Immunotherapy of Ovarian Cancer with Particular Emphasis on the PD-1/PDL-1 as Target Points
Abstract
:Simple Summary
Abstract
1. Introduction
2. Selected Immune Molecules as Components of the Immune Response against Cancer Cells
2.1. Innate Immune Mechanisms and the Mechanisms of Resistance to Immunotherapy
2.2. Immune Checkpoints
2.3. CTLA-4
2.4. PD-1/PD-L1
3. Immunotherapy in Ovarian Cancer
3.1. Immunotherapy Based on Innate Immune Response
3.2. Cancer Vaccines
3.3. Adoptive Cell Therapy
Adoptive Cell Therapy Using Tumor Infiltrating Lymphocytes
3.4. CAR-T Therapy
3.5. Anti-CTLA-4 Monotherapy
3.6. Anti-PD-1/PD-L1 Monotherapy
3.7. Anti-PD-1/PD-L1 Immunotherapy in Combination with Other Agents
3.8. Double Checkpoint Inhibition
3.9. Anti-PD-1/PD-L1 Immunotherapy in Combination with Chemotherapy
3.10. Anti-PD-1/PD-L1 Immunotherapy in Combination with PARP Inhibitors
4. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
- Didkowska, J.; Wojciechowska, U.; Czaderny, K.; Olasek, P.; Ciuba, A. Cancer in Poland in 2017; Polish National Cancer Registry: Warsaw, Poland, 2019. [Google Scholar]
- Ledermann, J.A.; Raja, F.A.; Fotopoulou, C.; Martín, A.G.; Colombo, N.; Sessa, C. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2013, 24, vi24–vi32. [Google Scholar] [CrossRef]
- Reid, B.M.; Permuth, J.B.; Sellers, T.A. Epidemiology of ovarian cancer: A review. Cancer Biol. Med. 2017, 14, 9–32. [Google Scholar] [CrossRef] [Green Version]
- Bowtell, D.D.; Böhm, S.; Ahmed, A.A.; Aspuria, P.-J.; Bast, R.C., Jr.; Beral, V.; Berek, J.S.; Birrer, M.J.; Blagden, S.; Bookman, M.A.; et al. Rethinking ovarian cancer II: Reducing mortality from high-grade serous ovarian cancer. Nat. Rev. Cancer 2015, 15, 668–679. [Google Scholar] [CrossRef] [PubMed]
- Ottevanger, P.B. Ovarian cancer stem cells more questions than answers. Semin. Cancer Biol. 2017, 44, 67–71. [Google Scholar] [CrossRef] [PubMed]
- Pietzner, K.; Nasser, S.; Alavi, S.; Darb-Esfahani, S.; Passler, M.; Muallem, M.Z.; Sehouli, J. Checkpoint-inhibition in ovarian cancer: Rising star or just a dream? J. Gynecol. Oncol. 2018, 29, e93. [Google Scholar] [CrossRef]
- Green, D.S.; Nunes, A.T.; David-Ocampo, V.; Ekwede, I.B.; Houston, N.D.; Highfill, S.L.; Khuu, H.; Stroncek, D.F.; Steinberg, S.M.; Zoon, K.C.; et al. A Phase 1 trial of autologous monocytes stimulated ex vivo with Sylatron® (Peginterferon alfa-2b) and Actimmune® (Interferon gamma-1b) for intra-peritoneal administration in recurrent ovarian cancer. J. Transl. Med. 2018, 16, 196. [Google Scholar] [CrossRef] [Green Version]
- Zhang, B.; Chen, F.; Xu, Q.; Han, L.; Xu, J.; Gao, L.; Sun, X.; Li, Y.; Li, Y.; Qian, M.; et al. Revisiting ovarian cancer microenvironment: A friend or a foe? Protein Cell 2018, 9, 674–692. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mortaz, E.; Tabarsi, P.; Mansouri, D.; Khosravi, A.; Garssen, J.; Velayati, A.; Adcock, I.M. Cancers Related to Immunodeficiencies: Update and Perspectives. Front. Immunol. 2016, 7, 365. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lee, Y.J.; Chung, Y.S.; Lee, J.-Y.; Nam, E.J.; Kim, S.W.; Kim, S.; Kim, Y.T. Pretreatment lymphocytopenia is an adverse prognostic biomarker in advanced-stage ovarian cancer. Cancer Med. 2019, 8, 564–571. [Google Scholar] [CrossRef]
- Zhang, L.; Conejo-Garcia, J.R.; Katsaros, D.; Gimotty, P.A.; Massobrio, M.; Regnani, G.; Makrigiannakis, A.; Gray, H.; Schlienger, K.; Liebman, M.N.; et al. Intratumoral T Cells, Recurrence, and Survival in Epithelial Ovarian Cancer. N. Engl. J. Med. 2003, 348, 203–213. [Google Scholar] [CrossRef] [Green Version]
- Hwang, W.-T.; Adams, S.F.; Tahirovic, E.; Hagemann, I.; Coukos, G. Prognostic significance of tumor-infiltrating T cells in ovarian cancer: A meta-analysis. Gynecol. Oncol. 2012, 124, 192–198. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Roelofsen, T.; Wefers, C.; Gorris, M.A.J.; Textor, J.C.; Massuger, L.F.A.G.; De Vries, I.J.M.; Van Altena, A.M. Spontaneous Regression of Ovarian Carcinoma After Septic Peritonitis; A Unique Case Report. Front. Oncol. 2018, 8, 562. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Perales-Puchalt, A.; Svoronos, N.; Villarreal, D.O.; Zankharia, U.; Reuschel, E.; Wojtak, K.; Payne, K.K.; Duperret, E.K.; Muthumani, K.; Conejo-Garcia, J.; et al. IL-33 delays metastatic peritoneal cancer progression inducing an allergic microenvironment. OncoImmunology 2018, 8, e1515058. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sekiya, A.; Suzuki, S.; Tanaka, A.; Hattori, S.; Shimizu, Y.; Yoshikawa, N.; Koya, Y.; Kajiyama, H.; Kikkawa, F. Interleukin-33 expression in ovarian cancer and its possible suppression of peritoneal carcinomatosis. Int. J. Oncol. 2019, 55, 755–765. [Google Scholar] [CrossRef] [PubMed]
- Rogiers, A.; Boekhout, A.; Schwarze, J.K.; Awada, G.; Blank, C.U.; Neyns, B. Long-Term Survival, Quality of Life, and Psychosocial Outcomes in Advanced Melanoma Patients Treated with Immune Checkpoint Inhibitors. J. Oncol. 2019, 2019, 5269062. [Google Scholar] [CrossRef]
- Michielin, O.; Van Akkooi, A.C.J.; Ascierto, P.A.; Dummer, R.; Keilholz, U. Cutaneous melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2019, 30, 1884–1901. [Google Scholar] [CrossRef] [Green Version]
- Escudier, B.; Porta, C.; Schmidinger, M.; Rioux-Leclercq, N.; Bex, A.; Khoo, V.; Grünwald, V.; Gillessen, S.; Horwich, A. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2019, 30, 706–720. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Planchard, D.; Popat, S.; Kerr, K.; Novello, S.; Smit, E.F.; Faivre-Finn, C.; Mok, T.S.; Reck, M.; Van Schil, P.E.; Hellmann, M.D.; et al. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2018, 29, iv192–iv237. [Google Scholar] [CrossRef]
- Vogel, A.; Cervantes, A.; Chau, I.; Daniele, B.; Llovet, J.M.; Meyer, T.; Nault, J.-C.; Neumann, U.; Ricke, J.; Sangro, B.; et al. Correction to: “Hepatocellular carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up”. Ann. Oncol. 2019, 30, 871–873. [Google Scholar] [CrossRef]
- Wang, L.; Ma, Q.; Yao, R.; Liu, J. Current status and development of anti-PD-1/PD-L1 immunotherapy for lung cancer. Int. Immunopharmacol. 2020, 79, 106088. [Google Scholar] [CrossRef]
- Emens, L.A. Breast Cancer Immunotherapy: Facts and Hopes. Clin. Cancer Res. 2018, 24, 511–520. [Google Scholar] [CrossRef] [Green Version]
- Drakes, M.L.; Mehrotra, S.; Aldulescu, M.; Potkul, R.K.; Liu, Y.; Grisoli, A.; Joyce, C.; O’Brien, T.E.; Stack, M.S.; Stiff, P.J. Stratification of ovarian tumor pathology by expression of programmed cell death-1 (PD-1) and PD-ligand- 1 (PD-L1) in ovarian cancer. J. Ovarian Res. 2018, 11, 43. [Google Scholar] [CrossRef]
- Blank, C.; Mackensen, A. Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: An update on implications for chronic infections and tumor evasion. Cancer Immunol. Immunother. 2007, 56, 739–745. [Google Scholar] [CrossRef] [PubMed]
- Kalbasi, A.; Ribas, A. Tumour-intrinsic resistance to immune checkpoint blockade. Nat. Rev. Immunol. 2020, 20, 25–39. [Google Scholar] [CrossRef] [PubMed]
- Wolchok, J.D.; Saenger, Y. The Mechanism of Anti-CTLA-4 Activity and the Negative Regulation of T-Cell Activation. Oncologist 2008, 13, 2–9. [Google Scholar] [CrossRef] [Green Version]
- Nishimura, H.; Minato, N.; Nakano, T.; Honjo, T. Immunological studies on PD-1 deficient mice: Implication of PD-1 as a negative regulator for B cell responses. Int. Immunol. 1998, 10, 1563–1572. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- 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, 141–151. [Google Scholar] [CrossRef] [Green Version]
- Nishimura, H.; Okazaki, T.; Tanaka, Y.; Nakatani, K.; Hara, M.; Matsumori, A.; Sasayama, S.; Mizoguchi, A.; Hiai, H.; Minato, N.; et al. Autoimmune Dilated Cardiomyopathy in PD-1 Receptor-Deficient Mice. Science 2001, 291, 319–322. [Google Scholar] [CrossRef]
- Freeman, G.J.; Long, A.J.; Iwai, Y.; Bourque, K.; Chernova, T.; Nishimura, H.; Fitz, L.J.; Malenkovich, N.; Okazaki, T.; Byrne, M.C.; et al. Engagement of the Pd-1 Immunoinhibitory Receptor by a Novel B7 Family Member Leads to Negative Regulation of Lymphocyte Activation. J. Exp. Med. 2000, 192, 1027–1034. [Google Scholar] [CrossRef] [Green Version]
- Platanias, L.C. Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat. Rev. Immunol. 2005, 5, 375–386. [Google Scholar] [CrossRef]
- Baron, S.; Hernandez, J.; Bekisz, J.; Poast, J.; Goldman, N.; Clouse, K.; Fields, K.; Bacot, S.; Wang, J.; Zoon, K. Clinical Model: Interferons Activate Human Monocytes to An Eradicative Tumor Cell Level In Vitro. J. Interferon Cytokine Res. 2007, 27, 157–164. [Google Scholar] [CrossRef]
- Baron, S.; Finbloom, J.; Horowitz, J.; Bekisz, J.; Morrow, A.; Zhao, T.; Fey, S.; Schmeisser, H.; Balinsky, C.; Miyake, K.; et al. Near Eradication of Clinically Relevant Concentrations of Human Tumor Cells by Interferon-Activated Monocytes In Vitro. J. Interferon Cytokine Res. 2011, 31, 569–573. [Google Scholar] [CrossRef]
- Ribas, A.; Butterfield, L.; Glaspy, J.A.; Economou, J.S. Current Developments in Cancer Vaccines and Cellular Immunotherapy. J. Clin. Oncol. 2003, 21, 2415–2432. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Oh, J.; Barve, M.; Matthews, C.M.; Koon, E.C.; Heffernan, T.P.; Fine, B.; Grosen, E.; Bergman, M.K.; Fleming, E.L.; DeMars, L.R.; et al. Phase II study of Vigil® DNA engineered immunotherapy as maintenance in advanced stage ovarian cancer. Gynecol. Oncol. 2016, 143, 504–510. [Google Scholar] [CrossRef]
- O’Cearbhaill, R.E.; Deng, W.; Chen, L.-M.; Lucci, J.A.; Behbakht, K.; Spirtos, N.M.; Muller, C.Y.; Benigno, B.B.; Powell, M.A.; Berry, E.; et al. A phase II randomized, double-blind trial of a polyvalent Vaccine-KLH conjugate (NSC 748933 IND# 14384)+ OPT-821 versus OPT-821 in patients with epithelial ovarian, fallopian tube, or peritoneal cancer who are in second or third complete remission: An NRG Oncology/GOG study. Gynecol. Oncol. 2019, 155, 393–399. [Google Scholar] [CrossRef] [PubMed]
- Coukos, G.; Tanyi, J.; Kandalaft, L.E. Opportunities in immunotherapy of ovarian cancer. Ann. Oncol. 2016, 27, i11–i15. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Freedman, R.S.; Edwards, C.L.; Kavanagh, J.J.; Kudelka, A.P.; Katz, R.L.; Carrasco, C.H.; Atkinson, E.N.; Scott, W.; Tomasovic, B.; Templin, S.; et al. Intraperitoneal Adoptive Immunotherapy of Ovarian Carcinoma with Tumor-Infiltrating Lymphocytes and Low-Dose Recombinant Interleukin-2. J. Immunother. 1994, 16, 198–210. [Google Scholar] [CrossRef] [PubMed]
- Aoki, Y.; Takakuwa, K.; Kodama, S.; Tanaka, K.; Takahashi, M.; Tokunaga, A.; Takahashi, T. Use of adoptive transfer of tumor-infiltrating lymphocytes alone or in combination with cisplatin-containing chemotherapy in patients with epithelial ovarian cancer. Cancer Res. 1991, 51, 1934–1939. [Google Scholar]
- Pedersen, M.; Westergaard, M.; Milne, K.; Nielsen, M.; Borch, T.H.; Poulsen, L.G.; Hendel, H.W.; Kennedy, M.; Briggs, G.; Ledoux, S.; et al. Adoptive cell therapy with tumor-infiltrating lymphocytes in patients with metastatic ovarian cancer: A pilot study. OncoImmunology 2018, 7, e1502905. [Google Scholar] [CrossRef] [Green Version]
- Friese, C.; Harbst, K.; Borch, T.H.; Westergaard, M.; Pedersen, M.; Kverneland, A.; Jönsson, G.; Donia, M.; Svane, I.M.; Met, Ö. CTLA-4 blockade boosts the expansion of tumor-reactive CD8+ tumor-infiltrating lymphocytes in ovarian cancer. Sci. Rep. 2020, 10, 3914. [Google Scholar] [CrossRef] [Green Version]
- Svane, I.M. T-cell Therapy in Combination with Checkpoint Inhibitors for Patients with Advanced Ovarian-, Fallopian Tube- and Primary Peritoneal Cancer. Available online: https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-002179-24/results (accessed on 3 July 2020).
- University Health Network, Toronto. Phase Ib Trial of Pembrolizumab Administered in Combination with or Following Adoptive Cell Therapy—A Multiple Cohort Study; The ACTIVATE (Adoptive Cell Therapy InVigorated to Augment Tumor Eradication) Trial. Available online: https://clinicaltrials.gov/ct2/show/NCT03158935 (accessed on 14 August 2020).
- Zhu, X.; Cai, H.; Zhao, L.; Ning, L.; Lang, J. CAR-T cell therapy in ovarian cancer: From the bench to the bedside. Oncotarget 2017, 8, 64607–64621. [Google Scholar] [CrossRef]
- Yan, W.; Hu, H.; Tang, B. Advances of Chimeric Antigen Receptor T Cell Therapy in Ovarian Cancer. OncoTargets Ther. 2019, 12, 8015–8022. [Google Scholar] [CrossRef] [Green Version]
- Xu, X.; Qiu, J.; Sun, Y. The basics of CAR T design and challenges in immunotherapy of solid tumors—Ovarian cancer as a model. Hum. Vaccines Immunother. 2017, 13, 1548–1555. [Google Scholar] [CrossRef] [PubMed]
- Phase II Study of Ipilimumab Monotherapy in Recurrent Platinum-Sensitive Ovarian Cancer. Available online: https://clinicaltrials.gov/ (accessed on 8 May 2021).
- Varga, A.; Piha-Paul, S.; Ott, P.A.; Mehnert, J.M.; Berton-Rigaud, D.; Morosky, A.; Yang, P.; Ruman, J.; Matei, D. Pembrolizumab in patients with programmed death ligand 1–positive advanced ovarian cancer: Analysis of KEYNOTE-028. Gynecol. Oncol. 2019, 152, 243–250. [Google Scholar] [CrossRef] [PubMed]
- Howitt, B.E.; Strickland, K.C.; Sholl, L.M.; Rodig, S.; Ritterhouse, L.L.; Chowdhury, D.; D’Andrea, A.D.; Matulonis, U.A.; Konstantinopoulos, P.A. Clear cell ovarian cancers with microsatellite instability: A unique subset of ovarian cancers with increased tumor-infiltrating lymphocytes and PD-1/PD-L1 expression. OncoImmunology 2017, 6, e1277308. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hamanishi, J.; Mandai, M.; Ikeda, T.; Minami, M.; Kawaguchi, A.; Murayama, T.; Kanai, M.; Mori, Y.; Matsumoto, S.; Chikuma, S.; et al. Safety and Antitumor Activity of Anti–PD-1 Antibody, Nivolumab, in Patients With Platinum-Resistant Ovarian Cancer. J. Clin. Oncol. 2015, 33, 4015–4022. [Google Scholar] [CrossRef]
- Disis, M.L.; Taylor, M.H.; Kelly, K.; Beck, J.T.; Gordon, M.; Moore, K.M.; Patel, M.R.; Chaves, J.; Park, H.; Mita, A.C.; et al. Efficacy and Safety of Avelumab for Patients with Recurrent or Refractory Ovarian Cancer. JAMA Oncol. 2019, 5, 393–401. [Google Scholar] [CrossRef] [Green Version]
- Topalian, S.L.; Taube, J.M.; Anders, R.A.; Pardoll, D.M. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat. Rev. Cancer 2016, 16, 275–287. [Google Scholar] [CrossRef]
- Leary, A.; Tan, D.; Ledermann, J. Immune checkpoint inhibitors in ovarian cancer: Where do we stand? Ther. Adv. Med Oncol. 2021, 13, 1–13. [Google Scholar] [CrossRef] [PubMed]
- Martín, A.G.; Sánchez-Lorenzo, L. Immunotherapy with checkpoint inhibitors in patients with ovarian cancer: Still promising? Cancer 2019, 125, 4616–4622. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lee, J.-Y.; Kim, J.W.; Lim, M.C.; Kim, S.; Kim, H.S.; Choi, C.H.; Yi, J.Y.; Park, S.-Y.; Kim, B.-G. A phase II study of neoadjuvant chemotherapy plus durvalumab and tremelimumab in advanced-stage ovarian cancer: A Korean Gynecologic Oncology Group Study (KGOG 3046), TRU-D. J. Gynecol. Oncol. 2019, 30, e112. [Google Scholar] [CrossRef] [Green Version]
- AstraZeneca. A Phase III Randomised, Double-Blind, Placebo-Controlled, Multicentre Study of Durvalumab in Combination with Chemotherapy and Bevacizumab, Followed by Maintenance Durvalumab, Bevacizumab and Olaparib in Newly Diag-nosed Advanced Ovarian Cancer Patients (DUO-O). Available online: https://clinicaltrials.gov/ (accessed on 8 May 2021).
- ARCAGY/GINECO GROUP. A GINECO Phase II Trialo Assessing the Safety and the Efficacy of the Bevacizumab (FKB238), Olaparib and Durvalumab (MEDI 4736) Combination in Patients with Advanced Epithelial Ovarian Cancer in Relapse. Available online: https://clinicaltrials.gov/ (accessed on 8 May 2020).
- ARCAGY/GINECO GROUP. A Multicentre Feasibility Randomized Study of Anti-PD-L1 Durvalumab (MEDI4736) with or without An-ti-CTLA-4 Tremelimumab in Patients with Ovarian, Fallopian Tube or Primary Peritoneal Adenocarcinoma, Treated with a First-Line Neo-Adjuvant Strategy. Available online: https://clinicaltrials.gov/ (accessed on 8 May 2021).
- Tinker, A.; Lim, P.; Aquino-Parsons, C.; Hoskins, P.; Khalaf, D.; Lheureux, S.; Han, K.; Liu, M.; Lum, J.J. Phase I (safety assessment) of durvalumab (MEDI4736) with focal sensitizing radiotherapy in platinum resistant ovarian, primary peritoneal or fallopian tube epithelial carcinoma. J. Clin. Oncol. 2019, 37, TPS5604. [Google Scholar] [CrossRef]
- Sugiura, D.; Maruhashi, T.; Okazaki, I.-M.; Shimizu, K.; Maeda, T.K.; Takemoto, T.; Okazaki, T. Restriction of PD-1 function by cis-PD-L1/CD80 interactions is required for optimal T cell responses. Science 2019, 364, 558–566. [Google Scholar] [CrossRef]
- Zamarin, D.; Burger, R.A.; Sill, M.W.; Powell, D.J., Jr.; Lankes, H.A.; Feldman, M.D.; Zivanovic, O.; Gunderson, C.; Ko, E.; Mathews, C.; et al. Randomized Phase II Trial of Nivolumab Versus Nivolumab and Ipilimumab for Recurrent or Persistent Ovarian Cancer: An NRG Oncology Study. J. Clin. Oncol. 2020, 38, 1814–1823. [Google Scholar] [CrossRef] [PubMed]
- Wang, C.; Kulkarni, P.; Salgia, R. Combined Checkpoint Inhibition and Chemotherapy: New Era of 1st-Line Treatment for Non-Small-Cell Lung Cancer. Mol. Ther. -Oncolytics 2019, 13, 1–6. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pujade-Lauraine, E.; Fujiwara, K.; A Ledermann, J.; Oza, A.M.; Kristeleit, R.; Ray-Coquard, I.-L.; E Richardson, G.; Sessa, C.; Yonemori, K.; Banerjee, S.; et al. Avelumab alone or in combination with chemotherapy versus chemotherapy alone in platinum-resistant or platinum-refractory ovarian cancer (JAVELIN Ovarian 200): An open-label, three-arm, randomised, phase 3 study. Lancet Oncol. 2021, 22, 1034–1046. [Google Scholar] [CrossRef]
- Omatsu, K.; Hamanishi, J.; Katsumata, N.; Nishio, S.; Sawada, K.; Takeuchi, S.; Aoki, D.; Fujiwara, K.; Sugiyama, T.; Konishi, I. 807O Nivolumab versus gemcitabine or pegylated liposomal doxorubicin for patients with platinum-resistant (advanced or recurrent) ovarian cancer: Open-label, randomized trial in Japan (NINJA trial). Ann. Oncol. 2020, 31, S611. [Google Scholar] [CrossRef]
- Vikas, P.; Borcherding, N.; Chennamadhavuni, A.; Garje, R. Therapeutic Potential of Combining PARP Inhibitor and Immunotherapy in Solid Tumors. Front. Oncol. 2020, 10, 570. [Google Scholar] [CrossRef]
- Shen, J.; Zhao, W.; Ju, Z.; Wang, L.; Peng, Y.; Labrie, M.; Yap, T.A.; Mills, G.B.; Peng, G. PARPi Triggers the STING-Dependent Immune Response and Enhances the Therapeutic Efficacy of Immune Checkpoint Blockade Independent of BRCAness. Cancer Res. 2019, 79, 311–319. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Drew, Y.; Kaufman, B.; Banerjee, S.; Lortholary, A.; Hong, S.; Park, Y.; Zimmermann, S.; Roxburgh, P.; Ferguson, M.; Alvarez, R.; et al. Phase II study of olaparib + durvalumab (MEDIOLA): Updated results in germline BRCA-mutated platinum-sensitive relapsed (PSR) ovarian cancer (OC). Ann. Oncol. 2019, 30, v485–v486. [Google Scholar] [CrossRef]
- Konstantinopoulos, P.A.; Waggoner, S.; Vidal, G.A.; Mita, M.; Moroney, J.W.; Holloway, R.; Van Le, L.; Sachdev, J.C.; Chapman-Davis, E.; Colon-Otero, G.; et al. Single-Arm Phases 1 and 2 Trial of Niraparib in Combination With Pembrolizumab in Patients With Recurrent Platinum-Resistant Ovarian Carcinoma. JAMA Oncol. 2019, 5, 1141–1149. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lee, J.-M.; Annunziata, C.; Houston, N.; Kohn, E.; Lipkowitz, S.; Minasian, L.; Nichols, E.; Trepel, J.; Trewhitt, K.; Zia, F.; et al. A phase II study of durvalumab, a PD-L1 inhibitor and olaparib in recurrent ovarian cancer (OvCa). Ann. Oncol. 2018, 29, viii334. [Google Scholar] [CrossRef]
- Drew, Y.; Penson, R.; O’Malley, D.; Kim, J.-W.; Zimmermann, S.; Roxburgh, P.; Sohn, J.; Stemmer, S.; Bastian, S.; Ferguson, M.; et al. 814MO Phase II study of olaparib (O) plus durvalumab (D) and bevacizumab (B) (MEDIOLA): Initial results in patients (pts) with non-germline BRCA-mutated (non-gBRCAm) platinum sensitive relapsed (PSR) ovarian cancer (OC). Ann. Oncol. 2020, 31, S615–S616. [Google Scholar] [CrossRef]
- Pfizer. A Randomized, Open-Label, Multicenter, Phase 3 Study to Evaluate the Efficacy and Safety of Avelumab in Combination with Chemotherapy Followed by Maintenance Therapy of Avelumab in Combination with the Poly (Adenosine Diphosphate [Adp]-Ribose) Polymerase (PARP) Inhibitor Talazoparib in Patients with Previously Untreated Advanced Ovarian Cancer (JAVELIN OVARIAN PARP100). Available online: https://clinicaltrials.gov/ct2/show/NCT03642132 (accessed on 4 August 2021).
- Clovis Oncology, Inc. ATHENA (A Multicenter, Randomized, Double-Blind, Placebo- Controlled Phase 3 Study in Ovarian Cancer Patients Evaluating Rucaparib and Nivolumab as Maintenance Treatment Following Response to Front-Line Platinum-Based Chemotherapy). Available online: https://clinicaltrials.gov/ct2/show/NCT03522246 (accessed on 5 November 2021).
- NCI. A Randomized, Phase II/III Study of Pegylated Liposomal Doxorubicin and CTEP-Supplied Atezolizumab versus Pegylated Liposomal Doxorubicin, CTEP-Supplied Bevacizumab and CTEP-Supplied Atezolizumab versus Pegylated Liposomal Doxorubicin and CTEP-Supplied Bevacizumab in Platinum Resistant Ovarian Cancer. Available online: https://clinicaltrials.gov/ct2/show/NCT02839707 (accessed on 19 October 2021).
- Moore, K.N.; Pignata, S. Trials in progress: IMagyn050/GOG 3015/ENGOT-OV39. A Phase III, multicenter, randomized study of atezolizumab versus placebo administered in combination with paclitaxel, carboplatin, and bevacizumab to patients with newly-diagnosed stage III or stage IV ovarian, fallopian tube, or primary peritoneal cancer. Int. J. Gynecol. Cancer 2019, 29, 430–433. [Google Scholar] [CrossRef]
- Grupo Español de Investigación en Cáncer de Ovario. A Phase III Randomized, Double-blinded Trial of Platinum-Based Chemotherapy with or without Atezolizumab Followed by Niraparib Maintenance with or without Atezolizumab in Patients with Recurrent Ovarian, Tubal or Peritoneal Cancer and Platinum Treatment-Free Interval (TFIp) >6 Months. Available online: https://clinicaltrials.gov/ct2/show/NCT03598270 (accessed on 13 August 2021).
- ARCAGY/GINECO GROUP. A Randomized, Double-blinded, Phase III Study of Atezolizumab versus Placebo in Patients with Late Relapse of Epithelial Ovarian, Fallopian Tube, or Peritoneal Cancer Treated by Platinum-Based Chemotherapy and Bevacizumab. Available online: https://clinicaltrials.gov/ct2/show/NCT02891824 (accessed on 26 May 2021).
- Study of Chemotherapy with Pembrolizumab (MK-3475) Followed by Maintenance with Olaparib (MK-7339) for the First-Line Treatment of Women with BRCA Non-mutated Advanced Epithelial Ovarian Cancer (EOC) (MK-7339-001/KEYLYNK-001/ENGOT-ov43/GOG-3036). Available online: https://www.clinicaltrials.gov/ct2/show/NCT03740165 (accessed on 29 June 2021).
- Rojas, V.; Hirshfield, K.M.; Ganesan, S.; Rodriguez-Rodriguez, L. Molecular Characterization of Epithelial Ovarian Cancer: Implications for Diagnosis and Treatment. Int. J. Mol. Sci. 2016, 17, 2113. [Google Scholar] [CrossRef] [Green Version]
- Zhao, Y.; Harrison, D.L.; Song, Y.; Ji, J.; Huang, J.; Hui, E. Antigen-Presenting Cell-Intrinsic PD-1 Neutralizes PD-L1 in cis to Attenuate PD-1 Signaling in T Cells. Cell Rep. 2018, 24, 379–390. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Study Title | Study Drug | Study Type | No. of Patients | Previous Chemotherapy Lines | Treatment Response | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|
CR | PR | SD | CR +PR | Disease Control CR + PR +SD | Median PFS Months | Median OS Months | |||||
KEYNOTE-28 | Pembrolysumab (Humanized IgG4) 10 mg/kg i.v. every 3 weeks | Phase 1b Open label | 26 | 0–>5 | 3.8% | 7.7% | 26.9% | 11.5% | 38.4% | 1.9 | 13.8 |
KEYNOTE-100 | Pembrolysumab (Humanized IgG4) 200 mg i.v. every 3 weeks | Phase II study Open label | 376 | 1–6 | 1.9% | 6.1% | 29.3% | 8% | 37% | 2.1 | Not achieved |
UMIN000005714 | Nivolumab (Human IgG4) 1 mg/kg or 3 mg/kg i.v. every 2 weeks | Phase II study Open-label | 20 | >2 | 10% | 5% | 30% | 15% | 45% | 3.5 | 20 |
JAVELIN Solid Tumor Trial | Avelumab (Fully Humanized IgG1) 10 mg/kg i.v. every 2 weeks. | Phase 1b Open label | 125 | n.a. | 0.8% | 8.8% (12% according to the modified irRECIST criteria) | 42.2% | 9.6% | 51.8% | 2.6 | 11.2 |
Trial | CI + PARPi | N | Population | ORR (%) | DCR (%) | Reference |
---|---|---|---|---|---|---|
NCT02484404 | Durvalumab + Olaparib | 35 | Platinum resistant 83% gBRCAm; 17% BRCAwt; 83% | 14 | 37 | Lee et al., ESMO 2018 [69] |
MEDIOLA | Durvalumab + Olaparib | 34 | gBRCAm, platinum sensitive | 71.9 | 80 at 12 weeks | Drew et al., ESMO 2019 [67] |
Durvalumab + Olaparib+ Bevacizumab | 32 | gBRCA WT platinum sensitive | 34.4 | 28.1 at 24 weeks | Drew et al. ESMO 2020 [70] | |
31 | gBRCA WT platinum sensitive | 87.1 | 77.4 at 24 weeks | |||
TOPACIO/Keynote-162 | Pembrolizumab + Niraparib | 62 | Platinum –resistant or platinum unable tBRCA wild type 79% | 18 | 65 | Konstantinopoulos et al., Jama Oncol 2019 [68] |
Study Title or Number | Enrolled Patients | Study Treatment | Study Endpoints | Comments |
---|---|---|---|---|
JAVELIN OVARIAN PARP 100 | Patients with locally advanced or metastatic ovarian cancer Stage III or IV. |
| PFS | Enrollment stopped after JAVELIN Ovarian 100 study results were presented; the expected efficacy of avelumab in the first-line treatment of non-preselected patient population was not achieved. |
DUO-O | Newly diagnosed patients with ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. Stage III or IV. |
| Primary: PFS Secondary: OS, PFS2, HRQoL, pCR, PK, ORR, DoR, TFST, TSST, TDT | Randomized, quadruple-blinded, placebo-controlled. Ongoing recruitment. Estimated Primary Completion Date 06/2023. |
ATHENA | Newly diagnosed patients with epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer who had achieved complete or partial response to the first line of chemotherapy | Maintenance treatment:
| Primary: PFS Secondary: OS, ORR, DoR, AEs, treatment safety and tolerance | Randomized, quadruple-blinded, placebo-controlled. Completed target enrollment. Estimated primary completion date 12/2024. |
NCT02839707 | Patients with recurrent ovarian cancer/primary peritoneal cancer/fallopian tube cancer |
| Primary: DLT, PFS, OS Secondary: ORR, AE, PRO, PD-L1 expression | Phase II and phase III study. Open-label. Ongoing recruitment. Estimated Primary Completion date 06/2023. |
IMagyn050 | Patients with newly diagnosed ovarian cancer, fallopian tube cancer, or peritoneal cancer Stage III or IV. Following PDS R = 2 or following neoadjuvant chemotherapy and IDS |
| Primary: PFS, OS, including separate determination in PD-L1-positive patients. Secondary: OR, DoR, HRQoL, AEs, ADAs | Randomized, double-blinded, placebo-controlled trial. Enrollment complete. Estimated Primary Completion Date 12/2022. |
ANITA | Patients with recurrent, platinum-sensitive ovarian cancer. |
| Primary: PFS Secondary: OS, TFST, TSST, PFS2, AE, ORR, DoR, PROs, HRQoL, and the dependence of the above on the BRCA, PK, ATA status | Randomized, triple-blinded, placebo-controlled. Ongoing recruitment. Estimated Primary Completion Date 08/2024. |
ATLANTE | Patients with platinum-sensitive recurrence of epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. |
| Primary: PFS Secondary: OS, TSST, AEs | Randomized, triple-blinded. Enrollment complete. Estimated Primary Completion Date 10/2021. |
NCT03353831 | Patients with first or second recurrence of ovarian cancer, Fallopian tube cancer or primary peritoneal cancer within <6 months since the last treatment. Along with patients with third disease recurrence. |
| Primary: OS, PFS Secondary: QLQ, ORR, DOR | Randomized, partially blinded. Ongoing recruitment. Estimated Primary Completion Date 12/2023. |
MK-7339-001/KEYLYNK-001/ENGOT-ov43 | Patients with newly diagnosed low-differentiated ovarian cancer, primary peritoneal cancer, and stage III or IV ovarian cancer after PDS or planned for IDS. |
| Primary: OS, PFS Secondary: PFS2, AES, treatment discontinuation due to AEs, QoL, TFST, TSST, TDT, PCR, Twist, | Randomized, quadropoly blinded. Completed target enrollment. Estimated primary completion date 10/2023. |
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Świderska, J.; Kozłowski, M.; Kwiatkowski, S.; Cymbaluk-Płoska, A. Immunotherapy of Ovarian Cancer with Particular Emphasis on the PD-1/PDL-1 as Target Points. Cancers 2021, 13, 6063. https://doi.org/10.3390/cancers13236063
Świderska J, Kozłowski M, Kwiatkowski S, Cymbaluk-Płoska A. Immunotherapy of Ovarian Cancer with Particular Emphasis on the PD-1/PDL-1 as Target Points. Cancers. 2021; 13(23):6063. https://doi.org/10.3390/cancers13236063
Chicago/Turabian StyleŚwiderska, Janina, Mateusz Kozłowski, Sebastian Kwiatkowski, and Aneta Cymbaluk-Płoska. 2021. "Immunotherapy of Ovarian Cancer with Particular Emphasis on the PD-1/PDL-1 as Target Points" Cancers 13, no. 23: 6063. https://doi.org/10.3390/cancers13236063