Skip to main content
Log in

Dose-finding/phase II trial: bevacizumab, immunotherapy, and chemotherapy (BIC) in metastatic renal cell cancer (mRCC). Antitumor effects and variations of circulating T regulatory cells (Treg)

  • Original Research
  • Published:
Targeted Oncology Aims and scope Submit manuscript

Abstract

The aim of this study was to explore the efficacy and toxicities of a combined regimen of bevacizumab plus immunotherapy and chemotherapy (BIC) and the circulating T regulatory cells (Treg) in metastatic renal cell cancer (mRCC). Nephrectomized mRCC patients were enrolled into a multicenter single-arm dose-finding study with five escalated dose levels of chemotherapy with intravenous gemcitabine and 5-fluorouracil associated with fixed intravenous doses of bevacizumab, subcutaneous low doses of interleukin-2, and interferon-α-2a. An expanded cohort (phase II study) was treated at the recommended dose for additional safety and efficacy information according to minimax Simon two-stage design. Blood samples for Treg were collected and evaluated by fluorescence-activated cell sorting (FACS) analysis on cycle 1. Fifty-one patients were entered to receive one of five dose levels. Median age was 58 years (male 67 %, pretreated 49 %): 15 patients were low risk according to Memorial Sloan-Kettering Cancer Center (MSKCC) criteria, while 27 and nine were respectively intermediate- and high-risk patients. More frequent grade 3 and 4 toxicities included nonfebrile neutropenia, thrombocytopenia, and fever. Among patients evaluable for response (49), 29.5 % had partial response and 37 % stable disease. Overall median time to progression and median overall survival were 8.8 and 22.67 months, respectively. We observed a rapid increase in the percentage of Treg after immunotherapy and a reduction after bevacizumab only in patient who obtained a partial response or stable disease. The BIC was feasible, well tolerated, and shown interesting activity. Further studies are needed to explore if Treg could have a role in clinical response in mRCC treated with bevacizumab.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Lilleby W, Fossa SD (2005) Chemotherapy in metastatic renal cell cancer. World J Urol 23:175–179

    Article  CAS  PubMed  Google Scholar 

  2. Amato RJ (2005) Renal cell carcinoma: review of novel single-agent therapeutics and combination regimens. Ann Oncol 16(7–1516):7–15

    Article  CAS  PubMed  Google Scholar 

  3. Buti S, Brighenti M, Bongiovanni C et al (2007) Role of chemotherapy with gemcitabine plus 5-fluorouracil and chemoimmunotherapy in metastatic renal cell cancer. J Immunother 30:780–786

    Article  CAS  PubMed  Google Scholar 

  4. Buzaid AC, Todd MB (1989) Therapeutic options in renal cell carcinoma. Semin Oncol 16(1):12–19

    CAS  PubMed  Google Scholar 

  5. Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307:58–62

    Article  CAS  PubMed  Google Scholar 

  6. Motl S (2005) Bevacizumab in combination chemotherapy for colorectal and other cancers. Am J Health Syst Pharm 62:1021–1032

    CAS  PubMed  Google Scholar 

  7. Buti S, Lazzarelli S, Chiesa MD et al (2010) Dose-finding trial of a combined regimen with Bevacizumab, immunotherapy, and chemotherapy in patients with metastatic renal cell cancer: an Italian oncology group for clinical research (GOIRC) study. J Immunother 33(7):735–741

    Article  CAS  PubMed  Google Scholar 

  8. Aoyamaa A, Klarina D, Yamadaa Y et al. Low-dose IL-2 for in vivo expansion of CD4+ and CD8+ regulatory T cells in nonhuman primates. American Journal of Transplantation Brief Communication doi: 10.1111/j.1600-6143.2012.04133.x

  9. Rowe JH, Ertelt JM, Way SS (2012) Foxp3+ regulatory T cells, immune stimulation and host defence against infection. Immunology 136(1):1–10

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Xia Liu, Xun Xu, Xin Lin et al. PTD-hFOXP3 protein acts as an immune regulator to convert human CD4+CD25- T cells to regulatory T-like cells. Journal of cellular biochemistry. doi:10.1002/jcb.24255

  11. Liu VC, Wong LY, Jang T et al (2007) Tumor evasion of the immune system by converting CD4+CD25- T cells into CD4+CD25+ T regulatory cells: role of tumor-derived TGF-beta. J immunol 1 178(5):2883–2892

    Article  CAS  Google Scholar 

  12. Therasse P, Arbuck SG, Eisenhauer EA et al (2000) 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 92:205–216

    Article  CAS  PubMed  Google Scholar 

  13. NCI Common Terminology Criteria for Adverse Events v3.0 (CTCAE) Publish Date: December 12, 2003. http://ctep.cancer.gov/reporting/ctc.html.

  14. Motzer RJ, Mazumdar M, Bacik J et al (1999) Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol 17(8):2530–2540

    CAS  PubMed  Google Scholar 

  15. Motzer RJ, Hutson TE, Tomczak P et al (2007) Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356:115–124

    Article  CAS  PubMed  Google Scholar 

  16. Escudier B, Eisen T, Stadlre WM et al (2007) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356:125–134

    Article  CAS  PubMed  Google Scholar 

  17. Escudier B, Pluzanska A, Koralewski P et al (2007) Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 370:2103–2111

    Article  PubMed  Google Scholar 

  18. Rini BI, Halabi S, Rosenberg JE et al (2008) Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol 26:5422–5428

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Sternberg CN, Davis ID, Mardiak J et al (2010) Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 28:1061–1068

    Article  CAS  PubMed  Google Scholar 

  20. Rini B, Escudier B, Tomczak P et al (2011) Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomized phase 3 trial. Lancet 2011 378(9807):1931–1939. doi:10.1016/S0140-6736(11)61613-9

    CAS  Google Scholar 

  21. Hudes G, Carducci M, Tomczak P et al (2007) Temsirolimus, interferon alfa, or both for advanced renal cell carcinoma. N Engl J Med 356:2271–2281

    Article  CAS  PubMed  Google Scholar 

  22. Motzer RJ, Escudier B, Oudard S et al (2008) Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-cont rolled phase III trial. Lancet 372:449–456

    Article  CAS  PubMed  Google Scholar 

  23. Motzer RJ, Hutson TE, Tomczak P et al (2009) Overall survival and updated results for sunitinib compared with interferon alpha in patients with metastatic renal cell carcinoma. J Clin Oncol 27(22):3584–3590

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Dandamudi UB, Ghebremichael M, Sosman JA et al (2013) A phase II study of Bevacizumab and high-dose interleukin-2 in patients with metastatic renal cell carcinoma: a cytokine working group (CWG) study. J Immunother 36(9):490–495. doi:10.1097/CJI.0000000000000003

    Article  CAS  PubMed  Google Scholar 

  25. Cameron RB, McIntosh JK, Rosenberg SA (1988) Synergic antitumor effects of combination immunotherapy with recombinant interleukin-2 and a recombinant hybrid alpha-interferon in the treatment of established murine hepatic metastases. Cancer Res 48:5810–5817

    CAS  PubMed  Google Scholar 

  26. Rini BI, Weinberg V, Small EJ (2005) A phase I trial of fixed dose rate gemcitabine and capecitabine in metastatic renal cell carcinoma. Cancer 103:553–558

    Article  CAS  PubMed  Google Scholar 

  27. Tannir NM, Thall PF, Ng CS et al (2008) A phase II trial of gemcitabine plus capecitabine for metastatic renal cell cancer previously treated with immunotherapy and targeted agents. J Urol 180:867–872

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Soga N, Yamada Y, Nishikawa K et al (2009) Gemcitabine and capecitabine chemotherapy in Japanese patients with immunotherapy-resistant renal cell carcinoma. Int J Urol 16:576–579

    Article  CAS  PubMed  Google Scholar 

  29. Buti S, Bersanelli M, Sikokis A et al (2013) Chemotherapy in metastatic renal cell carcinoma today? A systemic review. Anti-Cancer Drugs 24(6):535–554. doi:10.1097/CAD.0b013e3283609ec1

    CAS  PubMed  Google Scholar 

  30. Stadler WM (1995) Low-dose interleukin-2 in the treatment of metastatic renal-cell carcinoma. Semin Oncol 22:67–73

    CAS  PubMed  Google Scholar 

  31. Vogelzang NJ, Lipton A, Figlin RA (1993) Subcutaneous interleukin-2 plus interferon alfa-2a in metastatic renal cancer: an outpatient multicenter trial. J Clin Oncol 11:1809–1816

    CAS  PubMed  Google Scholar 

  32. Tempero M, Plunkett W, Ruiz Van Haperen VW et al (2003) Randomized phase II comparison of dose-intense gemcitabine: thirty-minute infusion and fixed dose rate infusion in patients with pancreatic adenocarcinoma. J Clin Oncol 21:3402–3408

    Article  CAS  PubMed  Google Scholar 

  33. Ahmadzadeh M, Rosenberg SA (2006) IL-2 administration increases CD4+CD25highFOXP3+ regulatory T cells in cancer patients. Blood 107:2409–2414

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Guangxian Liu, Wuwei Yang, Mei Guo et al. Effective modulation of CD4+CD25+high regulatory T and NK cells in malignant patients by combination of interferon-a and interleukin-2. Cancer Immunol Immunother doi 10.1007/s00262-012-1297-2

  35. Sanarico N, Ciamarella A, Sacchi A et al (2006) Human monocyte-derived dendritic-cells differentiated in the presence of IL-2 produce proinflammatory cytokines and prime Th1 immune response. J Leukoc Biol 80:555–562

    Article  CAS  PubMed  Google Scholar 

  36. Yamazaki S, Steinman RM (2009) Dendritic cells as controllers of antigen-specific Foxp3+ regulatory T cells. J Dermatol Sci 54:69–75

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Sabbatino M, Kim-Schulze S, Panelli MC et al (2009) Serum vascular endothelial growth factor and fibronectin predict clinical response to high-dose interleukin-2 therapy. JCO 27:2645–2652

    Article  Google Scholar 

Download references

Acknowledgments

The study was sponsored by the Italian Oncology Group for Clinical Research (GOIRC), with a financial support by the Roche.

Conflict of interest

The authors have declared no conflicts of interest.

Author information

Authors and Affiliations

Authors

Consortia

Corresponding author

Correspondence to M. Donini.

Additional information

From the GOIRC (Italian Oncology Group for Clinical Research)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Donini, M., Buti, S., Lazzarelli, S. et al. Dose-finding/phase II trial: bevacizumab, immunotherapy, and chemotherapy (BIC) in metastatic renal cell cancer (mRCC). Antitumor effects and variations of circulating T regulatory cells (Treg). Targ Oncol 10, 277–286 (2015). https://doi.org/10.1007/s11523-014-0337-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11523-014-0337-6

Keywords

Navigation