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Immunotherapy and radiation combinatorial trials in gynecologic cancer: A potential synergy?

  • Larissa Lee
    Correspondence
    Corresponding author at: Brigham and Women's Hospital, Department of Radiation Oncology, 75 Francis Street ASBI-L2, Boston MA 02115, USA.
    Affiliations
    Department of Radiation Oncology, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, MA, USA
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  • Ursula Matulonis
    Affiliations
    Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
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      Highlights

      • In an abscopal response, tumor regression occurs at a distant metastatic site following local radiation treatment.
      • Radiation therapy can prime the immune system by creating a T-cell mediated response that acts locally and distally.
      • Immune checkpoint blockade may synergize with radiotherapy to enhance local tumor control and systemic response.
      • Prospective trials will evaluate the combination of radiation and immunotherapy in the definitive and metastatic setting.
      • Th optimal timing, radiation dose, and technique in combination with immunotherapy have yet to be determined.

      Abstract

      Immunotherapy (IO) is an important new pillar in the treatment of solid tumors, and the integration of IO agents with chemotherapy, targeted therapy, surgery and radiation has yet to be defined. As preclinical and clinical studies have described synergistic activity with the combination of radiation and immunotherapy, many clinical trials are underway to explore both the safety and efficacy of this approach both in the metastatic and definitive setting. Through immune priming, radiation may enhance local tumor control at the irradiated site, as well as induce a systemic response to control distant metastasis, known as the abscopal effect. On a mechanistic level, radiation therapy releases tumor neoantigens and activates an adaptive immune response that is mediated by cytotoxic T-cells, which then hone to sites of irradiated tumor as well as non-irradiated tumor metastases to induce immunogenic tumor cell death. Although the abscopal effect is rare in clinical practice, strategies that combine immune checkpoint blockade with radiation are being studied to overcome immune tolerance or suppression and increase systemic response rates to IO agents. Gynecologic cancers are attractive targets for immune checkpoint blockade, and IO agents may be used in combination with definitive chemoradiotherapy to enhance radiosensitivity and thus local control for unresected disease as well as control distant micrometastatic spread. For patients with metastatic disease, immune checkpoint blockade in combination with stereotactic radiotherapy is being evaluated as a strategy for immune activation and tumor cytoreduction. In this review, we highlight the current use of IO agents in gynecologic cancer, describe the immunogenic potential of radiation through clinical observation and preclinical study, and discuss strategies for combining IO and radiation in reported and ongoing clinical trials.

      Keywords

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      References

        • Le D.T.
        • et al.
        PD-1 blockade in tumors with mismatch-repair deficiency.
        N. Engl. J. Med. 2015; 372: 2509-2520
        • U.S. Federal Drug Administration
        FDA approves pembrolizumab for advanced cervical cancer with disease progression during or after chemotherapy.
        ([cited 2018 October 27]; Available from)
      1. . Hamanishi, J., et al., Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc. Natl. Acad. Sci. U. S. A., 2007. 104(9): p. 3360–5.

      2. Zhang, L., et al., Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N. Engl. J. Med., 2003. 348(3): p. 203–13.

      3. Sato, E., et al., Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc. Natl. Acad. Sci. U. S. A., 2005. 102(51): p. 18538–43.

      4. Nielsen, J.S., et al., CD20+ tumor-infiltrating lymphocytes have an atypical CD27- memory phenotype and together with CD8+ T cells promote favorable prognosis in ovarian cancer. Clin. Cancer Res., 2012. 18(12): p. 3281–92.

      5. Brahmer, J.R., et al., Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med., 2012. 366(26): p. 2455–65.

      6. Hamanishi, J., et al., Safety and antitumor activity of anti-PD-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer. J. Clin. Oncol., 2015. 33(34): p. 4015–22.

      7. Disis, M.L., et al., Avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with previously treated, recurrent or refractory ovarian cancer: a phase Ib, open-label expansion trial. J. Clin. Oncol., 2015. 33(15_suppl): p. 5509–5509.

      8. Matulonis, U.A., et al., Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: interim results from the phase 2 KEYNOTE-100 study. J. Clin. Oncol., 2018. 36(15_suppl): p. 5511–5511.

      9. Burger, R.A., et al., The addition of a CTLA4 targeted therapy to a PD-1 targeted therapy could benefit women with ovarian cancer, in Biennial Meeting of the International Gynecologic Cancer Society (IGCS). 2018: (Kyoto, Japan).

      10. Howitt, B.E., et al., Genetic basis for PD-L1 expression in squamous cell carcinomas of the cervix and vulva. JAMA Oncol, 2016. 2(4): p. 518–22.

      11. Chung, H.C., et al., Pembrolizumab treatment of advanced cervical cancer: updated results from the phase 2 KEYNOTE-158 study. J. Clin. Oncol., 2018. 36(15_suppl): p. 5522–5522.

        • Cancer Genome Atlas Research, N
        • et al.
        Integrated genomic characterization of endometrial carcinoma.
        Nature. 2013; 497: 67-73
        • Howitt B.E.
        • et al.
        Association of polymerase e-mutated and microsatellite-instable endometrial cancers with neoantigen load, number of tumor-infiltrating lymphocytes, and expression of PD-1 and PD-L1.
        JAMA Oncol. 2015; 1: 1319-1323
        • Eriksson D.
        • Stigbrand T.
        Radiation-induced cell death mechanisms.
        Tumour Biol. 2010; 31: 363-372
        • Stone H.B.
        • Peters L.J.
        • Milas L.
        Effect of host immune capability on radiocurability and subsequent transplantability of a murine fibrosarcoma.
        J. Natl. Cancer Inst. 1979; 63: 1229-1235
      12. Sharabi, A.B., et al., Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy. Lancet Oncol, 2015. 16(13): p. e498–509.

        • Mole R.H.
        Whole body irradiation; radiobiology or medicine?.
        Br. J. Radiol. 1953; 26: 234-241
      13. Siva, S., et al., Abscopal effects of radiation therapy: a clinical review for the radiobiologist. Cancer Lett., 2015. 356(1): p. 82–90.

        • Abuodeh Y.
        • Venkat P.
        • Kim S.
        Systematic review of case reports on the abscopal effect.
        Curr. Probl. Cancer. 2016; 40: 25-37
        • Thoroddsen A.
        • et al.
        Spontaneous regression of pleural metastases after nephrectomy for renal cell carcinoma—a histologically verified case with nine-year follow-up.
        Scand. J. Urol. Nephrol. 2002; 36: 396-398
        • Smith Jr., J.L.
        • Stehlin J.S.
        Jr., Spontaneous regression of primary malignant melanomas with regional metastases.
        Cancer. 1965; 18: 1399-1415
      14. Takaya, M., et al., Abscopal effect of radiation on toruliform para-aortic lymph node metastases of advanced uterine cervical carcinoma–a case report. Anticancer Res., 2007. 27(1B): p. 499–503.

      15. Postow, M.A., et al., Immunologic correlates of the abscopal effect in a patient with melanoma. N. Engl. J. Med., 2012. 366(10): p. 925–31.

        • Oh M.S.
        • Chae Y.K.
        Repeated abscopal effect with radiotherapy and programmed death 1 blockade in mismatch repair–deficient endometrial cancer.
        JCO Precis Oncol. 2018; : 1-6
      16. Sharabi, A., et al., Exceptional response to nivolumab and Stereotactic Body Radiation Therapy (SBRT) in neuroendocrine cervical carcinoma with high tumor mutational burden: management considerations from the center for personalized cancer therapy at UC San Diego Moores Cancer Center. Oncologist, 2017. 22(6): p. 631–637.

      17. Chajon, E., et al., The synergistic effect of radiotherapy and immunotherapy: a promising but not simple partnership. Crit Rev Oncol Hematol, 2017. 111: p. 124–132.

        • Wrzesinski S.H.
        • Wan Y.Y.
        • Flavell R.A.
        Transforming growth factor-beta and the immune response: implications for anticancer therapy.
        Clin. Cancer Res. 2007; 13: 5262-5270
        • Kang J.
        • Demaria S.
        • Formenti S.
        Current clinical trials testing the combination of immunotherapy with radiotherapy.
        J Immunother Cancer. 2016; 4: 51
      18. Sharabi, A.B., et al., Stereotactic radiation therapy combined with immunotherapy: augmenting the role of radiation in local and systemic treatment. Oncology (Williston Park, NY), 2015. 29(5).

      19. Sharabi, A.B., et al., Stereotactic radiation therapy combined with immunotherapy: augmenting the role of radiation in local and systemic treatment. Oncology (Williston Park), 2015. 29(5): p. 331–40.

      20. Twyman-Saint Victor, C., et al., Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature, 2015. 520(7547): p. 373–7.

        • Johnson C.B.
        • Jagsi R.
        The promise of the abscopal effect and the future of trials combining immunotherapy and radiation therapy.
        Int. J. Radiat. Oncol. Biol. Phys. 2016; 95: 1254-1256
      21. Huang, A.C., et al., T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature, 2017. 545(7652): p. 60–65.

        • Demaria S.
        • Formenti S.C.
        Radiation as an immunological adjuvant: current evidence on dose and fractionation.
        Front. Oncol. 2012; 2: 153
      22. Deng, L., et al., Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J. Clin. Invest., 2014. 124(2): p. 687–95.

      23. Kwon, E.D., et al., Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol, 2014. 15(7): p. 700–12.

      24. . Beer, T.M., et al., Randomized, double-blind, phase III trial of ipilimumab versus placebo in asymptomatic or minimally symptomatic patients with metastatic chemotherapy-naive castration-resistant prostate cancer. J. Clin. Oncol., 2017. 35(1): p. 40–47.

      25. Luke, J.J., et al., Safety and clinical activity of pembrolizumab and multisite stereotactic body radiotherapy in patients with advanced solid tumors. J. Clin. Oncol., 2018. 36(16): p. 1611–1618.

      26. Shaverdian, N., et al., Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial. Lancet Oncol, 2017. 18(7): p. 895–903.

      27. Antonia, S.J., et al., Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer. N. Engl. J. Med., 2017. 377(20): p. 1919–1929.

      28. Antonia, S.J., et al., Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N. Engl. J. Med., 2018.

      29. Mayadev, J., et al., A phase I study of sequential ipilimumab in the definitive treatment of node positive cervical cancer: GOG 9929. J. Clin. Oncol., 2017. 35(15_suppl): p. 5526–5526.

      30. Creutzberg, C.L., et al., Survival after relapse in patients with endometrial cancer: results from a randomized trial. Gynecol. Oncol., 2003. 89(2): p. 201–9.

      31. Charra-Brunaud, C., et al., Impact of 3D image-based PDR brachytherapy on outcome of patients treated for cervix carcinoma in France: results of the French STIC prospective study. Radiother. Oncol., 2012. 103(3): p. 305–13.

      32. Potter, R., et al., The EMBRACE II study: the outcome and prospect of two decades of evolution within the GEC-ESTRO GYN working group and the EMBRACE studies. Clin Transl Radiat Oncol, 2018. 9: p. 48–60.

      33. Dewan, M.Z., et al., Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin. Cancer Res., 2009. 15(17): p. 5379–88.

      34. Farooque, A., et al., Low-dose radiation therapy of cancer: role of immune enhancement. Expert. Rev. Anticancer. Ther., 2011. 11(5): p. 791–802.

        • Postow M.A.
        • Sidlow R.
        • Hellmann M.D.
        Immune-related adverse events associated with immune checkpoint blockade.
        N. Engl. J. Med. 2018; 378: 158-168
      35. Larkin, J., et al., Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med., 2015. 373(1): p. 23–34.

      36. Verma, V., et al., Toxicity of radiation and immunotherapy combinations. Adv Radiat Oncol, 2018. 3(4): p. 506–511.

      37. Bang, A., et al., Multicenter evaluation of the tolerability of combined treatment with PD-1 and CTLA-4 immune checkpoint inhibitors and palliative radiation therapy. Int. J. Radiat. Oncol. Biol. Phys., 2017. 98(2): p. 344–351.