Cancer Immunology, Immunotherapy

, Volume 63, Issue 12, pp 1329–1340 | Cite as

Sequential immune monitoring in patients with melanoma and renal cell carcinoma treated with high-dose interleukin-2: immune patterns and correlation with outcome

  • David M. Foureau
  • Asim Amin
  • Richard L. White
  • William Anderson
  • Chase P. Jones
  • Terry Sarantou
  • Iain H. McKillop
  • Jonathan C. Salo
Original Article

Abstract

Interleukin-2 (IL-2) therapy leads to clinically relevant responses in 10–16 % of patients with metastatic melanoma (MMEL) or 10–30 % of patients with metastatic renal cell carcinoma (MRCC). To date, no biomarkers have been validated to identify patients who are likely to respond. We hypothesized that changes in T cell subset distribution in patients undergoing IL-2 therapy may correlate with treatment outcomes. Immune profiles of 64 patients (27-MMEL, 37-MRCC) were evaluated using flow cytometry at baseline, during (≥three doses) and at the end of treatment cycle (30 ± 6 h after last dose), through two courses of IL-2 therapy. Changes in distribution and phenotype of circulating CD4 and CD8 lymphocyte subsets were compared (1) based on cancer types and (2) intra-patient during the course of the IL-2 therapy. Exploratory analysis of immunologic profiles was also performed based on treatment outcome. Independent of cancer type, IL-2 led to a transient decrease of circulating effector lymphocytes, while regulatory T cells gradually increased. Interleukin-2 differentially affected a subset of CD8 T cell expressing Foxp3, depending on malignancy type. In MMEL patients, IL-2 gradually expanded circulating CD8 Foxp3+ cells; in MRCC patients, IL-2 transiently increased expression of CD103 and CCR4 homing markers. Monitoring of adaptive immune variables early on and during the course of IL-2 therapy revealed transient alterations in immune profiles, specific to MMEL and MRCC patients, related to immune balance (and ultimately response to IL-2 therapy) or T cell egress from the circulation.

Keywords

Melanoma Renal cell carcinoma Interleukin-2 Immune monitoring Biomarkers 

Abbreviations

CR

Complete response

Foxp3

Forkhead box P3

GEE

Generalized estimating equations

IL-2

Interleukin-2

LDH

Lactate dehydrogenase

MIATA

Minimal information about T cell assay

MMEL

Metastatic melanoma

MR

Minor response

MRCC

Metastatic renal cell carcinoma

PBMC

Peripheral mononuclear cells

PD

Progressive disease

PR

Partial response

RECIST

Response evaluation criteria in solid tumor

RT

Room temperature

SD

Stable disease

Treg

Regulatory T cell

ULN

Upper limit of normal

Supplementary material

262_2014_1605_MOESM1_ESM.pdf (418 kb)
Supplementary material 1 (PDF 417 kb)

References

  1. 1.
    Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, Sznol M, Parkinson D, Hawkins M, Paradise C, Kunkel L, Rosenberg SA (1999) High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 17(7):2105–2116PubMedGoogle Scholar
  2. 2.
    Riker AI, Radfar S, Liu S, Wang Y, Khong HT (2007) Immunotherapy of melanoma: a critical review of current concepts and future strategies. Expert Opin Biol Ther 7(3):345–358. doi:10.1517/14712598.7.3.345 PubMedCrossRefGoogle Scholar
  3. 3.
    Rosenberg SA, Lotze MT, Muul LM, Chang AE, Avis FP, Leitman S, Linehan WM, Robertson CN, Lee RE, Rubin JT et al (1987) 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. N Engl J Med 316(15):889–897. doi:10.1056/NEJM198704093161501 PubMedCrossRefGoogle Scholar
  4. 4.
    Sun M, Lughezzani G, Perrotte P, Karakiewicz PI (2010) Treatment of metastatic renal cell carcinoma. Nat Rev Urol 7(6):327–338. doi:10.1038/nrurol.2010.57 PubMedCrossRefGoogle Scholar
  5. 5.
    Ma A, Koka R, Burkett P (2006) Diverse functions of IL-2, IL-15, and IL-7 in lymphoid homeostasis. Annu Rev Immunol 24:657–679. doi:10.1146/annurev.immunol.24.021605.090727 PubMedCrossRefGoogle Scholar
  6. 6.
    Boyman O, Sprent J (2012) The role of interleukin-2 during homeostasis and activation of the immune system. Nat Rev Immunol 12(3):180–190. doi:10.1038/nri3156 PubMedGoogle Scholar
  7. 7.
    Foureau DM, McKillop IH, Jones CP, Amin A, White RL, Salo JC (2011) Skin tumor responsiveness to interleukin-2 treatment and CD8 Foxp3+ T cell expansion in an immunocompetent mouse model. Cancer Immunol Immunother 60(9):1347–1356. doi:10.1007/s00262-011-1035-1 PubMedCrossRefGoogle Scholar
  8. 8.
    Garibal J, Laforge M, Silvestre R, Mouhamad S, Campillo-Gimenez L, Levy Y, Estaquier J (2012) IL-2 immunotherapy in chronically SIV-infected Rhesus macaques. Virol J 9:220. doi:10.1186/1743-422X-9-220 PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Sparano JA, Fisher RI, Sunderland M, Margolin K, Ernest ML, Sznol M, Atkins MB, Dutcher JP, Micetich KC, Weiss GR et al (1993) Randomized phase III trial of treatment with high-dose interleukin-2 either alone or in combination with interferon alfa-2a in patients with advanced melanoma. J Clin Oncol 11(10):1969–1977PubMedGoogle Scholar
  10. 10.
    Curran SD, Muellner AU, Schwartz LH (2006) Imaging response assessment in oncology. Cancer Imaging 6:S126–S130. doi:10.1102/1470-7330.2006.9039 PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Kirkwood JM, Tarhini AA (2009) Biomarkers of therapeutic response in melanoma and renal cell carcinoma: potential inroads to improved immunotherapy. J Clin Oncol 27(16):2583–2585. doi:10.1200/JCO.2008.21.1540 PubMedCrossRefGoogle Scholar
  12. 12.
    McDermott DF, Regan MM, Atkins MB (2006) Interleukin-2 therapy of metastatic renal cell carcinoma: update of phase III trials. Clin Genitourin Cancer 5(2):114–119. doi:10.3816/CGC.2006.n.027 PubMedCrossRefGoogle Scholar
  13. 13.
    Petrella T, Quirt I, Verma S, Haynes AE, Charette M, Bak K (2007) Single-agent interleukin-2 in the treatment of metastatic melanoma. Curr Oncol 14(1):21–26PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    White RL Jr, Amin A (2011) Cancer immunotherapy. Surg Oncol Clin N Am 20(3):531–554, ix. doi:10.1016/j.soc.2011.01.010
  15. 15.
    Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (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(3):205–216PubMedCrossRefGoogle Scholar
  16. 16.
    Janetzki S, Britten CM, Kalos M, Levitsky HI, Maecker HT, Melief CJ, Old LJ, Romero P, Hoos A, Davis MM (2009) “MIATA”-minimal information about T cell assays. Immunity 31(4):527–528. doi:10.1016/j.immuni.2009.09.007 PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Kmieciak M, Gowda M, Graham L, Godder K, Bear HD, Marincola FM, Manjili MH (2009) Human T cells express CD25 and Foxp3 upon activation and exhibit effector/memory phenotypes without any regulatory/suppressor function. J Transl Med 7:89. doi:10.1186/1479-5876-7-89 PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Khattak M, Fisher R, Turajlic S, Larkin J (2013) Targeted therapy and immunotherapy in advanced melanoma: an evolving paradigm. Ther Adv Med Oncol 5(2):105–118. doi:10.1177/1758834012466280 PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Friedlander P, Hodi FS (2010) Advances in targeted therapy for melanoma. Clin Adv Hematol Oncol 8(9):619–627PubMedGoogle Scholar
  20. 20.
    Eisen T, Sternberg CN, Robert C, Mulders P, Pyle L, Zbinden S, Izzedine H, Escudier B (2012) Targeted therapies for renal cell carcinoma: review of adverse event management strategies. J Natl Cancer Inst 104(2):93–113. doi:10.1093/jnci/djr511 PubMedCrossRefGoogle Scholar
  21. 21.
    Cunningham-Rundles C, Bodian C, Ochs HD, Martin S, Reiter-Wong M, Zhuo Z (2001) Long-term low-dose IL-2 enhances immune function in common variable immunodeficiency. Clin Immunol 100(2):181–190. doi:10.1006/clim.2001.5052 PubMedCrossRefGoogle Scholar
  22. 22.
    Smith-Garvin JE, Koretzky GA, Jordan MS (2009) T cell activation. Annu Rev Immunol 27:591–619. doi:10.1146/annurev.immunol.021908.132706 PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY (2005) A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol 6(11):1142–1151. doi:10.1038/ni1263 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • David M. Foureau
    • 1
  • Asim Amin
    • 2
  • Richard L. White
    • 1
    • 2
  • William Anderson
    • 3
  • Chase P. Jones
    • 1
  • Terry Sarantou
    • 1
    • 2
  • Iain H. McKillop
    • 1
  • Jonathan C. Salo
    • 1
    • 2
  1. 1.Department of General SurgeryCarolinas Healthcare SystemCharlotteUSA
  2. 2.Levine Cancer InstituteCarolinas Healthcare SystemCharlotteUSA
  3. 3.Dickson Advanced Analytic GroupCarolinas Healthcare SystemCharlotteUSA

Personalised recommendations