Immunotherapy in endometrial cancer - an evolving therapeutic paradigm

Teresa C Longoria, Ramez N Eskander, Teresa C Longoria, Ramez N Eskander

Abstract

Endometrial cancer is the only gynecologic malignancy with a rising incidence and mortality. While cure is routinely achieved with surgery alone or in combination with adjuvant pelvic radiotherapy when disease is confined to the uterus, patients with metastatic or recurrent disease exhibit limited response rates to cytotoxic chemotherapy, targeted agents, or hormonal therapy. Given the unmet clinical need in this patient population, exploration of novel therapeutic approaches is warranted, and attention is turning to immunomodulation of the tumor microenvironment. Existing evidence suggests that endometrial cancer is sufficiently immunogenic to be a reasonable candidate for active and/or passive immunotherapy. In this review, we critically examine what is known about the microenvironment in endometrial cancer and what has been learned from preliminary immunotherapy trials that enrolled endometrial cancer patients, encouraging further attempts at immunomodulation in the treatment of aggressive forms of this disease.

Keywords: Adoptive cellular therapy; Bispecific T-cell engager antibodies; Endometrial cancer; Immune checkpoint inhibitors; Therapeutic vaccination; Tumor microenvironment.

References

    1. National Cancer Institute: SEER Stat Fact Sheets: Endometrial Cancer. . Accessed August 23 2015.
    1. Fleming GF, Brunetto VL, Cella D, Look KY, Reid GC, Munkarah AR, et al. Phase III trial of doxorubicin plus cisplatin with or without paclitaxel plus filgrastim in advanced endometrial carcinoma: a Gynecologic Oncology Group Study. J Clin Oncol. 2004;22(11):2159–2166. doi: 10.1200/JCO.2004.07.184.
    1. Aghajanian C, Sill MW, Darcy KM, Greer B, McMeekin DS, Rose PG, et al. Phase II trial of bevacizumab in recurrent or persistent endometrial cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2011;29(16):2259–2265. doi: 10.1200/JCO.2010.32.6397.
    1. Coleman RL, Sill MW, Lankes HA, Fader AN, Finkler NJ, Hoffman JS, et al. A phase II evaluation of aflibercept in the treatment of recurrent or persistent endometrial cancer: a Gynecologic Oncology Group study. Gynecol Oncol. 2012;127(3):538–543. doi: 10.1016/j.ygyno.2012.08.020.
    1. Alvarez EA, Brady WE, Walker JL, Rotmensch J, Zhou XC, Kendrick JE, et al. Phase II trial of combination bevacizumab and temsirolimus in the treatment of recurrent or persistent endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2013;129(1):22–27. doi: 10.1016/j.ygyno.2012.12.022.
    1. Dizon DS, Sill MW, Schilder JM, McGonigle KF, Rahman Z, Miller DS, et al. A phase II evaluation of nintedanib (BIBF-1120) in the treatment of recurrent or persistent endometrial cancer: an NRG Oncology/Gynecologic Oncology Group Study. Gynecol Oncol. 2014;135(3):441–445. doi: 10.1016/j.ygyno.2014.10.001.
    1. Makker V FV, Chen L, Darus C, Kendrick JE, Sutton G, Moxley K, Aghajanian C. Phase II evaluation of dalantercept, a soluble recombinant activin receptor-like kinase 1 (ALK1) receptor-fusion protein, for treatment of recurrent/persistent endometrial cancer: GOG 0229 N. J Clin Oncol. 2014;32(5 s):Abst#5594.
    1. Powell MA, Sill MW, Goodfellow PJ, Benbrook DM, Lankes HA, Leslie KK, et al. A phase II trial of brivanib in recurrent or persistent endometrial cancer: an NRG Oncology/Gynecologic Oncology Group Study. Gynecol Oncol. 2014;135(1):38–43. doi: 10.1016/j.ygyno.2014.07.083.
    1. Bender DP SM, Lankes H, Darus CJ, Delmore J, Rotmensch J, Gray HJ, Mannel RS, Schilder JM, Leslie KK. A phase II evaluation of cediranib in the treatment of recurrent or persistent endometrial cancer: An NRG Oncology/Gynecologic Oncology Group (GOG) study. Gynecol Oncol. 2015;SGO Annula Meeting 2015:Late Breaking Abstract 3.
    1. Pectasides D, Pectasides E, Economopoulos T. Systemic therapy in metastatic or recurrent endometrial cancer. Cancer Treat Rev. 2007;33(2):177–190. doi: 10.1016/j.ctrv.2006.10.007.
    1. Dellinger TH, Monk BJ. Systemic therapy for recurrent endometrial cancer: a review of North American trials. Expert Rev Anticancer Ther. 2009;9(7):905–916. doi: 10.1586/era.09.54.
    1. Dizon DS. Treatment options for advanced endometrial carcinoma. Gynecol Oncol. 2010;117(2):373–381. doi: 10.1016/j.ygyno.2010.02.007.
    1. Shekarian T, Valsesia-Wittmann S, Caux C, Marabelle A. Paradigm shift in oncology: targeting the immune system rather than cancer cells. Mutagenesis. 2015;30(2):205–211. doi: 10.1093/mutage/geu073.
    1. Longoria TC, Eskander RN. Immune checkpoint inhibition: therapeutic implications in epithelial ovarian cancer. Recent Pat Anticancer Drug Discov. 2015;10(2):133–144. doi: 10.2174/1574892810666150504121000.
    1. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, et al. Signatures of mutational processes in human cancer. Nature. 2013;500(7463):415–421. doi: 10.1038/nature12477.
    1. Galli SJ, Borregaard N, Wynn TA. Phenotypic and functional plasticity of cells of innate immunity: macrophages, mast cells and neutrophils. Nat Immunol. 2011;12(11):1035–1044. doi: 10.1038/ni.2109.
    1. Wira CR, Fahey JV, Ghosh M, Patel MV, Hickey DK, Ochiel DO. Sex hormone regulation of innate immunity in the female reproductive tract: the role of epithelial cells in balancing reproductive potential with protection against sexually transmitted pathogens. American journal of reproductive immunology (New York, NY : 1989). 2010;63(6):544–65. doi:10.1111/j.1600-0897.2010.00842.x.
    1. Vanderstraeten A, Tuyaerts S, Amant F. The immune system in the normal endometrium and implications for endometrial cancer development. J Reprod Immunol. 2015;109:7–16. doi: 10.1016/j.jri.2014.12.006.
    1. Hwang WT, Adams SF, Tahirovic E, Hagemann IS, Coukos G. Prognostic significance of tumor-infiltrating T cells in ovarian cancer: a meta-analysis. Gynecol Oncol. 2012;124(2):192–198. doi: 10.1016/j.ygyno.2011.09.039.
    1. Deligdisch L. Morphologic correlates of host response in endometrial carcinoma. Am J Reproduc Immunol (New York, NY: 1989) 1982;2(1):54–57. doi: 10.1111/j.1600-0897.1982.tb00086.x.
    1. Silverberg SG, Sasano N, Yajima A. Endometrial carcinoma in Miyagi Prefecture, Japan: histopathologic analysis of a cancer registry-based series and comparison with cases in American women. Cancer. 1982;49(7):1504–1510. doi: 10.1002/1097-0142(19820401)49:7<1504::AID-CNCR2820490733>;2-9.
    1. Ambros RA, Kurman RJ. Combined assessment of vascular and myometrial invasion as a model to predict prognosis in stage I endometrioid adenocarcinoma of the uterine corpus. Cancer. 1992;69(6):1424–1431. doi: 10.1002/1097-0142(19920315)69:6<1424::AID-CNCR2820690620>;2-5.
    1. Kondratiev S, Sabo E, Yakirevich E, Lavie O, Resnick MB. Intratumoral CD8+ T lymphocytes as a prognostic factor of survival in endometrial carcinoma. Clin Cancer Res. 2004;10(13):4450–4456. doi: 10.1158/1078-0432.CCR-0732-3.
    1. de Jong RA, Leffers N, Boezen HM, ten Hoor KA, van der Zee AG, Hollema H, et al. Presence of tumor-infiltrating lymphocytes is an independent prognostic factor in type I and II endometrial cancer. Gynecol Oncol. 2009;114(1):105–110. doi: 10.1016/j.ygyno.2009.03.022.
    1. Yamagami W, Susumu N, Tanaka H, Hirasawa A, Banno K, Suzuki N, et al. Immunofluorescence-detected infiltration of CD4 + FOXP3+ regulatory T cells is relevant to the prognosis of patients with endometrial cancer. Int J Gynecol Cancer. 2011;21(9):1628–1634. doi: 10.1097/IGC.0b013e31822c271f.
    1. Giatromanolaki A, Bates GJ, Koukourakis MI, Sivridis E, Gatter KC, Harris AL, et al. The presence of tumor-infiltrating FOXP3+ lymphocytes correlates with intratumoral angiogenesis in endometrial cancer. Gynecol Oncol. 2008;110(2):216–221. doi: 10.1016/j.ygyno.2008.04.021.
    1. Kubler K, Ayub TH, Weber SK, Zivanovic O, Abramian A, Keyver-Paik MD, et al. Prognostic significance of tumor-associated macrophages in endometrial adenocarcinoma. Gynecol Oncol. 2014;135(2):176–183. doi: 10.1016/j.ygyno.2014.08.028.
    1. Chang WC, Li CH, Huang SC, Chang DY, Chou LY, Sheu BC. Clinical significance of regulatory T cells and CD8+ effector populations in patients with human endometrial carcinoma. Cancer. 2010;116(24):5777–5788. doi: 10.1002/cncr.25371.
    1. Vanderstraeten A, Luyten C, Verbist G, Tuyaerts S, Amant F. Mapping the immunosuppressive environment in uterine tumors: implications for immunotherapy. Cancer Immunol Immunother. 2014;63(6):545–557. doi: 10.1007/s00262-014-1537-8.
    1. Zsiros E, Odunsi K. Tumor-associated macrophages: co-conspirators and orchestrators of immune suppression in endometrial adenocarcinoma. Gynecol Oncol. 2014;135(2):173–175. doi: 10.1016/j.ygyno.2014.10.012.
    1. Dun EC, Hanley K, Wieser F, Bohman S, Yu J, Taylor RN. Infiltration of tumor-associated macrophages is increased in the epithelial and stromal compartments of endometrial carcinomas. Int J Gynecol Pathol. 2013;32(6):576–584. doi: 10.1097/PGP.0b013e318284e198.
    1. Jiang XF, Tang QL, Li HG, Shen XM, Luo X, Wang XY, et al. Tumor-associated macrophages correlate with progesterone receptor loss in endometrial endometrioid adenocarcinoma. J Obstet Gynaecol Res. 2013;39(4):855–863. doi: 10.1111/j.1447-0756.2012.02036.x.
    1. Salvesen HB, Akslen LA. Significance of tumour-associated macrophages, vascular endothelial growth factor and thrombospondin-1 expression for tumour angiogenesis and prognosis in endometrial carcinomas. Int J Cancer. 1999;84(5):538–543. doi: 10.1002/(SICI)1097-0215(19991022)84:5<538::AID-IJC17>;2-B.
    1. Hashimoto I, Kodama J, Seki N, Hongo A, Miyagi Y, Yoshinouchi M, et al. Macrophage infiltration and angiogenesis in endometrial cancer. Anticancer Res. 2000;20(6c):4853–4856.
    1. Soeda S, Nakamura N, Ozeki T, Nishiyama H, Hojo H, Yamada H, et al. Tumor-associated macrophages correlate with vascular space invasion and myometrial invasion in endometrial carcinoma. Gynecol Oncol. 2008;109(1):122–128. doi: 10.1016/j.ygyno.2007.12.033.
    1. Espinosa I, Jose Carnicer M, Catasus L, Canet B, D'Angelo E, Zannoni GF, et al. Myometrial invasion and lymph node metastasis in endometrioid carcinomas: tumor-associated macrophages, microvessel density, and HIF1A have a crucial role. Am J Surg Pathol. 2010;34(11):1708–1714.
    1. Ohno S, Ohno Y, Suzuki N, Kamei T, Koike K, Inagawa H, et al. Correlation of histological localization of tumor-associated macrophages with clinicopathological features in endometrial cancer. Anticancer Res. 2004;24(5c):3335–3342.
    1. Fujimoto J, Aoki I, Khatun S, Toyoki H, Tamaya T. Clinical implications of expression of interleukin-8 related to myometrial invasion with angiogenesis in uterine endometrial cancers. Ann Oncol. 2002;13(3):430–434. doi: 10.1093/annonc/mdf078.
    1. Tanaka Y, Kobayashi H, Suzuki M, Kanayama N, Suzuki M, Terao T. Thymidine phosphorylase expression in tumor-infiltrating macrophages may be correlated with poor prognosis in uterine endometrial cancer. Hum Pathol. 2002;33(11):1105–1113. doi: 10.1053/hupa.2002.129203.
    1. Melero I, Gaudernack G, Gerritsen W, Huber C, Parmiani G, Scholl S, et al. Therapeutic vaccines for cancer: an overview of clinical trials. Nat Rev Clin Oncol. 2014;11(9):509–524. doi: 10.1038/nrclinonc.2014.111.
    1. Coosemans A, Moerman P, Verbist G, Maes W, Neven P, Vergote I, et al. Wilms' tumor gene 1 (WT1) in endometrial carcinoma. Gynecol Oncol. 2008;111(3):502–508. doi: 10.1016/j.ygyno.2008.08.032.
    1. Ohno S, Kyo S, Myojo S, Dohi S, Ishizaki J, Miyamoto K, et al. Wilms' tumor 1 (WT1) peptide immunotherapy for gynecological malignancy. Anticancer Res. 2009;29(11):4779–4784.
    1. Coosemans A, Vanderstraeten A, Tuyaerts S, Verschuere T, Moerman P, Berneman ZN, et al. Wilms' Tumor Gene 1 (WT1)--loaded dendritic cell immunotherapy in patients with uterine tumors: a phase I/II clinical trial. Anticancer Res. 2013;33(12):5495–5500.
    1. Coosemans A, Wolfl M, Berneman ZN, Van Tendeloo V, Vergote I, Amant F, et al. Immunological response after therapeutic vaccination with WT1 mRNA-loaded dendritic cells in end-stage endometrial carcinoma. Anticancer Res. 2010;30(9):3709–3714.
    1. Gjerstorff MF, Andersen MH, Ditzel HJ. Oncogenic cancer/testis antigens: prime candidates for immunotherapy. Oncotarget. 2015;6(18):15772–15787. doi: 10.18632/oncotarget.4694.
    1. Resnick MB, Sabo E, Kondratev S, Kerner H, Spagnoli GC, Yakirevich E. Cancer-testis antigen expression in uterine malignancies with an emphasis on carcinosarcomas and papillary serous carcinomas. Int J Cancer. 2002;101(2):190–195. doi: 10.1002/ijc.10585.
    1. Okada T, Akada M, Fujita T, Iwata T, Goto Y, Kido K, et al. A novel cancer testis antigen that is frequently expressed in pancreatic, lung, and endometrial cancers. Clin Cancer Res. 2006;12(1):191–197. doi: 10.1158/1078-0432.CCR-05-1206.
    1. Hasegawa K, Koizumi F, Noguchi Y, Hongo A, Mizutani Y, Kodama J, et al. SSX expression in gynecological cancers and antibody response in patients. Cancer Immun. 2004;4:16.
    1. Jager E, Karbach J, Gnjatic S, Neumann A, Bender A, Valmori D, et al. Recombinant vaccinia/fowlpox NY-ESO-1 vaccines induce both humoral and cellular NY-ESO-1-specific immune responses in cancer patients. Proc Natl Acad Sci U S A. 2006;103(39):14453–14458. doi: 10.1073/pnas.0606512103.
    1. Santin AD, Bellone S, Gokden M, Palmieri M, Dunn D, Agha J, et al. Overexpression of HER-2/neu in uterine serous papillary cancer. Clin Cancer Res. 2002;8(5):1271–1279.
    1. Slomovitz BM, Broaddus RR, Burke TW, Sneige N, Soliman PT, Wu W, et al. Her-2/neu overexpression and amplification in uterine papillary serous carcinoma. J Clin Oncol. 2004;22(15):3126–3132. doi: 10.1200/JCO.2004.11.154.
    1. Odicino FE, Bignotti E, Rossi E, Pasinetti B, Tassi RA, Donzelli C, et al. HER-2/neu overexpression and amplification in uterine serous papillary carcinoma: comparative analysis of immunohistochemistry, real-time reverse transcription-polymerase chain reaction, and fluorescence in situ hybridization. Int J Gynecol Cancer. 2008;18(1):14–21. doi: 10.1111/j.1525-1438.2007.00946.x.
    1. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353(16):1659–1672. doi: 10.1056/NEJMoa052306.
    1. Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE, Jr, Davidson NE, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353(16):1673–1684. doi: 10.1056/NEJMoa052122.
    1. Kaumaya PT, Foy KC, Garrett J, Rawale SV, Vicari D, Thurmond JM, et al. Phase I active immunotherapy with combination of two chimeric, human epidermal growth factor receptor 2, B-cell epitopes fused to a promiscuous T-cell epitope in patients with metastatic and/or recurrent solid tumors. J Clin Oncol. 2009;27(31):5270–5277. doi: 10.1200/JCO.2009.22.3883.
    1. Inoue M, Shimizu H, Shimizu C, Sasagawa T, Ueda G, Tanizawa O, et al. Antitumor efficacy of recombinant interleukin 2-activated killer cells against endometrial cancers. Nihon Sanka Fujinka Gakkai zasshi. 1987;39(1):143–144.
    1. Shimizu H, Inoue M, Tanizawa O. Adoptive cellular immunotherapy to the endometrial carcinoma cell line xenografts in nude mice. Gynecol Oncol. 1989;34(2):195–199. doi: 10.1016/0090-8258(89)90141-8.
    1. Steis RG, Urba WJ, VanderMolen LA, Bookman MA, Smith JW, 2nd, Clark JW, et al. Intraperitoneal lymphokine-activated killer-cell and interleukin-2 therapy for malignancies limited to the peritoneal cavity. J Clin Oncol. 1990;8(10):1618–1629.
    1. Santin AD, Hermonat PL, Ravaggi A, Bellone S, Cowan C, Coke C, et al. Development and therapeutic effect of adoptively transferred T cells primed by tumor lysate-pulsed autologous dendritic cells in a patient with metastatic endometrial cancer. Gynecol Obstet Invest. 2000;49(3):194–203. doi: 10.1159/000010246.
    1. Santin AD, Bellone S, Ravaggi A, Roman JJ, Pecorelli S, Parham GP, et al. Induction of tumour-specific CD8(+) cytotoxic T lymphocytes by tumour lysate-pulsed autologous dendritic cells in patients with uterine serous papillary cancer. Br J Cancer. 2002;86(1):151–157. doi: 10.1038/sj.bjc.6600026.
    1. Wickramasinghe D. Tumor and T cell engagement by BiTE. Discov Med. 2013;16(88):149–152.
    1. Topp MS, Gokbuget N, Zugmaier G, Klappers P, Stelljes M, Neumann S, et al. Phase II trial of the anti-CD19 bispecific T cell-engager blinatumomab shows hematologic and molecular remissions in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia. J Clin Oncol. 2014;32(36):4134–4140. doi: 10.1200/JCO.2014.56.3247.
    1. Bellone S, Black J, English DP, Schwab CL, Lopez S, Cocco E et al. Solitomab, an EpCAM/CD3 bispecific antibody construct (BiTE(R)), is highly active against primary uterine serous papillary carcinoma cell lines in vitro. American journal of obstetrics and gynecology. 2015. doi:10.1016/j.ajog.2015.08.011.
    1. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–264. doi: 10.1038/nrc3239.
    1. Herzog T, Arguello D, Reddy S, Gatalica Z. PD-1 and PD-L1 expression in 1599 gynecological malignancies - implications for immunotherapy. Gynecol Oncol. 2015;137:Suppl. 1.
    1. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, 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):2455–2465. doi: 10.1056/NEJMoa1200694.
    1. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. 2015;372(26):2509–2520. doi: 10.1056/NEJMoa1500596.

Source: PubMed

3
Tilaa