The AAPS Journal

, 20:28 | Cite as

Cancer Immunotherapy: Factors Important for the Evaluation of Safety in Nonclinical Studies

Review Article Theme: Cancer Immunotherapy: Promises and Challenges
Part of the following topical collections:
  1. Theme: Cancer Immunotherapy: Promises and Challenges

Abstract

The development of novel therapies that can harnass the immune system to eradicate cancer is an area of intensive research. Several new biopharmaceuticals that target the immune system rather than the tumor itself have recently been approved and fundamentally transformed treatment of many cancer diseases. This success has intensified the search for new targets and modalities that could be developed as even more effective therapeutic agents either as monotherapy or in combination. While great benefits of novel immunotherapies in oncology are evident, the safety of these therapies has to also be addressed as their desired pharmacology, immune activation, can lead to “exaggerated” effects and toxicity. This review is focused on the unique challenges of the nonclinical safety assessment of monoclonal antibodies that target immune checkpoint inhibitors and costimulatory molecules. This class of molecules represents several approved drugs and many more drug candidates in clinical development, for which significant experience has been gained. Their development illustrates challenges regarding the predictivity of the animal models for assessing safety and setting starting doses for first-in-human trials as well as the translatability of nonclinical in vitro and in vivo data to the human findings. Based on learnings from the experience to date, factors to consider and novel approaches to explore are discussed to help address the unique safety issues of immuno-oncology drug development.

KEY WORDS

cancer checkpoint inhibitor immunotherapy immunostimulatory immune-related adverse events nonclinical safety 

References

  1. 1.
    Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39(1):1–10.  https://doi.org/10.1016/j.immuni.2013.07.012.CrossRefPubMedGoogle Scholar
  2. 2.
    Ponce R. Adverse consequences of immunostimulation. J Immunotoxicol. 2008;5(1):33–41.  https://doi.org/10.1080/15476910801897920.CrossRefPubMedGoogle Scholar
  3. 3.
    Gribble EJ, Sivakumar PV, Ponce RA, Hughes SD. Toxicity as a result of immunostimulation by biologics. Expert Opin Drug Metab Toxicol. 2007;3(2):209–34.  https://doi.org/10.1517/17425255.3.2.209.CrossRefPubMedGoogle Scholar
  4. 4.
    Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes J, Brunner MD, et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med. 2006;355(10):1018–28.  https://doi.org/10.1056/NEJMoa063842.CrossRefPubMedGoogle Scholar
  5. 5.
    Eastwood D, Findlay L, Poole S, Bird C, Wadhwa M, Moore M, et al. Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4+ effector memory T-cells. Br J Pharmacol. 2010;161(3):512–26.  https://doi.org/10.1111/j.1476-5381.2010.00922.x.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    EMEA/CHMP/SWP/294648/. Guideline on strategies to identify and mitigate risks for first-in-man human clinical trials with investigational medicinal products. 2007.Google Scholar
  7. 7.
    ICH S9. Nonclinical evaluation for anticancer pharmaceuticals. March 2010. www.ich.org
  8. 8.
    Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–64.  https://doi.org/10.1038/nrc3239.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Sanmamed MF, Pastor F, Rodriguez A, Perez-Gracia JL, Rodriguez-Ruiz ME, Jure-Kunkel M, et al. Agonists of co-stimulation in cancer immunotherapy directed against CD137, OX40, GITR, CD27, CD28, and ICOS. Semin Oncol. 2015;42(4):640–55.  https://doi.org/10.1053/j.seminoncol.2015.05.014.CrossRefPubMedGoogle Scholar
  10. 10.
    Hellmann MD, Friedman CF, Wolchok JD. Combinatorial cancer immunotherapies. Adv Immunol. 2016;130:251–77.  https://doi.org/10.1016/bs.ai.2015.12.005.CrossRefPubMedGoogle Scholar
  11. 11.
    Saber H, Gudi R, Manning M, Wearne E, Leighton JK. An FDA oncology analysis of immune activating products and first-in-human dose selection. Regul Toxicol Pharmacol. 2016;81:448–56.  https://doi.org/10.1016/j.yrtph.2016.10.002.CrossRefPubMedGoogle Scholar
  12. 12.
    Segal NH, Logan TF, Hodi S, McDermott D, Meleros I, et al. Results from an integrated safety analysis of urelumab, an agonist anti-CD137 monoclonal antibody. Clin Cancer Res. 2016;23(8):1929–36.  https://doi.org/10.1158/1078-0432.CCR-16-1272.CrossRefPubMedGoogle Scholar
  13. 13.
    Melero I, et al. A phase I study of the safety, tolerability, pharmacokinetics, and immunoregulatory activity of urelumab (BMS-663513) in subjects with advanced and/or metastatic solid tumors and relapsed/refractory B-cell non-Hodgkin’s lymphoma (B-NHL) [abstract]. J Clin Oncol. 2013;31(Suppl):TPS3107.Google Scholar
  14. 14.
    Sznol M, et al. Phase I study of BMS-663513 a fully human anti-CD137 agonist monoclonal antibody, in patients (pts) with advanced cancer (CA) [abstract]. J Clin Oncol. 2008;26(Suppl):a3007.CrossRefGoogle Scholar
  15. 15.
    Ascierto PA, Simeone E, Sznol M, Fu YX, Melero I. Clinical experiences with anti-CD137 and anti-PD1 therapeutic antibodies. Semin Oncol. 2010;37(5):508–16.  https://doi.org/10.1053/j.seminoncol.2010.09.008.CrossRefPubMedGoogle Scholar
  16. 16.
    Niu L, Strahotin S, Hewes B, Zhang B, Zhang Y, Archer D, et al. Cytokine-mediated disruption of lymphocyte trafficking, hemopoiesis, and induction of lymphopenia, anemia, and thrombocytopenia in anti-CD137-treated mice. J Immunol. 2007;178(7):4194–213.  https://doi.org/10.4049/jimmunol.178.7.4194.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Wang M, Baumgart BR, Simutis F, Freebern W, Chadwick K, Bunch RT, Ju C, and Price K. Understanding anti-CD137-induced liver toxicity. In: The Toxicologist: Supplement to Toxicological Sciences, 150 (1), Society of Toxicology, 2016. Abstract no.1323.Google Scholar
  18. 18.
    Murphy JT, Burey AP, Beebe AM, Gu D, Presta LG, Merghoub T, et al. Anaphylaxis caused by repetitive doses of a GITR agonist monoclonal antibody in mice. Blood. 2014;123(14):2172–80.  https://doi.org/10.1182/blood-2013-12-544742.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH, et al. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity. 1995;3(5):541–7.  https://doi.org/10.1016/1074-7613(95)90125-6.CrossRefPubMedGoogle Scholar
  20. 20.
    Waterhouse P, Penninger JM, Timms E, Wakeham A, Shahinian A, Lee KP, et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science. 1995;270(5238):985–8.  https://doi.org/10.1126/science.270.5238.985.CrossRefPubMedGoogle Scholar
  21. 21.
    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.  https://doi.org/10.1016/S1074-7613(00)80089-8.CrossRefPubMedGoogle Scholar
  22. 22.
    Dong H, Zhu G, Tamada K, Flies DB, van Deursen JM, Chen L. B7-H1 determines accumulation and deletion of intrahepatic CD8(+) T lymphocytes. Immunity. 2004;20(3):327–36.  https://doi.org/10.1016/S1074-7613(04)00050-0.CrossRefPubMedGoogle Scholar
  23. 23.
    Nishimura H, Taku Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A, et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science. 2001;291(5502):319–22.  https://doi.org/10.1126/science.291.5502.319.CrossRefPubMedGoogle Scholar
  24. 24.
    Wang J, Okazaki IM, Yoshida T, Chikuma S, Kato Y, Nakaki F, et al. PD-1 deficiency results in the development of fatal myocarditis in MRL mice. Int Immunol. 2010;22(6):443–52.  https://doi.org/10.1093/intimm/dxq026.CrossRefPubMedGoogle Scholar
  25. 25.
    Ansari MJ1, Salama AD, Chitnis T, Smith RN, Yagita H, Akiba H, Yamazaki T, Azuma M, Iwai H, Khoury SJ, Auchincloss H Jr, Sayegh MH: The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice. J Exp Med, 2003; 198(1):63–69.Google Scholar
  26. 26.
    Miyazaki T, Dierich A, Benoist C, Mathis D. LAG-3 is not responsible for selecting T helper cells in CD4-deficient mice. Int Immunol. 1996;8(5):725–9.  https://doi.org/10.1093/intimm/8.5.725.CrossRefPubMedGoogle Scholar
  27. 27.
    Bettini M, Szymczak-Workman AL, Forbes K, Castellaw AH, Selby M, Pan X, et al. Accelerated autoimmune diabetes in the absence of LAG-3. J Immunol. 2011;187(7):3493–8.  https://doi.org/10.4049/jimmunol.1100714.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Vonderheide RH, Flaherty KT, Khalil M, Stumacher MS, Bajor DL, Hutnick NA, et al. Clinical activity and immune modulation in cancer patients treated with CP-870,893, a novel CD40 agonist monoclonal antibody. J Clin Oncol. 2007;25(7):876–83.  https://doi.org/10.1200/JCO.2006.08.3311.CrossRefPubMedGoogle Scholar
  29. 29.
    Vonderheide RH, Burg JM, Mick R, Trosko JA, Li D, Shaik MN, et al. Phase I study of the CD40 agonist antibody CP-870,893 combined with carboplatin and paclitaxel in patients with advanced solid tumors. Oncoimmunology. 2013;2(1):e23033.  https://doi.org/10.4161/onci.23033.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Beatty GL, Chiorean EG, Fishman MP, Saboury B, Teitelbaum UR, Sun W, et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science. 2011;331(6024):1612–6.  https://doi.org/10.1126/science.1198443.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Burris HA, Infante JR, Ansell SM, et al. Safety and activity of varlilumab, a novel and first-in-class agonist anti-CD27 antibody, in patients with advanced solid tumors. J Clin Oncol. 2017;35:1–18.CrossRefGoogle Scholar
  32. 32.
    Hodi FS, Mihm MC, Soiffer RJ, Haluska FG, Butler M, Seiden MV, et al. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci U S A. 2003;100(8):4712–7.  https://doi.org/10.1073/pnas.0830997100. CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Price KD, Rao GK. Biological therapies for cancer. In: Plitnick LM, Herzyk DJ, editors. Nonclinical development of novel biologics, biosimilars, vaccines and specialty biologics. Elsevier Inc.: USA; 2013. p. 303–42.  https://doi.org/10.1016/B978-0-12-394810-6.00013-7.CrossRefGoogle Scholar
  34. 34.
    Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol. 2015;25:9543–53.CrossRefGoogle Scholar
  35. 35.
    Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev. 2010;236(1):219–42.  https://doi.org/10.1111/j.1600-065X.2010.00923.x.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    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.  https://doi.org/10.1056/NEJMoa1200690.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23–34.  https://doi.org/10.1056/NEJMoa1504030.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Ribas A, Hanson DC, Noe DA, Millham R, Guyot DJ, Bernstein SH, et al. Tremelimumab (CP-675,206), a cytotoxic T lymphocyte associated antigen 4 blocking monoclonal antibody in clinical development for patients with cancer. Oncologist. 2007;12(7):873–83.  https://doi.org/10.1634/theoncologist.12-7-873.CrossRefPubMedGoogle Scholar
  39. 39.
    Price KP, Simutis F, Fletcher A, Ramaiah L, et al. Nonclinical safety evaluation of two distinct second generation variants of anti-CTLA4 monoclonal antibody, ipilimumab, in monkeys. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26–30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther, 2018;17(1 Suppl):Abstract nr LB-B33.Google Scholar
  40. 40.
    Wang C, Thudium KB, Han M, Wang XT, Huang H, Feingersh D, et al. In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human primates. Cancer Immunol Res. 2014;2(9):846–56.  https://doi.org/10.1158/2326-6066.CIR-14-0040.CrossRefPubMedGoogle Scholar
  41. 41.
    Center for Drug Evaluation and Research Application Number: 125554 Orig1s000, Summary Review for Nivolumab. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/125554Orig1s000SumR.pdf. 2014; Accessed 24 July 2017.
  42. 42.
    Center for Drug Evaluation and Research Application Number: 125514 Orig1s000, Summary Review for Pembrolizumab. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/125514Orig1s000SumR.pdf . 2014; Accessed 24 July 2017.
  43. 43.
    Stewart RS, Hammond SA, Oberst M, Wilkinson RW. The role of Fc gamma receptors in the activity of immunomodulatory antibodies for cancer. J Immunother Cancer. 2014;2(1):29–38.  https://doi.org/10.1186/s40425-014-0029-x.CrossRefGoogle Scholar
  44. 44.
    Wilson NS, Yang B, Yang A, Loeser S, Marsters S, Lawrence D, et al. An Fcgamma receptor-dependent mechanism drives antibody-mediated target-receptor signaling in cancer cells. Cancer Cell. 2011;19(1):101–13.  https://doi.org/10.1016/j.ccr.2010.11.012.CrossRefPubMedGoogle Scholar
  45. 45.
    Brennan FR, et al. Safety and immunotoxicity assessment of immunomodulatory monoclonal antibodies. Monoclon Antibodies. 2010;2:233e255.Google Scholar
  46. 46.
    Spigel D. et al. Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) [ASCO abstract 8008]. J Clin Oncol, 2013; 31(15)(suppl).Google Scholar
  47. 47.
    Simpson TR, Li F, Montalvo-Ortiz W, Sepulveda MA, Bergerhoff K, Arce F, et al. Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti–CTLA-4 therapy against melanoma. J Exp Med. 2013;210(9):1695–710.  https://doi.org/10.1084/jem.20130579.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Ribas A, Kefford R, Marshall MA, Punt CJ, Haanen JB, Marmol M, et al. Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol. 2013;31(5):616–22.  https://doi.org/10.1200/JCO.2012.44.6112.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Ribas A, Comin-Anduix B, Economou JS, Donahue TR, de la Rocha P, Morris LF, et al. Intratumoral immune cell infiltrates, FoxP3, and indoleamine 2,3-dioxygenase in patients with melanoma undergoing CTLA4 blockade. Clin Cancer Res. 2009;15(1):390–9.  https://doi.org/10.1158/1078-0432.CCR-08-0783.CrossRefPubMedGoogle Scholar
  50. 50.
    Li F, Ravetch JV. Inhibitory Fcgamma receptor engagement drives adjuvant and anti-tumor activities of agonistic CD40 antibodies. Science. 2011;333(6045):1030–4.  https://doi.org/10.1126/science.1206954.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    White AL, Chan HTC, Roghanian A, French RR, Mockridge CI, Tutt AL, et al. Interaction with FcgammaRIIB is critical for the agonistic activity of anti-CD40 monoclonal antibody. J Immunol. 2011;187(4):1754–63.  https://doi.org/10.4049/jimmunol.1101135.CrossRefPubMedGoogle Scholar
  52. 52.
    Ravetch JV and Nimmerjahn F. Fc receptors. In: Paul WE, editor. Fundamental Immunology. Lippincott-Raven; 2008. p. 684–705.Google Scholar
  53. 53.
    Morris NP, Peters C, Montler R, Hu HM, Curti BD, Urba WJ, et al. Development and characterization of recombinant human Fc:OX40L fusion protein linked via a coiled-coil trimerization domain. Mol Immunol. 2007;44(12):3112–21.  https://doi.org/10.1016/j.molimm.2007.02.004.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Vitale LA, He LZ, Thomas LJ, Widger J, Weidlick J, Crocker A, et al. Development of a human monoclonal antibody for potential therapy of CD27-expressing lymphoma and leukemia. Clin Cancer Res. 2012;18(14):3812–21.  https://doi.org/10.1158/1078-0432.CCR-11-3308.CrossRefPubMedGoogle Scholar
  55. 55.
    Sukumar S, Wilson DC, Yu Ying et al. Characterization of MK-4166, a clinical agonistic mAb that targets human GITR and inhibits the generation and activity of Tregs. Cancer Res; 2017. Published OnlineFirst on June 13, 2017;  https://doi.org/10.1158/0008-5472.CAN-16-1439.
  56. 56.
    Keler T, Halk E, Vitale L, O’Neill T, Blanset D, Lee S, et al. Activity and safety of CTLA-4 blockade combined with vaccines in cynomolgus macaques. J Immunol. 2003;171(11):6251–9.  https://doi.org/10.4049/jimmunol.171.11.6251.CrossRefPubMedGoogle Scholar
  57. 57.
    Dahan R, Barnhart BC, Li F, Yamniuk AP, Korman AJ, Ravetch JV. Therapeutic activity of agonistic, human anti-CD40 monoclonal antibodies requires selective FcγR engagement. Cancer Cell. 2016;29(6):820–31.  https://doi.org/10.1016/j.ccell.2016.05.001.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Semple KM and Howard KE. Human Fc receptor expression in immune humanized mice. In: The Toxicologist: Supplement to Toxicological Sciences, 156 (1), Society of Toxicology; 2017. Abstract no. 2550.Google Scholar
  59. 59.
    Howard KE, Zadrozny L, Semple KM, Shea K, and Weaver JL. Autoimmunity induced by ipilimumab in immune humanized mice. In: The Toxicologist: Supplement to Toxicological Sciences, 156 (1), Society of Toxicology; 2017. Abstract no. 1693.Google Scholar
  60. 60.
    Howard KE, Zadrozny L, and Weaver JL. Immune humanized mouse model: autoimmunity induced by nivolumab. American College of Toxicology; 2016. Abstract no. P516. www.actox.org
  61. 61.
    Morrissey KM, Yuraszeck TM, Li C-C, Zhang Y, Kasichayala S. Immunotherapy and novel combinations in oncology: current landscape, challenges, and opportunities. Clin Transl Sci. 2016;9(2):89–104.  https://doi.org/10.1111/cts.12391.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Selby MJ, Engelhardt JJ, Johnston RJ, LS L, Han M, Thudium K, et al. Preclinical development of ipilimumab and nivolumab combination immunotherapy: mouse tumor models, in vitro functional studies, and cynomolgus macaque toxicology. PLoS One. 2016;11(9):e0161779.  https://doi.org/10.1371/journal.pone.0161779.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    ICH S9 Guideline on nonclinical evaluation for anticancer pharmaceuticals - Qestions and Answers; September 2016 (Step 2).Google Scholar
  64. 64.
    ICH S5(R2). Detection of toxicity to reproduction for medicinal products and toxicity to male fertility. Addendum dated 9 November 2000, incorporated in November 2005. www.ich.org
  65. 65.
    ICH S6(R1). Preclinical safety evaluation of biotechnology-derived pharmaceuticals. Parent Guideline dated 16 July 1997, Addendum dated 12 June 2011, incorporated in June 2011. www.ich.org
  66. 66.
    Warning JC, McCracken SA, Morris JM. A balancing act: mechanisms by which the fetus avoids rejection by the maternal immune system. Reproduction. 2011;141(6):715–24.  https://doi.org/10.1530/REP-10-0360.CrossRefPubMedGoogle Scholar
  67. 67.
    Aluvihare VR, Kallikourdis M, Betz AG, Regulatory T. Cells mediate maternal tolerance to the fetus. Nat Immunol. 2004;5(3):266–71.  https://doi.org/10.1038/ni1037.CrossRefPubMedGoogle Scholar
  68. 68.
    Guleria I, Khosroshahi A, Ansari MJ, Habicht A, Azuma M, Yagita H, et al. A critical role for the programmed death ligand 1 in fetomaternal tolerance. J Exp Med. 2005;202(2):231–7.  https://doi.org/10.1084/jem.20050019.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Zenclussen AC, Gerlof K, Zenclussen ML, Sollwedel A, Zambon Bertoja A, Ritter T, et al. Abnormal T-cell reactivity against paternal antigens in spontaneous abortion: adoptive transfer of pregnancy-induced CD4+CD25+ T regulatory cells prevents fetal rejection in a murine abortion model. Am J Pathol. 2005;166(3):811–22.  https://doi.org/10.1016/S0002-9440(10)62302-4.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Zenclussen AC, Gerlof K, Zenclussen ML, Ritschel S, Zambon Bertoja A, Fest S, et al. Regulatory T cells induce a privileged tolerant microenvironment at the fetal-maternal interface. Eur J Immunol. 2006;36(1):82–94.  https://doi.org/10.1002/eji.200535428.CrossRefPubMedGoogle Scholar
  71. 71.
    Somerset DA, Zheng Y, Kilby MD, Sansom DM, Drayson MT. Normal human pregnancy is associated with an elevation in the immune suppressive CD25+ CD4+ regulatory T-cell subset. Immunology. 2004;112(1):38–43.  https://doi.org/10.1111/j.1365-2567.2004.01869.x.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Guleria I, Sayegh MH. Maternal acceptance of the fetus: true human tolerance. J Immunol. 2007;178(6):3345–51.  https://doi.org/10.4049/jimmunol.178.6.3345.CrossRefPubMedGoogle Scholar
  73. 73.
    Kaufman KA, Bowen JA, Tsai AF, Bluestone JA, Hunt JS, Ober C. The CTLA-4 gene is expressed in placental fibroblasts. Mol Hum Reprod. 1999;5(1):84–7.  https://doi.org/10.1093/molehr/5.1.84.CrossRefPubMedGoogle Scholar
  74. 74.
    Miwa N, Hayakawa S, Miyazaki S, Myojo S, Sasaki Y, Sakai M, et al. IDO expression on decidual and peripheral blood dendritic cells and monocytes/macrophages after treatment with CTLA-4 or interferon-ɣ increase in normal pregnancy but decrease in spontaneous abortion. Mol Hum Reprod. 2005;11(12):865–70.  https://doi.org/10.1093/molehr/gah246.CrossRefPubMedGoogle Scholar
  75. 75.
    Taglauer ES, Yankee TM, Petroff MG. Maternal PD-1 regulates accumulation of fetal antigen-specific CD8+ T cells in pregnancy. J Reprod Immunol. 2009;80(1-2):12–21.  https://doi.org/10.1016/j.jri.2008.12.001.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Wafula PO, Teles A, Schumacher A, Pohl K, Yagita H, Volk H-D, et al. PD-1 but not CTLA-4 blockage abrogates the protective effect of regulatory T cells in a pregnancy murine model. Am J Reprod Immunol. 2009;62(5):283–92.  https://doi.org/10.1111/j.1600-0897.2009.00737.x.CrossRefPubMedGoogle Scholar
  77. 77.
    Poulet FM, Wolf JJ, Herzyk DJ, DeGeorge JJ. An evaluation of the impact of PD-1 pathway blockade on reproductive safety of therapeutic PD-1 inhibitors. Birth Defects Res. 2016;107(2):108–19.  https://doi.org/10.1002/bdrb.21176.CrossRefGoogle Scholar
  78. 78.
    Prell RA, Halpern WG, Rao GK. Perspective on a modified developmental and reproductive toxicity testing strategy for cancer immunotherapy. Int J Toxicol. 2016;35(3):263–7.  https://doi.org/10.1177/1091581815625596.CrossRefPubMedGoogle Scholar
  79. 79.
    Krausz LT, Bianchini R, Ronchetti S, Fettucciari K, Nocentini G, Riccardi C. GITR-GITRL system, a novel player in shock and inflammation. Sci World J. 2007;7:533–66.  https://doi.org/10.1100/tsw.2007.106.CrossRefGoogle Scholar
  80. 80.
    Erlebacher A, Vencato D, Price KA, Zhang D, Glimcher LH. Constraints in antigen presentation severely restrict T cell recognition of the allogeneic fetus. J Clin Investig. 2007;117(5):1399–411.  https://doi.org/10.1172/JCI28214.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Habicht A, Dada S, Jurewicz M, Fife BT, Yagita H, Azuma M, et al. A link between PDL1 and T regulatory cells in fetomaternal tolerance. J Immunol. 2007;179(8):5211–9.  https://doi.org/10.4049/jimmunol.179.8.5211. CrossRefPubMedGoogle Scholar
  82. 82.
    Erlebacher A. Immunology of the maternal-fetal Interface. Annu Rev Immunol. 2013;31(1):387–411.  https://doi.org/10.1146/annurev-immunol-032712-100003.CrossRefPubMedGoogle Scholar
  83. 83.
    Rowe JH, Ertelt JM, Xin L, Way SS. Pregnancy imprints regulatory memory that sustains anergy to fetal antigen. Nature. 2012;490(7418):102–6.  https://doi.org/10.1038/nature11462.CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Samstein RM, Josefowicz SZ, Arvey A, Treuting PM, Rudensky AY. Extrathymic generation of regulatory T cells in placental mammals mitigates maternal-fetal conflict. Cell. 2012;150(1):29–38.  https://doi.org/10.1016/j.cell.2012.05.031.CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Cheng S-B, Sharma S. Interleukin-10: a pleiotropic regulator in pregnancy. Am J Reprod Immunol. 2015;73(6):487–500.  https://doi.org/10.1111/aji.12329.CrossRefPubMedGoogle Scholar

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© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  1. 1.Department of Safety Assessment and Laboratory Animal ResourcesMerck Research Laboratories, Merck & Co. IncWest PointUSA
  2. 2.Drug Safety EvaluationBristol-Myers SquibbNew BrunswickUSA

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