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Programmed Death 1 Pathway inhibition in Metastatic Renal Cell Cancer and Prostate Cancer

  • Evolving Therapies (RM Bukowski, Section Editor)
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Abstract

Programmed death 1 (PD-1) is a T cell co-inhibitory receptor with two ligands, PD-L1 and PD-L2. In cancer, this pathway plays a major role in immune resistance in the tumor environment. Blockade of this pathway can enhance antitumor immune responses. This review discusses the preclinical rationale for PD-1 pathway inhibition in advanced renal cell carcinoma and prostate cancer, in addition to the clinical activity and toxicity of the anti-PD-L1 antibody BMS-936559, as well as anti-PD-1 antibodies MK-3475 and BMS-936558.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Drake CG, Jaffee E, Pardoll DM. Mechanisms of immune evasion by tumors. Adv Immunol. 2006;90:51–81. doi:10.1016/S0065-2776(06)90002-9.

    Article  PubMed  CAS  Google Scholar 

  2. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480(7378):480–9. doi:10.1038/nature10673.

    Article  PubMed  CAS  Google Scholar 

  3. Mizoguchi H, O'Shea JJ, Longo DL, Loeffler CM, McVicar DW, Ochoa AC. Alterations in signal transduction molecules in T lymphocytes from tumor-bearing mice. Science. 1992;258(5089):1795–8.

    Article  PubMed  CAS  Google Scholar 

  4. Topalian SL, Weiner GJ, Pardoll DM. Cancer immunotherapy comes of age. J Clin Oncol. 2011;29(36):4828–36. doi:10.1200/JCO.2011.38.0899.

    Article  PubMed  CAS  Google Scholar 

  5. • Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–64. doi:10.1038/nrc3239. This is an excellent review explaining the basic science of immune checkpoints and the implications for cancer immunotherapy.

    Article  PubMed  CAS  Google Scholar 

  6. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23. doi:10.1056/NEJMoa1003466.

    Article  PubMed  CAS  Google Scholar 

  7. Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364(26):2517–26. doi:10.1056/NEJMoa1104621.

    Article  PubMed  CAS  Google Scholar 

  8. Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity. 1999;11(2):141–51.

    Article  PubMed  CAS  Google Scholar 

  9. Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol. 2007;19(7):813–24. doi:10.1093/intimm/dxm057.

    Article  PubMed  CAS  Google Scholar 

  10. Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med. 1999;5(12):1365–9. doi:10.1038/70932.

    Article  PubMed  CAS  Google Scholar 

  11. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192(7):1027–34.

    Article  PubMed  CAS  Google Scholar 

  12. Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2(3):261–8. doi:10.1038/85330.

    Article  PubMed  CAS  Google Scholar 

  13. Tseng SY, Otsuji M, Gorski K, Huang X, Slansky JE, Pai SI, et al. B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells. J Exp Med. 2001;193(7):839–46.

    Article  PubMed  CAS  Google Scholar 

  14. Curiel TJ, Wei S, Dong H, Alvarez X, Cheng P, Mottram P, et al. Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat Med. 2003;9(5):562–7. doi:10.1038/nm863.

    Article  PubMed  CAS  Google Scholar 

  15. Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A. 2002;99(19):12293–7. doi:10.1073/pnas.192461099.

    Article  PubMed  CAS  Google Scholar 

  16. Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol. 2008;8(6):467–77. doi:10.1038/nri2326.

    Article  PubMed  CAS  Google Scholar 

  17. • Brahmer JR, Tykodi SS, Chow LQM, Hwu W-J, Topalian SL, Hwu P, et al. Safety and activity of Anti–PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–65. doi:10.1056/NEJMoa1200694. This article reviews the clinical activity and toxicity of anti-PD-L1 antibody BMS-936559 in patients with advanced solid tumors.

    Article  PubMed  CAS  Google Scholar 

  18. • Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–54. doi:10.1056/NEJMoa1200690. This article reviews the clinical activity and toxicity of anti-PD1 antibody BMS-936558 in patients with advanced solid tumors.

    Article  PubMed  CAS  Google Scholar 

  19. Terme M, Ullrich E, Aymeric L, Meinhardt K, Desbois M, Delahaye N, et al. IL-18 induces PD-1-dependent immunosuppression in cancer. Cancer Res. 2011;71(16):5393–9. doi:10.1158/0008-5472.CAN-11-0993.

    Article  PubMed  CAS  Google Scholar 

  20. Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 1992;11(11):3887–95.

    PubMed  CAS  Google Scholar 

  21. Blank C, Brown I, Peterson AC, Spiotto M, Iwai Y, Honjo T, et al. PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer Res. 2004;64(3):1140–5.

    Article  PubMed  CAS  Google Scholar 

  22. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8(8):793–800. doi:10.1038/nm730. Erratum, Nat Med 2002;8:1039.

    PubMed  CAS  Google Scholar 

  23. Park JJ, Omiya R, Matsumura Y, Sakoda Y, Kuramasu A, Augustine MM, et al. B7-H1/CD80 interaction is required for the induction and maintenance of peripheral T-cell tolerance. Blood. 2010;116(8):1291–8. doi:10.1182/blood-2010-01-265975.

    Article  PubMed  CAS  Google Scholar 

  24. Paterson AM, Brown KE, Keir ME, Vanguri VK, Riella LV, Chandraker A, et al. The programmed death-1 ligand 1:B7-1 pathway restrains diabetogenic effector T cells in vivo. J Immunol. 2011;187(3):1097–105. doi:10.4049/jimmunol.1003496.

    Article  PubMed  CAS  Google Scholar 

  25. Velu V, Titanji K, Zhu B, Husain S, Pladevega A, Lai L, et al. Enhancing SIV-specific immunity in vivo by PD-1 blockade. Nature. 2009;458(7235):206–10. doi:10.1038/nature07662.

    Article  PubMed  CAS  Google Scholar 

  26. Kiniwa Y, Miyahara Y, Wang HY, Peng W, Peng G, Wheeler TM, et al. CD8+ Foxp3+ regulatory T cells mediate immunosuppression in prostate cancer. Clin Cancer Res. 2007;13(23):6947–58. doi:10.1158/1078-0432.CCR-07-0842.

    Article  PubMed  CAS  Google Scholar 

  27. Miller AM, Lundberg K, Ozenci V, Banham AH, Hellstrom M, Egevad L, et al. CD4+CD25high T cells are enriched in the tumor and peripheral blood of prostate cancer patients. J Immunol. 2006;177(10):7398–405.

    PubMed  CAS  Google Scholar 

  28. Sfanos KS, Bruno TC, Maris CH, Xu L, Thoburn CJ, DeMarzo AM, et al. Phenotypic analysis of prostate-infiltrating lymphocytes reveals TH17 and Treg skewing. Clin Cancer Res. 2008;14(11):3254–61. doi:10.1158/1078-0432.CCR-07-5164.

    Article  PubMed  CAS  Google Scholar 

  29. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411–22. doi:10.1056/NEJMoa1001294.

    Article  PubMed  CAS  Google Scholar 

  30. Ebelt K, Babaryka G, Frankenberger B, Stief CG, Eisenmenger W, Kirchner T, et al. Prostate cancer lesions are surrounded by FOXP3+, PD-1+ and B7-H1+ lymphocyte clusters. Eur J Cancer. 2009;45(9):1664–72. doi:10.1016/j.ejca.2009.02.015.

    Article  PubMed  CAS  Google Scholar 

  31. Thompson RH, Dong H, Lohse CM, Leibovich BC, Blute ML, Cheville JC, et al. PD-1 is expressed by tumor-infiltrating immune cells and is associated with poor outcome for patients with renal cell carcinoma. Clin Cancer Res. 2007;13(6):1757–61. doi:10.1158/1078-0432.CCR-06-2599.

    Article  PubMed  CAS  Google Scholar 

  32. Thompson RH, Kuntz SM, Leibovich BC, Dong H, Lohse CM, Webster WS, et al. Tumor B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term follow-up. Cancer Res. 2006;66(7):3381–5. doi:10.1158/0008-5472.CAN-05-4303.

    Article  PubMed  CAS  Google Scholar 

  33. Frigola X, Inman BA, Lohse CM, Krco CJ, Cheville JC, Thompson RH, et al. Identification of a soluble form of B7-H1 that retains immunosuppressive activity and is associated with aggressive renal cell carcinoma. Clin Cancer Res. 2011;17(7):1915–23. doi:10.1158/1078-0432.CCR-10-0250.

    Article  PubMed  CAS  Google Scholar 

  34. Wolchok JD, Hoos A, O'Day S, Weber JS, Hamid O, Lebbe C, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15(23):7412–20. doi:10.1158/1078-0432.CCR-09-1624.

    Article  PubMed  CAS  Google Scholar 

  35. Berger R, Rotem-Yehudar R, Slama G, Landes S, Kneller A, Leiba M, et al. Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin Cancer Res. 2008;14(10):3044–51. doi:10.1158/1078-0432.CCR-07-4079.

    Article  PubMed  CAS  Google Scholar 

  36. Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28(19):3167–75. doi:10.1200/JCO.2009.26.7609.

    Article  PubMed  CAS  Google Scholar 

  37. Patnaik A, Kang SP, Tolcher AW, Rasco DW, Papadopoulos KP, Beeram M, et al. Phase I study of MK-3475 (anti-PD-1 monoclonal antibody) in patients with advanced solid tumors. Presented at the American Society of Clinical Oncology, Chicago, IL, June 1-5, 2012. Abstract 2512.

  38. Virtual meeting presentation accessed via http://www.asco.org/ASCOv2/MultiMedia/Virtual+Meeting?&vmview=vm_session_presentations_view&confID=114&sessionID=4763.

  39. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372(9637):449–56. doi:10.1016/S0140-6736(08)61039-9.

    Article  PubMed  CAS  Google Scholar 

  40. Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378(9807):1931–9. doi:10.1016/S0140-6736(11)61613-9.

    Article  PubMed  CAS  Google Scholar 

  41. Zia MI, Siu LL, Pond GR, Chen EX. Comparison of outcomes of phase II studies and subsequent randomized control studies using identical chemotherapeutic regimens. J Clin Oncol. 2005;23(28):6982–91. doi:10.1200/JCO.2005.06.679.

    Article  PubMed  CAS  Google Scholar 

  42. Li B, VanRoey M, Wang C, Chen TH, Korman A, Jooss K. Anti-programmed death-1 synergizes with granulocyte macrophage colony-stimulating factor–secreting tumor cell immunotherapy providing therapeutic benefit to mice with established tumors. Clin Cancer Res. 2009;15(5):1623–34. doi:10.1158/1078-0432.CCR-08-1825.

    Article  PubMed  CAS  Google Scholar 

  43. Farsaci B, Higgins JP, Hodge JW. Consequence of dose scheduling of sunitinib on host immune response elements and vaccine combination therapy. Int J Cancer. 2012;130(8):1948–59. doi:10.1002/ijc.26219.

    Article  PubMed  CAS  Google Scholar 

  44. Ko JS, Zea AH, Rini BI, Ireland JL, Elson P, Cohen P, et al. Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients. Clin Cancer Res. 2009;15(6):2148–57. doi:10.1158/1078-0432.CCR-08-1332.

    Article  PubMed  CAS  Google Scholar 

  45. Kujawski M, Zhang C, Herrmann A, Reckamp K, Scuto A, Jensen M, et al. Targeting STAT3 in adoptively transferred T cells promotes their in vivo expansion and antitumor effects. Cancer Res. 2010;70(23):9599–610. doi:10.1158/0008-5472.CAN-10-1293.

    Article  PubMed  CAS  Google Scholar 

  46. Ozao-Choy J, Ma G, Kao J, Wang GX, Meseck M, Sung M, et al. The novel role of tyrosine kinase inhibitor in the reversal of immune suppression and modulation of tumor microenvironment for immune-based cancer therapies. Cancer Res. 2009;69(6):2514–22. doi:10.1158/0008-5472.CAN-08-4709.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Tom Baker Cancer Center, University of Calgary, 1331-29th St NW, Calgary, AB, T2N 4N2, Canada

    Patricia A. Tang & Daniel Y. C. Heng

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  1. Patricia A. Tang
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  2. Daniel Y. C. Heng
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Correspondence to Daniel Y. C. Heng.

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Tang, P.A., Heng, D.Y.C. Programmed Death 1 Pathway inhibition in Metastatic Renal Cell Cancer and Prostate Cancer. Curr Oncol Rep 15, 98–104 (2013). https://doi.org/10.1007/s11912-012-0284-2

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