall survival (OS) analysis of a phase II randomized controlled trial of a poxviral-based PSA targeted immunotherapy in metastatic castration-resistant prostate cancer. J Clin Oncol 2009; 28: 1099–1105.
Schwartzentruber DJ, Lawson D, Richards J, Conry RM, Miller D, Triesman J et al. A phase III multi-institutional randomized study of immunization with the gp100:209-217(210M) peptide followed by high-dose IL-2 compared with high-dose IL-2 alone in patients with metastatic melanoma. J Clin Oncol 2009; 27 (Suppl): 463s.
Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92: 205–216.
Schmitz M, Diestelkoetter P, Weigle B, Schmachtenberg F, Stevanovic S, Ockert D et al. Generation of survivin-specific CD8+ T effector cells by dendritic cells pulsed with protein or selected peptides. Cancer Res 2000; 60: 4845–4849.
Otto K, Andersen MH, Eggert A, Keikavoussi P, Pedersen LØ, Rath JC et al. Lack of toxicity of therapy-induced T cell responses against the universal tumour antigen survivin. Vaccine 2005; 23: 884–889.
Sadovnikova E, Jopling LA, Soo KS, Stauss HJ . Generation of human tumor-reactive cytotoxic T cells against peptides presented by non-self HLA class I molecules. Eur J Immunol 1998; 28: 193–200.
Weinschenk T, Gouttefangeas C, Schirle M, Obermayr F, Walter S, Schoor O et al. Integrated functional genomics approach for the design of patient- individual antitumor vaccines. Cancer Res 2002; 62: 5818–5827.
Brill TH, Kubler HR, van Randenborgh H, Fend F, Pohla H, Breul J et al. Allogeneic retrovirally transduced, IL-2- and IFN-gamma-secreting cancer cell vaccine in patients with hormone refractory prostate cancer--a phase I clinical trial. J Gene Med 2007; 9: 547–560.
Yotnda P, Firat H, Garcia-Pons F, Garcia Z, Gourru G, Vernant JP et al. Cytotoxic T cell response against the chimeric p210 BCR-ABL protein in patients with chronic myelogenous leukemia. J Clin Invest 1998; 101: 2290–2296.
Lukowsky A . Clonality analysis by T-cell receptor gamma PCR and high-resolution electrophoresis in the diagnosis of cutaneous T-cell lymphoma (CTCL). Methods Mol Biol 2003; 218: 303–320.
Van Dongen JJ, Langerak AW, Brüggemann M, Evans PA, Hummel M, Lavender FL et al. Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98-3936. Leukemia 2003; 17: 2257–2317.
Wieczorek G, Asemissen A, Model F, Turbachova I, Floess S, Liebenberg V et al. Quantitative DNA methylation analysis of FOXP3 as a new method for counting regulatory T cells in peripheral blood and solid tissue. Cancer Res 2009; 69: 599–608.
Acknowledgements
This work was supported by grants from the Federal Ministry of Education and Research (01 GE 9624/1) to TB and DJS, German Research Foundation (SFB-455, SFB-650) and Helmholtz-Association for Immunotherapy of Cancer.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Westermann, J., Flörcken, A., Willimsky, G. et al. Allogeneic gene-modified tumor cells (RCC-26/IL-7/CD80) as a vaccine in patients with metastatic renal cell cancer: a clinical phase-I study. Gene Ther 18, 354–363 (2011). https://doi.org/10.1038/gt.2010.143
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/gt.2010.143