Assessment Study to Evaluate Specific Immune Response in Locally Advanced Cervix Cancer After Radio-chemotherapy

Summary

Perspectives: * To set-up another clinical trial with this specific phenotype as the main stratification factor. Therefore a more aggressive or a more specific systemic treatment (with or without an immunomodulator) could be proposed to those selected patients in the field of personalized medicine. * To evaluate the use of the smear as a surrogate non-invasive technique to biopsy for immunomonitoring. * To use the CTC/PD-L1 assay as a liquid biopsy in future clinical trials for stratification and monitoring of cancer patients undergoing immune checkpoint treatments. This specific subset of CTCs might represent metastatic cells with a high potential to escape T cell-mediated lysis and might therefore be the actual targets of immunotherapy.

Timeline

Start

2017-07-15

Primary completion

2022-06-16

Completion

2023-11-23

Outcome

Outcome not reported

Stopped (Enrollment): “insufficient recruitment”

Publications

• Background Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015 Mar 1;136(5):E359-86. doi: 10.1002/ijc.29210. Epub 2014 Oct 9.
• Background De Vuyst H, Clifford G, Li N, Franceschi S. HPV infection in Europe. Eur J Cancer. 2009 Oct;45(15):2632-9. doi: 10.1016/j.ejca.2009.07.019. Epub 2009 Aug 24.
• Background zur Hausen H. Papillomavirus infections--a major cause of human cancers. Biochim Biophys Acta. 1996 Oct 9;1288(2):F55-78. doi: 10.1016/0304-419x(96)00020-0.
• Background Mauch P, Constine L, Greenberger J, Knospe W, Sullivan J, Liesveld JL, Deeg HJ. Hematopoietic stem cell compartment: acute and late effects of radiation therapy and chemotherapy. Int J Radiat Oncol Biol Phys. 1995 Mar 30;31(5):1319-39. doi: 10.1016/0360-3016(94)00430-S.
• Background Mell LK, Tiryaki H, Ahn KH, Mundt AJ, Roeske JC, Aydogan B. Dosimetric comparison of bone marrow-sparing intensity-modulated radiotherapy versus conventional techniques for treatment of cervical cancer. Int J Radiat Oncol Biol Phys. 2008 Aug 1;71(5):1504-10. doi: 10.1016/j.ijrobp.2008.04.046.
• Background Kobayashi A, Weinberg V, Darragh T, Smith-McCune K. Evolving immunosuppressive microenvironment during human cervical carcinogenesis. Mucosal Immunol. 2008 Sep;1(5):412-20. doi: 10.1038/mi.2008.33. Epub 2008 Jul 2.
• Background Jordanova ES, Gorter A, Ayachi O, Prins F, Durrant LG, Kenter GG, van der Burg SH, Fleuren GJ. Human leukocyte antigen class I, MHC class I chain-related molecule A, and CD8+/regulatory T-cell ratio: which variable determines survival of cervical cancer patients? Clin Cancer Res. 2008 Apr 1;14(7):2028-35. doi: 10.1158/1078-0432.CCR-07-4554.
• Background Hasim A, Abudula M, Aimiduo R, Ma JQ, Jiao Z, Akula G, Wang T, Abudula A. Post-transcriptional and epigenetic regulation of antigen processing machinery (APM) components and HLA-I in cervical cancers from Uighur women. PLoS One. 2012;7(9):e44952. doi: 10.1371/journal.pone.0044952. Epub 2012 Sep 14.
• Background Gadducci A, Guerrieri ME, Greco C. Tissue biomarkers as prognostic variables of cervical cancer. Crit Rev Oncol Hematol. 2013 May;86(2):104-29. doi: 10.1016/j.critrevonc.2012.09.003. Epub 2012 Sep 30.
• Background Bell MC, Edwards RP, Partridge EE, Kuykendall K, Conner W, Gore H, Turbat-Herrara E, Crowley-Nowick PA. CD8+ T lymphocytes are recruited to neoplastic cervix. J Clin Immunol. 1995 May;15(3):130-6. doi: 10.1007/BF01543104.
• Background Yamazawa K, Matsui H, Ishikura H, Seki K, Mitsuhashi A, Sekiya S. Significance of perivascular lymphocytic infiltrates on survival of patients with invasive cervical cancer. J Immunother. 2003 Mar-Apr;26(2):149-55. doi: 10.1097/00002371-200303000-00007.
• Background Piersma SJ, Jordanova ES, van Poelgeest MI, Kwappenberg KM, van der Hulst JM, Drijfhout JW, Melief CJ, Kenter GG, Fleuren GJ, Offringa R, van der Burg SH. High number of intraepithelial CD8+ tumor-infiltrating lymphocytes is associated with the absence of lymph node metastases in patients with large early-stage cervical cancer. Cancer Res. 2007 Jan 1;67(1):354-61. doi: 10.1158/0008-5472.CAN-06-3388.
• Background de Vos van Steenwijk PJ, Ramwadhdoebe TH, Goedemans R, Doorduijn EM, van Ham JJ, Gorter A, van Hall T, Kuijjer ML, van Poelgeest MI, van der Burg SH, Jordanova ES. Tumor-infiltrating CD14-positive myeloid cells and CD8-positive T-cells prolong survival in patients with cervical carcinoma. Int J Cancer. 2013 Dec 15;133(12):2884-94. doi: 10.1002/ijc.28309. Epub 2013 Jul 5.
• Background Sznol M, Chen L. Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer. Clin Cancer Res. 2013 Mar 1;19(5):1021-34. doi: 10.1158/1078-0432.CCR-12-2063.
• Background Karim R, Jordanova ES, Piersma SJ, Kenter GG, Chen L, Boer JM, Melief CJ, van der Burg SH. Tumor-expressed B7-H1 and B7-DC in relation to PD-1+ T-cell infiltration and survival of patients with cervical carcinoma. Clin Cancer Res. 2009 Oct 15;15(20):6341-7. doi: 10.1158/1078-0432.CCR-09-1652. Epub 2009 Oct 13.
• Background Yan J, Zhang Y, Zhang JP, Liang J, Li L, Zheng L. Tim-3 expression defines regulatory T cells in human tumors. PLoS One. 2013;8(3):e58006. doi: 10.1371/journal.pone.0058006. Epub 2013 Mar 5.
• Background Bastid J, Cottalorda-Regairaz A, Alberici G, Bonnefoy N, Eliaou JF, Bensussan A. ENTPD1/CD39 is a promising therapeutic target in oncology. Oncogene. 2013 Apr 4;32(14):1743-51. doi: 10.1038/onc.2012.269. Epub 2012 Jul 2.
• Background Bastid J, Regairaz A, Bonnefoy N, Dejou C, Giustiniani J, Laheurte C, Cochaud S, Laprevotte E, Funck-Brentano E, Hemon P, Gros L, Bec N, Larroque C, Alberici G, Bensussan A, Eliaou JF. Inhibition of CD39 enzymatic function at the surface of tumor cells alleviates their immunosuppressive activity. Cancer Immunol Res. 2015 Mar;3(3):254-65. doi: 10.1158/2326-6066.CIR-14-0018. Epub 2014 Nov 17.
• Background Bonnefoy N, Bastid J, Alberici G, Bensussan A, Eliaou JF. CD39: A complementary target to immune checkpoints to counteract tumor-mediated immunosuppression. Oncoimmunology. 2015 Feb 3;4(5):e1003015. doi: 10.1080/2162402X.2014.1003015. eCollection 2015 May.
• Background Ma Y, Adjemian S, Mattarollo SR, Yamazaki T, Aymeric L, Yang H, Portela Catani JP, Hannani D, Duret H, Steegh K, Martins I, Schlemmer F, Michaud M, Kepp O, Sukkurwala AQ, Menger L, Vacchelli E, Droin N, Galluzzi L, Krzysiek R, Gordon S, Taylor PR, Van Endert P, Solary E, Smyth MJ, Zitvogel L, Kroemer G. Anticancer chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting cells. Immunity. 2013 Apr 18;38(4):729-41. doi: 10.1016/j.immuni.2013.03.003. Epub 2013 Apr 4.
• Background Ko A, Kanehisa A, Martins I, Senovilla L, Chargari C, Dugue D, Marino G, Kepp O, Michaud M, Perfettini JL, Kroemer G, Deutsch E. Autophagy inhibition radiosensitizes in vitro, yet reduces radioresponses in vivo due to deficient immunogenic signalling. Cell Death Differ. 2014 Jan;21(1):92-9. doi: 10.1038/cdd.2013.124. Epub 2013 Sep 13.
• Background Evans EM, Man S, Evans AS, Borysiewicz LK. Infiltration of cervical cancer tissue with human papillomavirus-specific cytotoxic T-lymphocytes. Cancer Res. 1997 Jul 15;57(14):2943-50.
• Background Hohn H, Pilch H, Gunzel S, Neukirch C, Freitag K, Necker A, Maeurer MJ. Human papillomavirus type 33 E7 peptides presented by HLA-DR*0402 to tumor-infiltrating T cells in cervical cancer. J Virol. 2000 Jul;74(14):6632-6. doi: 10.1128/jvi.74.14.6632-6636.2000.
• Background Hohn H, Pilch H, Gunzel S, Neukirch C, Hilmes C, Kaufmann A, Seliger B, Maeurer MJ. CD4+ tumor-infiltrating lymphocytes in cervical cancer recognize HLA-DR-restricted peptides provided by human papillomavirus-E7. J Immunol. 1999 Nov 15;163(10):5715-22.
• Background Hilders CG, Ras L, van Eendenburg JD, Nooyen Y, Fleuren GJ. Isolation and characterization of tumor-infiltrating lymphocytes from cervical carcinoma. Int J Cancer. 1994 Jun 15;57(6):805-13. doi: 10.1002/ijc.2910570608.
• Background Santin AD, Bellone S, Palmieri M, Bossini B, Roman JJ, Cannon MJ, Bignotti E, Cane S, Pecorelli S. Induction of tumor-specific cytotoxicity in tumor infiltrating lymphocytes by HPV16 and HPV18 E7-pulsed autologous dendritic cells in patients with cancer of the uterine cervix. Gynecol Oncol. 2003 May;89(2):271-80. doi: 10.1016/s0090-8258(03)00083-0.
• Background de Jong A, van Poelgeest MI, van der Hulst JM, Drijfhout JW, Fleuren GJ, Melief CJ, Kenter G, Offringa R, van der Burg SH. Human papillomavirus type 16-positive cervical cancer is associated with impaired CD4+ T-cell immunity against early antigens E2 and E6. Cancer Res. 2004 Aug 1;64(15):5449-55. doi: 10.1158/0008-5472.CAN-04-0831.
• Background Kenter GG, Welters MJ, Valentijn AR, Lowik MJ, Berends-van der Meer DM, Vloon AP, Essahsah F, Fathers LM, Offringa R, Drijfhout JW, Wafelman AR, Oostendorp J, Fleuren GJ, van der Burg SH, Melief CJ. Vaccination against HPV-16 oncoproteins for vulvar intraepithelial neoplasia. N Engl J Med. 2009 Nov 5;361(19):1838-47. doi: 10.1056/NEJMoa0810097.
• Background Heusinkveld M, Welters MJ, van Poelgeest MI, van der Hulst JM, Melief CJ, Fleuren GJ, Kenter GG, van der Burg SH. The detection of circulating human papillomavirus-specific T cells is associated with improved survival of patients with deeply infiltrating tumors. Int J Cancer. 2011 Jan 15;128(2):379-89. doi: 10.1002/ijc.25361. Epub 2010 Apr 5.
• Background van der Burg SH, Ressing ME, Kwappenberg KM, de Jong A, Straathof K, de Jong J, Geluk A, van Meijgaarden KE, Franken KL, Ottenhoff TH, Fleuren GJ, Kenter G, Melief CJ, Offringa R. Natural T-helper immunity against human papillomavirus type 16 (HPV16) E7-derived peptide epitopes in patients with HPV16-positive cervical lesions: identification of 3 human leukocyte antigen class II-restricted epitopes. Int J Cancer. 2001 Mar 1;91(5):612-8. doi: 10.1002/1097-0215(200002)9999:99993.0.co;2-c.
• Background Welters MJ, de Jong A, van den Eeden SJ, van der Hulst JM, Kwappenberg KM, Hassane S, Franken KL, Drijfhout JW, Fleuren GJ, Kenter G, Melief CJ, Offringa R, van der Burg SH. Frequent display of human papillomavirus type 16 E6-specific memory t-Helper cells in the healthy population as witness of previous viral encounter. Cancer Res. 2003 Feb 1;63(3):636-41.
• Background Welters MJ, van der Logt P, van den Eeden SJ, Kwappenberg KM, Drijfhout JW, Fleuren GJ, Kenter GG, Melief CJ, van der Burg SH, Offringa R. Detection of human papillomavirus type 18 E6 and E7-specific CD4+ T-helper 1 immunity in relation to health versus disease. Int J Cancer. 2006 Feb 15;118(4):950-6. doi: 10.1002/ijc.21459.
• Background Ressing ME, van Driel WJ, Celis E, Sette A, Brandt MP, Hartman M, Anholts JD, Schreuder GM, ter Harmsel WB, Fleuren GJ, Trimbos BJ, Kast WM, Melief CJ. Occasional memory cytotoxic T-cell responses of patients with human papillomavirus type 16-positive cervical lesions against a human leukocyte antigen-A *0201-restricted E7-encoded epitope. Cancer Res. 1996 Feb 1;56(3):582-8.
• Background Bontkes HJ, de Gruijl TD, van den Muysenberg AJ, Verheijen RH, Stukart MJ, Meijer CJ, Scheper RJ, Stacey SN, Duggan-Keen MF, Stern PL, Man S, Borysiewicz LK, Walboomers JM. Human papillomavirus type 16 E6/E7-specific cytotoxic T lymphocytes in women with cervical neoplasia. Int J Cancer. 2000 Oct 1;88(1):92-8.
• Background Luxton JC, Rowe AJ, Cridland JC, Coletart T, Wilson P, Shepherd PS. Proliferative T cell responses to the human papillomavirus type 16 E7 protein in women with cervical dysplasia and cervical carcinoma and in healthy individuals. J Gen Virol. 1996 Jul;77 ( Pt 7):1585-93. doi: 10.1099/0022-1317-77-7-1585.
• Background Steinert G, Scholch S, Niemietz T, Iwata N, Garcia SA, Behrens B, Voigt A, Kloor M, Benner A, Bork U, Rahbari NN, Buchler MW, Stoecklein NH, Weitz J, Koch M. Immune escape and survival mechanisms in circulating tumor cells of colorectal cancer. Cancer Res. 2014 Mar 15;74(6):1694-704. doi: 10.1158/0008-5472.CAN-13-1885. Epub 2014 Mar 5.
• Background Mazel M, Jacot W, Pantel K, Bartkowiak K, Topart D, Cayrefourcq L, Rossille D, Maudelonde T, Fest T, Alix-Panabieres C. Frequent expression of PD-L1 on circulating breast cancer cells. Mol Oncol. 2015 Nov;9(9):1773-82. doi: 10.1016/j.molonc.2015.05.009. Epub 2015 Jun 9.
• Background Golden EB, Apetoh L. Radiotherapy and immunogenic cell death. Semin Radiat Oncol. 2015 Jan;25(1):11-7. doi: 10.1016/j.semradonc.2014.07.005.
• Background Delgado FG, Martinez E, Cespedes MA, Bravo MM, Navas MC, Combita Rojas AL. Increase of human papillomavirus-16 E7-specific T helper type 1 response in peripheral blood of cervical cancer patients after radiotherapy. Immunology. 2009 Apr;126(4):523-34. doi: 10.1111/j.1365-2567.2008.02912.x. Epub 2008 Sep 5.
• Background Lim K, Small W Jr, Portelance L, Creutzberg C, Jurgenliemk-Schulz IM, Mundt A, Mell LK, Mayr N, Viswanathan A, Jhingran A, Erickson B, De los Santos J, Gaffney D, Yashar C, Beriwal S, Wolfson A, Taylor A, Bosch W, El Naqa I, Fyles A; Gyn IMRT Consortium. Consensus guidelines for delineation of clinical target volume for intensity-modulated pelvic radiotherapy for the definitive treatment of cervix cancer. Int J Radiat Oncol Biol Phys. 2011 Feb 1;79(2):348-55. doi: 10.1016/j.ijrobp.2009.10.075. Epub 2010 May 14.

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