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Immunotherapy in Cervical Cancer

  • Gynecologic Cancers (J Brown and RW Naumann, Section Editors)
  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

This review aims to summarize the current immunotherapy studies and the potential targeted therapies showing promise in the treatment of cervical cancer.

Recent Findings

There are promising ongoing monotherapy and combination therapy trials using different immune checkpoint inhibitors, poly adenosine diphosphate ribose polymerase inhibitors, tumor angiogenesis inhibitors (i.e., bevacizumab), antibody-drug conjugates, therapeutic vaccines, and tumor-infiltrating T lymphocytes (adoptive immunotherapy). Some of these novel modalities are also being evaluated in combination with standard platinum-based chemotherapy regimen. At this time, pembrolizumab is approved for the treatment of relapsed or metastatic programmed death ligand 1 (PD-L1) positive cervical cancer after frontline chemotherapy treatment.

Summary

Multiple novel therapeutic modalities are emerging as safe and effective for the treatment of cervical cancer patients. Development and participation in investigative treatments can provide benefit and improve outcomes in cervical cancer.

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References

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

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. https://doi.org/10.3322/caac.21492 Erratum in: CA Cancer J Clin. 2020 Jul;70(4):313.

    Article  PubMed  Google Scholar 

  2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020 Jan;70(1):7–30. https://doi.org/10.3322/caac.21590.

    Article  PubMed  Google Scholar 

  3. National Comprehensive Cancer Network, Clinical practice guidelines in oncology: cervical cancer, version 4. 2019. https://www.nccn.org/professionals/physician_gls/pdf/cervical.pdf. March 29 2019.

  4. National Cancer Institute: cancer stat facts: cervix uteri cancer.https://seer.cancer.gov/statfacts/html/cervix.htm.

  5. Pfaendler KS, Tewari KS. Changing paradigms in the systemic treatment of advanced cervical cancer. Am J Obstet Gynecol. 2016;214(1):22–30. https://doi.org/10.1016/j.ajog.2015.07.022.

    Article  PubMed  Google Scholar 

  6. Ries LAG, Harkins D, Krapcho M, et al. SEER cancer statistics review, 1975 to 2003. Bethesda: National Cancer Institute; 2006.

    Google Scholar 

  7. Surveillance, epidemiology, and end results. SEER registry data, 2000 to 2004. http://seer.cancer.gov/. Accessed 25 April 2011.

  8. Long HJ III, Bundy BN, Grendys EC Jr, et al. Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: a gynecologic oncology group study. J Clin Oncol. 2005;23:4626–33.

    Article  CAS  PubMed  Google Scholar 

  9. Monk BJ, Sill MW, McMeekin DS, et al. Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a gynecologic oncology group study. J Clin Oncol. 2009;27:4649–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Moore DH, Blessing JA, McQuellon RP, et al. Phase III study of cisplatin with or without paclitaxel in stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix: a gynecologic oncology group study. J Clin Oncol. 2004;22:3113–9.

    Article  CAS  PubMed  Google Scholar 

  11. Tewari KS, Sill MW, Long HJ 3rd, Penson RT, Huang H, Ramondetta LM, et al. Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med. 2014;370(8):734–43. https://doi.org/10.1056/NEJMoa1309748 Erratum in: N Engl J Med. 2017 Aug 17;377(7):702.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. de Sanjose S, Quint WG, Alemany L, Geraets DT, Klaustermeier JE, Lloveras B, et al. Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncol. 2010;11:1048–56.

    Article  PubMed  Google Scholar 

  13. Varga A, Piha-Paul SA, Ott PA, et al. Pembrolizumab in patients (pts) with PD-L1-positive (PD-L1+) advanced ovarian cancer: updated analysis of KEYNOTE-028. J Clin Oncol. 2017;35:abstr 5513.

    Article  Google Scholar 

  14. Lyford-Pike S, Peng S, Young GD, Taube JM, Westra WH, Akpeng B, et al. Evidence for a role of the PD-1:PD-L1 pathway in immune resistance of HPV-associated head and neck squamous cell carcinoma. Cancer Res. 2013;73:1733–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Mezache L, Paniccia B, Nyinawabera A, Nuovo GJ. Enhanced expression of PD L1 in cervical intraepithelial neoplasia and cervical cancers. Mod Pathol. 2015;28:1594–602.

    Article  CAS  PubMed  Google Scholar 

  16. Chung HC, Ros W, Delord JP, et al. Efficacy and safety of pembrolizumab in previously treated advanced cervical cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol. 2019;37:1470 The findings in KEYNOTE-158 led to the FDA approval of pembrolizumab for the treatment of relapsed or metastatic cervical cancer after frontline chemotherapy treatment who had tumors with PD-L1 expression.

    Article  CAS  PubMed  Google Scholar 

  17. Frenel JS, Le Tourneau C, O’Neil B, et al. Safety and efficacy of pembrolizumab in advanced, programmed death ligand 1-positive cervical cancer: results from the phase Ib KEYNOTE-028 Trial. J Clin Oncol. 2017;35:4035–41.

    Article  CAS  PubMed  Google Scholar 

  18. Hollebecque A, Meyer T, Nadine Moore K: et al: an open-label, multicohort, phase 1/2 study of nivolumab in patients with virus-associated tumors (CheckMate 358): efficacy and safety in recurrent or metastatic cervical, vaginal, and vulvar cancers. Presented at American Society of Clinical Oncology Annual Meeting, Chicago, IL, June 2-6, 2017 (abstr 5504).

  19. Santin AD, Deng W, Frumovitz M, Buza N, Bellone S, Huh W, et al. Phase II evaluation of nivolumab in the treatment of persistent or recurrent cervical cancer (NCT02257528/NRG-GY002). Gynecol Oncol. 2020;157(1):161–6. https://doi.org/10.1016/j.ygyno.2019.12.034This NRG-GY002 trial evaluated the activity of single agent nivolumab in persistent or recurrent cervical cancer patients. Nivolumab had acceptable safety profile but low antitumor activity in cervical cancer. Combination treatment with immune check-point inhibitors may be necessary to increase clinical responses in cervical cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Friedman CF, Snyder Charen A, Zhou Q, Carducci MA, Buckley De Meritens A, Corr BR, et al. Phase II study of atezolizumab in combination with bevacizumab in patients with advanced cervical cancer. J Immunother Cancer. 2020;8(2):e001126. https://doi.org/10.1136/jitc-2020-001126.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Mayadev J, Nunes AT, Li M, Marcovitz M, Lanasa MC, Monk BJ. CALLA: Efficacy and safety of concurrent and adjuvant durvalumab with chemoradiotherapy versus chemoradiotherapy alone in women with locally advanced cervical cancer: a phase III, randomized, double-blind, multicenter study. Int J Gynecol Cancer. 2020;30(7):1065–70. https://doi.org/10.1136/ijgc-2019-001135.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Callahan MK, Wolchok JD. At the bedside: CTLA-4 and PD-1 blocking antibodies in cancer immunotherapy. J Leukoc Biol. 2013;94:41–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Naumann RW, Oaknin A, Meyer T, et al: Efficacy and safety of nivolumab + ipilimumab in patients with recurrent/metastatic cervical cancer. ESMO Congress 2019. Abstract LBA62. Presented September 29, 2019. This abstract reported the interim results suggesting clinical benefit from two regimens of combination nivolumab and ipilimumab for the recurrent and metastatic cervical cancer regardless of PD-L1 status.

  24. O’Malley DM, Oaknin A, Monk BJ, Leary A, Selle F, Alexandre J, et al. LBA34 Single-agent anti-PD-1 balstilimab or in combination with anti-CTLA-4 zalifrelimab for recurrent/metastatic (R/M) cervical cancer (CC): preliminary results of two independent phase II trials. Ann Oncol. 2020;31(Supplement 4):S1164–5, ISSN 0923-7534. https://doi.org/10.1016/j.annonc.2020.08.2264.

    Article  Google Scholar 

  25. Grau JF, Farinas-Madrid L, Oaknin A. A randomized phase III trial of platinum chemotherapy plus paclitaxel with bevacizumab and atezolizumab versus platinum chemotherapy plus paclitaxel and bevacizumab in metastatic (stage IVB), persistent, or recurrent carcinoma of the cervix: the BEATcc study (ENGOT-Cx10/GEICO 68-C/JGOG1084/GOG-3030). Int J Gynecol Cancer. 2020;30(1):139–43. https://doi.org/10.1136/ijgc-2019-000880.

    Article  PubMed  Google Scholar 

  26. Fujiwara K, Shapira-Frommer R, Alexandre J, Monk B, Fehm T, Colombo N, et al. 265TiP - KEYNOTE-826: A phase III randomized study of chemotherapy with or without pembrolizumab for first-line treatment of persistent, recurrent, or metastatic cervical cancer. Ann Oncol. 2019;30(9):ix89–90 ISSN 0923-7534. https://doi.org/10.1093/annonc/mdz426.040.

    Article  Google Scholar 

  27. Duska LR, Scalici JM, Temkin SM, Schwarz JK, Crane EK, Moxley KM, et al. Results of an early safety analysis of a study of the combination of pembrolizumab and pelvic chemoradiation in locally advanced cervical cancer. Cancer. 2020;126(22):4948–56. https://doi.org/10.1002/cncr.33136.

    Article  CAS  PubMed  Google Scholar 

  28. Lorusso D, Colombo N, Coleman R, et al. 164 ENGOT-cx11/GOG 3047/KEYNOTE-A18: a phase 3, randomized, double-blind study of pembrolizumab with chemoradiotherapy in patients with high-risk locally advanced cervical cancer. Int J Gynecol Cancer. 2020;30:A71.

    Google Scholar 

  29. Fong PC, Yap TA, Boss DS, Carden CP, Mergui-Roelvink M, Gourley C, et al. Poly (ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. J Clin Oncol. 2010;28:2512–9.

    Article  CAS  PubMed  Google Scholar 

  30. Pujade-Lauraine E, Ledermann JA, Selle F, Gebski V, Penson RT, Oza AM, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18:1274–84.

    Article  CAS  PubMed  Google Scholar 

  31. Fukushima M, Kuzuya K, Ota K, Ikai K. Poly(ADP-ribose) synthesis in human cervical cancer cell-diagnostic cytological usefulness. Cancer Lett. 1981;14:227–36.

    Article  CAS  PubMed  Google Scholar 

  32. Hassumi-Fukasawa MK, Miranda-Camargo FA, Zanetti BR, Galano DF, Ribeiro-Silva A, Soares EG. Expression of BAG-1 and PARP-1 in precursor lesions and invasive cervical cancer associated with human papillomavirus (HPV). Pathol Oncol Res. 2012;18:929–37.

    Article  CAS  PubMed  Google Scholar 

  33. Bianchi A, Lopez S, Altwerger G, Bellone S, Bonazzoli E, Zammataro L, et al. PARP-1 activity (PAR) determines the sensitivity of cervical cancer to olaparib. Gynecol Oncol. 2019;155:144–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Michels J, Vitale I, Galluzzi L, Adam J, Olaussen KA, Kepp O, et al. Cisplatin resistance associated with PARP hyperactivation. Cancer Res. 2013;73:2271–80.

    Article  CAS  PubMed  Google Scholar 

  35. Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 2005;23(5):1011–27. https://doi.org/10.1200/JCO.2005.06.081.

    Article  CAS  PubMed  Google Scholar 

  36. Tewari KS, Sill MW, Penson RT, Huang H, Ramondetta LM, Landrum LM, et al. Bevacizumab for advanced cervical cancer: final overall survival and adverse event analysis of a randomised, controlled, open-label, phase 3 trial (Gynecologic Oncology Group 240). Lancet. 2017;390(10103):1654 This is the final analysis of GOG 240 trial, showing the addition of bevacizumab to chemotherapy resulted in significant improvements in OS and PFS compared to chemotherapy alone.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Suzuki K, Nagao S, Shibutani T, Yamamoto K, Jimi T, Yano H, et al. Phase II trial of paclitaxel, carboplatin, and bevacizumab for advanced or recurrent cervical cancer. Gynecol Oncol. 2019;154(3):554–7. https://doi.org/10.1016/j.ygyno.2019.05.018.

    Article  CAS  PubMed  Google Scholar 

  38. Santin AD, Sill MW, McMeekin DS, Leitao MM Jr, Brown J, Sutton GP, et al. Phase II trial of cetuximab in the treatment of persistent or recurrent squamous or non-squamous cell carcinoma of the cervix: a gynecologic oncology group study. Gynecol Oncol. 2011;122(3):495–500. https://doi.org/10.1016/j.ygyno.2011.05.040.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Farley J, Sill MW, Birrer M, Walker J, Schilder RJ, Thigpen JT, et al. Phase II study of cisplatin plus cetuximab in advanced, recurrent, and previously treated cancers of the cervix and evaluation of epidermal growth factor receptor immunohistochemical expression: a gynecologic oncology group study. Gynecol Oncol. 2011;121(2):303–8. https://doi.org/10.1016/j.ygyno.2011.01.030.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zeybek B, Manzano A, Bianchi A, Bonazzoli E, Bellone S, Buza N, et al. Cervical carcinomas that overexpress human trophoblast cell-surface marker (Trop-2) are highly sensitive to the antibody-drug conjugate sacituzumab govitecan. Sci Rep. 2020;10(1):973. https://doi.org/10.1038/s41598-020-58009-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Hong DS, Concin N, Vergote I, de Bono JS, Slomovitz BM, Drew Y, et al. Tisotumab vedotin in previously treated recurrent or metastatic cervical cancer. Clin Cancer Res. 2020;26(6):1220–8. https://doi.org/10.1158/1078-0432.CCR-19-2962.

    Article  CAS  PubMed  Google Scholar 

  42. Coleman RL, Lorusso D, Gennigens C, et al. Tisotumab vedotin in previously treated recurrent or metastatic cervical cancer: Results from the phase II innovaTV 204/GOG-3023/ENGOT-cx6 study. Ann Oncol. 2020;31(Supplement 4):S1162–3.

    Article  Google Scholar 

  43. Menderes G, Black J, Schwab CL, Santin AD. Immunotherapy and targeted therapy for cervical cancer: an update. Expert Rev Anticancer Ther. 2016;16(1):83–98. https://doi.org/10.1586/14737140.2016.1121108 Epub 2015 Dec 7.

    Article  CAS  PubMed  Google Scholar 

  44. Miles BA, Monk BJ, Safran HP. Mechanistic insights into ADXS11-001 human papillomavirus-associated cancer immunotherapy. Gynecol Oncol Res Pract. 2017;4:9. https://doi.org/10.1186/s40661-017-0046-9.

    Article  PubMed  PubMed Central  Google Scholar 

  45. • Huh WK, Brady WE, Fracasso PM, Dizon DS, Powell MA, Monk BJ, et al. Phase II study of axalimogene filolisbac (ADXS-HPV) for platinum-refractory cervical carcinoma: an NRG oncology/gynecologic oncology group study. Gynecol Oncol. 2020;158(3):562–9. https://doi.org/10.1016/j.ygyno.2020.06.493This trial reported therapeutic vaccine, axalimogene filolisbac, in patients with progressed cervical cancer a 12-month OS of 38%, median OS of 6.1 months and median PFS of 2.8 months.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Basu P, Mehta A, Jain M, Gupta S, Nagarkar RV, John S, et al. A Randomized Phase 2 Study of ADXS11-001 Listeria monocytogenes-Listeriolysin O Immunotherapy with or without cisplatin in treatment of advanced cervical cancer. Int J Gynecol Cancer. 2018;28(4):764–72. https://doi.org/10.1097/IGC.0000000000001235.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Choi YJ, Hur SY, Kim TJ, Hong SR, Lee JK, Cho CH, et al. A Phase II, Prospective, randomized, multicenter, open-label study of GX-188E, an HPV DNA vaccine, in patients with cervical intraepithelial neoplasia 3. Clin Cancer Res. 2020;26(7):1616–23. https://doi.org/10.1158/1078-0432.CCR-19-1513.

    Article  CAS  PubMed  Google Scholar 

  48. Bollard CM, Gottschalk S, Torrano V, Diouf O, Ku S, Hazrat Y, et al. Sustained complete responses in patients with lymphoma receiving autologous cytotoxic T lymphocytes targeting Epstein-Barr virus latent membrane proteins. J Clin Oncol. 2014;32:798–808.

    Article  CAS  PubMed  Google Scholar 

  49. Heslop HE, Slobod KS, Pule MA, Hale GA, Rousseau A, Smith CA, et al. Longterm outcome of EBV-specific T cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients. Blood. 2010;115:925–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Robbins PF, Morgan RA, Feldman SA, Yang JC, Sherry RM, Dudley ME, et al. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol. 2011;29:917–24.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Rosenberg SA, Yang JC, Sherry RM, et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T cell transfer immunotherapy. Clin Cancer Res. 2011;17:45504557.

    Article  Google Scholar 

  52. Stevanovic S, Draper LM, Langhan MM, et al. Complete regression of metastatic cervical cancer after treatment with human papillomavirus-targeted tumor-infiltrating T cells. J Clin Oncol. 2015;33:1543–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Stevanovic S, Helman SR, Wunderlich JR, et al. A phase II study of tumor-infiltrating lymphocyte therapy for human papillomavirus-associated epithelial cancers. Clin Cancer Res. 2019;25:1486–93.

    Article  CAS  PubMed  Google Scholar 

  54. Jazaeri AA, et al. Safety and efficacy of adoptive cell transfer using autologous tumor-infiltrating lymphocytes (LN-145) for treatment of recurrent, metastatic, or persistent cervical carcinoma. J Clin Oncol. 2019;37(15_suppl):2538.

    Article  Google Scholar 

  55. Stevanović S, Pasetto A, Helman SR, Gartner JJ, Prickett TD, Howie B, et al. Landscape of immunogenic tumor antigens in successful immunotherapy of virally induced epithelial cancer. Science. 2017;356(6334):200–5. https://doi.org/10.1126/science.aak9510.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, LSOG Bld. Room 305, 333 Cedar Street, PO Box 208063, New Haven, CT, 06520-8063, USA

    Dennis Mauricio, Burak Zeybek, Joan Tymon-Rosario, Justin Harold & Alessandro D. Santin

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  1. Dennis Mauricio
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  2. Burak Zeybek
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Correspondence to Alessandro D. Santin.

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All authors fulfill the conditions required for authorship.

Dennis Mauricio, Burak Zeybek, Joan Tymon-Rosario, and Justin Harold declare no conflict of interest. Alessandro D. Santin has received research funding from Puma Biotechnology, Immunomedics, Gilead Sciences, Synthon, Merck, Boehringer-Ingelheim, Genentech, and Tesaro

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Mauricio, D., Zeybek, B., Tymon-Rosario, J. et al. Immunotherapy in Cervical Cancer. Curr Oncol Rep 23, 61 (2021). https://doi.org/10.1007/s11912-021-01052-8

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