Skip to main content
SpringerLink
Log in

Immune checkpoint combinations from mouse to man

  • Focussed Research Review
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

The discovery that antibody blockade of the T cell co-inhibitory receptor cytotoxic T lymphocyte-associated protein 4 (CTLA-4) can restore tumor immunity against many murine transplantable tumors leading to complete rejection of established cancer forever changed the field of immunotherapy. In more robust murine models as well as human cancer, however, CTLA-4 blockade alone can slow tumor growth and extend patient survival, but is rarely curative. Subsequent studies have revealed a large family of T cell immune checkpoint receptors which tumors engage to shield themselves from host immunity. As with CTLA-4, blockade of one of these additional inhibitory receptors, programmed death 1, has led to remarkable therapeutic responses against tumors of multiple lineages. Checkpoint monotherapy has demonstrated that durable, immune-mediated cures of established metastatic cancers are possible, yet the percentage of patients experiencing these outcomes remains low due to both redundant mechanisms of immune suppression in the tumor and limiting toxicity associated with some therapies. Thus, extending the curative potential of immunotherapy to a larger percentage of patients with a broader spectrum of malignancies will likely require combinations of co-inhibitory blockade and co-stimulatory activation designed to peel back multiple layers of tumor immune suppression while at the same time minimizing immune-mediated toxicity. As over a dozen T cell immune checkpoints and an additional dozen more co-stimulatory receptors have now been described, the challenge before us is to identify the most advantageous combinations of these agents based on the knowledge of their underlying biology and preclinical studies in murine tumor models.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

CAR:

Chimeric antigen receptor

CSF1R:

Colony stimulating factor 1 receptor

CTLA-4:

Cytotoxic T lymphocyte-associated protein 4

EAE:

Experimental autoimmune encephalomyelitis

FVAX:

B16-Flt3 ligand

ICOS:

Inducible T cell co-stimulator

IFN-γ:

Interferon gamma

IRAE:

Immune-related adverse events

MHC:

Major histocompatibility complex

PBMC:

Peripheral blood mononuclear cells

PD-1:

Programmed death 1

RECIST:

Response Evaluation Criteria In Solid Tumors

TNF:

Tumor necrosis factor

Treg:

Regulatory T cells (CD4+FoxP3+)

References

  1. Ehrlich P (1909) Über den jetzigen Stand der Chemotherapie. Ber Dtsch Chem Ges 42:17–47

    Article  CAS  Google Scholar 

  2. Zinkernagel RM, Doherty PC (1974) Immunological surveillance against altered self components by sensitised T lymphocytes in lymphocytic choriomeningitis. Nature 251:547–548

    Article  CAS  PubMed  Google Scholar 

  3. Rosenberg SA, Yang JC, Restifo NP (2004) Cancer immunotherapy: moving beyond current vaccines. Nat Med 10:909–915

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Wick M, Dubey P, Koeppen H, Siegel CT, Fields PE, Chen L, Bluestone JA, Schreiber H (1997) Antigenic cancer cells grow progressively in immune hosts without evidence for T cell exhaustion or systemic anergy. J Exp Med 186:229–238

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Krummel MF, Allison JP (1995) CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med 182:459–465

    Article  CAS  PubMed  Google Scholar 

  6. Leach DR, Krummel MF, Allison JP (1996) Enhancement of antitumor immunity by CTLA-4 blockade. Science 271:1734–1736

    Article  CAS  PubMed  Google Scholar 

  7. Ishida Y, Agata Y, Shibahara K, Honjo T (1992) Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J 11:3887–3895

    CAS  PubMed Central  PubMed  Google Scholar 

  8. Melero I, Shuford WW, Newby SA, Aruffo A, Ledbetter JA, Hellstrom KE, Mittler RS, Chen L (1997) Monoclonal antibodies against the 4-1BB T-cell activation molecule eradicate established tumors. Nat Med 3:682–685

    Article  CAS  PubMed  Google Scholar 

  9. Weinberg AD, Rivera MM, Prell R et al (2000) Engagement of the OX-40 receptor in vivo enhances antitumor immunity. J Immunol 164:2160–2169

    Article  CAS  PubMed  Google Scholar 

  10. Moran AE, Kovacsovics-Bankowski M, Weinberg AD (2013) The TNFRs OX40, 4-1BB, and CD40 as targets for cancer immunotherapy. Curr Opin Immunol 25:230–237

    Article  CAS  PubMed  Google Scholar 

  11. Croft M, Benedict CA, Ware CF (2013) Clinical targeting of the TNF and TNFR superfamilies. Nat Rev Drug Discov 12:147–168

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Podojil JR, Miller SD (2013) Targeting the B7 family of co-stimulatory molecules: successes and challenges. BioDrugs 27:1–13

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Hutloff A, Dittrich AM, Beier KC, Eljaschewitsch B, Kraft R, Anagnostopoulos I, Kroczek RA (1999) ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature 397:263–266

    Article  CAS  PubMed  Google Scholar 

  14. Waterhouse P, Penninger JM, Timms E, Wakeham A, Shahinian A, Lee KP, Thompson CB, Griesser H, Mak TW (1995) Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 270:985–988

    Article  CAS  PubMed  Google Scholar 

  15. Nishimura H, Nose M, Hiai H, Minato N, Honjo T (1999) Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11:141–151

    Article  CAS  PubMed  Google Scholar 

  16. Nishimura H, Okazaki T, Tanaka Y et al (2001) Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 291:319–322

    Article  CAS  PubMed  Google Scholar 

  17. Curran MA, Montalvo W, Yagita H, Allison JP (2010) PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A 107:4275–4280

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ (2007) Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity 27:111–122

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Melero I, Grimaldi AM, Perez-Gracia JL, Ascierto PA (2013) Clinical development of immunostimulatory monoclonal antibodies and opportunities for combination. Clin Cancer Res 19:997–1008

    Article  CAS  PubMed  Google Scholar 

  20. Wolchok JD, Kluger H, Callahan MK et al (2013) Nivolumab plus ipilimumab in advanced melanoma. New Engl J Med 369:122–133

    Article  CAS  PubMed  Google Scholar 

  21. Sznol M, Kluger HM, Callahan MK et al (2014) Survival, response duration, and activity by BRAF mutation (MT) status of nivolumab (NIVO, anti-PD-1, BMS-936558, ONO-4538) and ipilimumab (IPI) concurrent therapy in advanced melanoma (MEL). J Clin Oncol 32(5s Suppl):LBA9003

    Google Scholar 

  22. Duraiswamy J, Kaluza KM, Freeman GJ, Coukos G (2013) Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors. Cancer Res 73:3591–3603

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Callahan MK, Horak CE, Curran MA et al (2013) Peripheral and tumor immune correlates in patients with advanced melanoma treated with combination nivolumab (anti-PD-1, BMS-936558, ONO-4538) and ipilimumab. J Clin Oncol 31(Suppl):3003

    Google Scholar 

  24. Wang W, Yu D, Sarnaik AA, Yu B, Hall M, Morelli D, Zhang Y, Zhao X, Weber JS (2012) Biomarkers on melanoma patient T cells associated with ipilimumab treatment. J Transl Med 10:146

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Ng Tang D, Shen Y, Sun J, Wen S, Wolchok JD, Yuan J, Allison JP, Sharma P (2013) Increased frequency of ICOS+ CD4 T cells as a pharmacodynamic biomarker for anti-CTLA-4 therapy. Cancer Immunol Res 1:229–234

    Article  PubMed  Google Scholar 

  26. Carthon BC, Wolchok JD, Yuan J et al (2010) Preoperative CTLA-4 blockade: tolerability and immune monitoring in the setting of a presurgical clinical trial. Clin Cancer Res 16:2861–2871

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Fu T, He Q, Sharma P (2011) The ICOS/ICOSL pathway is required for optimal antitumor responses mediated by anti-CTLA-4 therapy. Cancer Res 71:5445–5454

    Article  CAS  PubMed  Google Scholar 

  28. Fan X, Quezada SA, Sepulveda MA, Sharma P, Allison JP (2014) Engagement of the ICOS pathway markedly enhances efficacy of CTLA-4 blockade in cancer immunotherapy. J Exp Med 211:715–725

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Lee SW, Croft M (2009) 4-1BB as a therapeutic target for human disease. Adv Exp Med Biol 647:120–129

    Article  CAS  PubMed  Google Scholar 

  30. Wang C, Lin GH, McPherson AJ, Watts TH (2009) Immune regulation by 4-1BB and 4-1BBL: complexities and challenges. Immunol Rev 229:192–215

    Article  CAS  PubMed  Google Scholar 

  31. Li B, Lin J, Vanroey M, Jure-Kunkel M, Jooss K (2007) Established B16 tumors are rejected following treatment with GM-CSF-secreting tumor cell immunotherapy in combination with anti-4-1BB mAb. Clin Immunol 125:76–87

    Article  CAS  PubMed  Google Scholar 

  32. Curran MA, Geiger TL, Montalvo W, Kim M, Reiner SL, Al-Shamkhani A, Sun JC, Allison JP (2013) Systemic 4-1BB activation induces a novel T cell phenotype driven by high expression of Eomesodermin. J Exp Med 210:743–755

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Belcaid Z, Phallen JA, Zeng J et al (2014) Focal radiation therapy combined with 4-1BB activation and CTLA-4 blockade yields long-term survival and a protective antigen-specific memory response in a murine glioma model. PLoS One 9:e101764

    Article  PubMed Central  PubMed  Google Scholar 

  34. Curran MA, Kim M, Montalvo W, Al-Shamkhani A, Allison JP (2011) Combination CTLA-4 blockade and 4-1BB activation enhances tumor rejection by increasing T-cell infiltration, proliferation, and cytokine production. PLoS One 6:e19499

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Kocak E, Lute K, Chang X et al (2006) Combination therapy with anti-CTL antigen-4 and anti-4-1BB antibodies enhances cancer immunity and reduces autoimmunity. Cancer Res 66:7276–7284

    Article  CAS  PubMed  Google Scholar 

  36. Sun Y, Lin X, Chen HM, Wu Q, Subudhi SK, Chen L, Fu YX (2002) Administration of agonistic anti-4-1BB monoclonal antibody leads to the amelioration of experimental autoimmune encephalomyelitis. J Immunol 168:1457–1465

    Article  CAS  PubMed  Google Scholar 

  37. Kim YH, Choi BK, Shin SM et al (2011) 4-1BB triggering ameliorates experimental autoimmune encephalomyelitis by modulating the balance between Th17 and regulatory T cells. J Immunol 187:1120–1128

    Article  CAS  PubMed  Google Scholar 

  38. Callahan MK, Yang A, Tandon S et al (2011) Evaluation of serum IL-17 levels during ipilimumab therapy: correlation with colitis. J Clin Oncol 29(Suppl):2505

    Google Scholar 

  39. Vudattu NK, Waldron-Lynch F, Truman LA, Deng S, Preston-Hurlburt P, Torres R, Raycroft MT, Mamula MJ, Herold KC (2014) Humanized mice as a model for aberrant responses in human T cell immunotherapy. J Immunol 193:587–596

    Article  CAS  PubMed  Google Scholar 

  40. Ascierto PA, Simeone E, Sznol M, Fu YX, Melero I (2010) Clinical experiences with anti-CD137 and anti-PD1 therapeutic antibodies. Semin Oncol 37:508–516

    Article  CAS  PubMed  Google Scholar 

  41. Kvistborg P, Philips D, Kelderman S et al (2014) Anti-CTLA-4 therapy broadens the melanoma-reactive CD8+ T cell response. Sci Transl Med 6:254ra128

    Article  PubMed  Google Scholar 

  42. Spranger S, Bao R, Gajewski TF (2014) Melanoma-intrinsic β-catenin signaling prevents T cell infiltration and anti-tumor immunity. J ImmunoTherapy Cancer 2(Suppl 3):O15

    Article  Google Scholar 

  43. Gubin MM, Zhang X, Schuster H et al (2014) Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 515:577–581

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. van Rooij N, van Buuren MM, Philips D et al (2013) Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma. J Clin Oncol 31:e439–e442

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The work from our laboratory cited in this review was partially funded by a U.T. MD Anderson Moonshot Knowledge Gap award.

Conflict of interest

Dr. Curran has a research collaboration with Threshold Pharmaceuticals for which his laboratory has received funding, and an active collaboration with Astrazeneca in which compounds are provided free of charge. Dr. Curran also receives royalties from the patent “Methods and Compositions for Localized Secretion of anti-CTLA-4 Antibodies.” Dr. Ai has no conflicts to disclose.

Author information

Authors and Affiliations

  1. Department of Immunology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit Number: 901, Houston, TX, 77030, USA

    Midan Ai & Michael A. Curran

Authors
  1. Midan Ai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael A. Curran
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael A. Curran.

Additional information

This paper is a Focussed Research Review based on a presentation given at the Twelfth Annual Meeting of the Association for Cancer Immunotherapy (CIMT), held in Mainz, Germany, 6th-8th May, 2014. It is part of a CII series of Focussed Research Reviews and meeting report.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ai, M., Curran, M.A. Immune checkpoint combinations from mouse to man. Cancer Immunol Immunother 64, 885–892 (2015). https://doi.org/10.1007/s00262-014-1650-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-014-1650-8

Keywords

Search

Navigation