Immunotherapy with IL12 and PD1/CTLA4 inhibition is effective in advanced ovarian cancer and associates with reversal of myeloid cell-induced immunosuppression

References

• Torre LA, Trabert B, DeSantis CE, Miller KD, Samimi G, Runowicz CD, Gaudet MM, Jemal A, Siegel RL. Ovarian cancer statistics, 2018. CA Cancer J Clin. 2018;68(4):284–14. doi:10.3322/caac.21456.
   PubMed Web of Science ®Google Scholar
• Herzog TJ. The current treatment of recurrent ovarian cancer. Curr Oncol Rep. 2006;8(6):448–454. doi:10.1007/s11912-006-0074-9.
   PubMedGoogle Scholar
• Wright AA, Bohlke K, Armstrong DK, Bookman MA, Cliby WA, Coleman RL, Dizon DS, Kash JJ, Meyer LA, Moore KN, et al. Neoadjuvant chemotherapy for newly diagnosed, advanced ovarian cancer: society of Gynecol Oncol and American society of clinical oncology clinical practice guideline. Gynecol Oncol. 2016;143(1):3–15. doi:10.1016/j.ygyno.2016.05.022.
   PubMed Web of Science ®Google Scholar
• Pujade-Lauraine E, Alexandre J. Update of randomized trials in recurrent disease. Ann Oncol. 2011;22(8):viii61–64. doi:10.1093/annonc/mdr518.
   PubMedGoogle Scholar
• Pujade-Lauraine E, Hilpert F, Weber B, Reuss A, Poveda A, Kristensen G, Sorio R, Vergote I, Witteveen P, Bamias A, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA open-label randomized phase III trial. J Clin Oncol. 2014;32(13):1302–1308. doi:10.1200/JCO.2013.51.4489.
   PubMed Web of Science ®Google Scholar
• Mutch DG, Orlando M, Goss T, Teneriello MG, Gordon AN, McMeekin SD, Wang Y, Scribner DR, Marciniack M, Naumann RW, et al. Randomized phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer. J Clin Oncol. 2007;25(19):2811–2818. doi:10.1200/JCO.2006.09.6735.
   PubMed Web of Science ®Google Scholar
• Monk BJ, Herzog TJ, Kaye SB, Krasner CN, Vermorken JB, Muggia FM, Pujade-Lauraine E, Park YC, Parekh TV, Poveda AM. Trabectedin plus pegylated liposomal doxorubicin (PLD) versus PLD in recurrent ovarian cancer: overall survival analysis. Eur J Cancer. 2012;48(15):2361–2368. doi:10.1016/j.ejca.2012.04.001.
   PubMed Web of Science ®Google Scholar
• Meier W, du Bois A, Reuss A, Kuhn W, Olbricht S, Gropp M, Richter B, Lück H-J, Kimmig R, Pfisterer J. Topotecan versus treosulfan, an alkylating agent, in patients with epithelial ovarian cancer and relapse within 12 months following 1st-line platinum/paclitaxel chemotherapy. A prospectively randomized phase III trial by the Arbeitsgemeinschaft gynaekologische onkologie ovarian cancer study group (AGO-OVAR). Gynecol Oncol. 2009;114(2):199–205. doi:10.1016/j.ygyno.2009.04.026.
   PubMed Web of Science ®Google Scholar
• Buda A, Floriani I, Rossi R, Colombo N, Torri V, Conte PF, Fossati R, Ravaioli A, Mangioni C. Randomised controlled trial comparing single agent paclitaxel vs epidoxorubicin plus paclitaxel in patients with advanced ovarian cancer in early progression after platinum-based chemotherapy: an Italian collaborative study from the Mario Negri institute, Milan, G.O.N.O. (Gruppo oncologico nord ovest) group and I.O.R. (Istituto oncologico romagnolo) group. Br J Cancer. 2004;90(11):2112–2117. doi:10.1038/sj.bjc.6601787.
   PubMed Web of Science ®Google Scholar
• ten Bokkel Huinink W, Gore M, Carmichael J, Gordon A, Malfetano J, Hudson I, Broom C, Scarabelli C, Davidson N, Spanczynski M, et al. Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer. J Clin Oncol. 1997;15(6):2183–2193. doi:10.1200/JCO.1997.15.6.2183.
   PubMed Web of Science ®Google Scholar
• Gaillard SL, Secord AA, Monk B. The role of immune checkpoint inhibition in the treatment of ovarian cancer. Gynecol Oncol Res Pract. 2016;3(1):11. doi:10.1186/s40661-016-0033-6.
   PubMedGoogle Scholar
• 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(34):4015–4022. doi:10.1200/JCO.2015.62.3397.
   PubMed Web of Science ®Google Scholar
• Zamarin D, Burger RA, Sill MW, Powell DJ, Lankes HA, Feldman MD, 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(16):1814–1823. doi:10.1200/JCO.19.02059.
   PubMed Web of Science ®Google Scholar
• Zhang M, He Y, Sun X, Li Q, Wang W, Zhao A, Di W. A high M1/M2 ratio of tumor-associated macrophages is associated with extended survival in ovarian cancer patients. J Ovarian Res. 2014;7(1):19. doi:10.1186/1757-2215-7-19.
   PubMed Web of Science ®Google Scholar
• Lyons YA, Pradeep S, Wu SY, Haemmerle M, Hansen JM, Wagner MJ, Villar-Prados A, Nagaraja AS, Dood RL, Previs RA, et al. Macrophage depletion through colony stimulating factor 1 receptor pathway blockade overcomes adaptive resistance to anti-VEGF therapy. Oncotarget. 2017;8(57):96496–96505. doi:10.18632/oncotarget.20410.
   PubMedGoogle Scholar
• Kryczek I, Wei S, Zhu G, Myers L, Mottram P, Cheng P, Chen L, Coukos G, Zou W. Relationship between B7-H4, regulatory T cells, and patient outcome in human ovarian carcinoma. Cancer Res. 2007;67(18):8900–8905. doi:10.1158/0008-5472.CAN-07-1866.
   PubMed Web of Science ®Google Scholar
• Ni Y, Soliman A, Joehlin-Price A, Abdul-Karim F, Rose PG, Mahdi H. Immune cells and signatures characterize tumor microenvironment and predict outcome in ovarian and endometrial cancers. Immunotherapy. 2021;13(14):1179–1192. doi:10.2217/imt-2021-0052.
   PubMed Web of Science ®Google Scholar
• Ni Y, Soliman A, Joehlin-Price A, Rose PG, Vlad A, Edwards RP, Mahdi H. High TGF-β signature predicts immunotherapy resistance in gynecologic cancer patients treated with immune checkpoint inhibition. NPJ Precis Oncol. 2021;5(1):101. doi:10.1038/s41698-021-00242-8.
   PubMed Web of Science ®Google Scholar
• Tannenbaum CS, Rayman PA, Pavicic PG, Kim JS, Wei W, Polefko A, Wallace W, Rini BI, Morris-Stiff G, et al. Mediators of inflammation-Driven Expansion, Trafficking, and Function of Tumor-Infiltrating MDSCs. Cancer Immunol Res. 2019;7(10):1687–1699. doi:10.1158/2326-6066.CIR-18-0578.
   PubMed Web of Science ®Google Scholar
• Schmidt CS, Mescher MF. Adjuvant effect of IL12: conversion of peptide antigen administration from tolerizing to immunizing for CD8+ T cells in vivo. J Immunol. 1999;163(5):2561–2567. doi:10.4049/jimmunol.163.5.2561.
   PubMed Web of Science ®Google Scholar
• Salem ML, Kadima AN, Zhou Y, Nguyen CL, Rubinstein MP, Demcheva M, Vournakis JN, Cole DJ, Gillanders WE. Paracrine release of IL-12 stimulates IFN-γ production and dramatically enhances the antigen-specific T cell response after vaccination with a novel peptide-based cancer vaccine. J Immunol. 2004;172(9):5159–5167. doi:10.4049/jimmunol.172.9.5159.
   PubMed Web of Science ®Google Scholar
• Chang J, Cho J-H, Lee S-W, Choi S-Y, Ha S-J, Sung Y-C. IL12 priming during in vitro antigenic stimulation changes properties of CD8 T cells and increases generation of effector and memory cells. J Immunol. 2004;172(5):2818–2826. doi:10.4049/jimmunol.172.5.2818.
   PubMed Web of Science ®Google Scholar
• Diaz-Montero CM, Ravichandran S, Pavicic PG, Rayman PA, Tannenbaum C, Finke J, Ko JS, Funchain P, Tarhini AA. Low-dose IL-12 preconditions the tumor microenvironment to enhance the efficacy of PD-1 blockade. J Clin Oncol. 2019;37(8_suppl). 20–20. doi:10.1200/JCO.2019.37.8_suppl.20.
   Web of Science ®Google Scholar
• Watford WT, Moriguchi M, Morinobu A, O’shea JJ. The biology of IL12: coordinating innate and adaptive immune responses. Cytokine Growth Factor Rev. 2003 ;14(5):361–368. doi:10.1016/s1359-.
   PubMed Web of Science ®Google Scholar
• Su W, Ito T, Oyama T, Kitagawa T, Yamori T, Fujiwara H, Matsuda H. The direct effect of IL-12 on tumor cells: iL-12 acts directly on tumor cells to activate NF-κB and enhance IFN-γ-mediated STAT1 phosphorylation. Biochem Biophys Res Commun. 2001;280(2):503–512. doi:10.1006/bbrc.2000.4150.
   PubMed Web of Science ®Google Scholar
• Duraiswamy J, Kaluza KM, Freeman GJ, Coukos G. Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors. Cancer Res. 2013;73(12):3591–3603. doi:10.1158/0008-5472.CAN-12-4100.
   PubMed Web of Science ®Google Scholar
• Dobin A, Gingeras TR. Mapping RNA-seq reads with STAR. Curr Protoc Bioinformatics. 2015;51(1). 14 11–11 14 19 . doi:10.1002/0471250953.bi1114s51.
   Google Scholar
• Liao Y, Smyth GK, Shi W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2014;30:923–930. doi:10.1093/bioinformatics/btt656.
   PubMed Web of Science ®Google Scholar
• Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15(12):550. doi:10.1186/s13059-014-0550-8.
   PubMed Web of Science ®Google Scholar
• Trinchieri G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol. 2003;3(2):133–146. doi:10.1038/nri1001.
   PubMed Web of Science ®Google Scholar
• Diaz-Montero CM, El Naggar S, Al Khami A, El Naggar R, Montero AJ, Cole DJ, Salem ML. Priming of naive CD8+ T cells in the presence of IL12 selectively enhances the survival of CD8+CD62Lhi cells and results in superior anti-tumor activity in a tolerogenic murine model. Cancer Immunol Immunother. 2008;57(4):563–572. doi:10.1007/s00262-007-0394-0.
   PubMed Web of Science ®Google Scholar
• Grasso CS, Tsoi J, Onyshchenko M, Abril-Rodriguez G, Ross-Macdonald P, Wind-Rotolo M, Champhekar A, Medina E, Torrejon DY, Shin DS, et al. Conserved interferon-γ signaling drives clinical response to immune checkpoint blockade therapy in melanoma. Cancer Cell. 2020;38(4):500–515 e503. doi:10.1016/j.ccell.2020.08.005.
   PubMed Web of Science ®Google Scholar
• Roby KF, Taylor CC, Sweetwood JP, Cheng Y, Pace JL, Tawfik O, Persons DL, Smith PG, Terranova PF. Development of a syngeneic mouse model for events related to ovarian cancer. Carcinogenesis. 2000;21(4):585–591. doi:10.1093/carcin/21.4.585.
   PubMed Web of Science ®Google Scholar
• Okla K, Czerwonka A, Wawruszak A, Bobiński M, Bilska M, Tarkowski R, Bednarek W, Wertel I, Kotarski J. Clinical relevance and immunosuppressive pattern of circulating and infiltrating subsets of myeloid-derived suppressor cells (MDSC) in epithelial ovarian cancer. Front Immunol. 2019;10:691. doi:10.3389/fimmu.2019.00691.
   PubMed Web of Science ®Google Scholar
• Furukawa S, Soeda SH, Kiko Y, Suzuki O, Hashimoto Y, Watanabe T, Nishiyama H, Tasaki K, Hojo H, Abe M, Fujimori K. et al. MCP-1 promotes invasion and adhesion of human ovarian cancer cell. Anti-Cancer Res 2013;3(11):4785–4790.
   Google Scholar
• Mandal PK, Biswas S, Mandal G, Purohit S, Gupta A, Majumdar (Giri) A, Roy Chowdhury S, Bhattacharyya A. CCL2 conditionally determines CCL22-dependent Th2-accumulation during TGF-β-induced breast cancer progression. Immunobiology. 2018;223(2):151–161. doi:10.1016/j.imbio.2017.10.031.
   PubMed Web of Science ®Google Scholar
• Lenzi R, Rosenblum M, Verschraegen C, Kudelka AP, Kavanagh JJ, Hicks ME, Lang EA, Nash MA, Levy LB, Garcia ME, et al. Phase I study of intraperitoneal recombinant human interleukin 12 in patients with Müllerian carcinoma, gastrointestinal primary malignancies, and mesothelioma. Clin Cancer Res. 2002;8(12):3686–3695.
   PubMed Web of Science ®Google Scholar
• Lenzi R, Edwards R, June C, Seiden MV, Garcia ME, Rosenblum M, Freedman RS. Phase II study of intraperitoneal recombinant interleukin-12 (rhIL-12) in patients with peritoneal carcinomatosis (residual disease < 1=cm) associated with ovarian cancer or primary peritoneal carcinoma. J Transl Med. 2007;5(1):66. doi:10.1186/1479-5876-5-66.
   PubMedGoogle Scholar
• Bekaii-Saab TS, Roda JM, Guenterberg KD, Ramaswamy B, Young DC, Ferketich AK, Lamb TA, Grever MR, Shapiro CL, Carson WE. A phase I trial of paclitaxel and trastuzumab in combination with interleukin-12 in patients with HER2/neu-expressing malignancies. Mol Cancer Ther. 2009 ;8(11):2983–2991. doi:10.1158/1535-.
   PubMed Web of Science ®Google Scholar
• Parihar R, Nadella P, Lewis A, Jensen R, De Hoff C, Dierksheide JE, VanBuskirk AM, Magro CM, Young DC, Shapiro CL, et al. A phase I study of interleukin 12 with trastuzumab in patients with human epidermal growth factor receptor-2-overexpressing malignancies: analysis of sustained interferon gamma production in a subset of patients. Clin Cancer Res. 2004;10(15):5027–5037. doi:10.1158/1078-0432.CCR-04-0265.
   PubMed Web of Science ®Google Scholar
• McMichael EL, Benner B, Atwal LS, Courtney NB, Mo X, Davis ME, Campbell AR, Duggan MC, Williams K, Martin K, et al. A phase I/II trial of cetuximab in combination with interleukin-12 administered to patients with unresectable primary or recurrent head and neck squamous cell carcinoma. Clin Cancer Res. 2019;25(16):4955–4965. doi:10.1158/1078-0432.CCR-18-2108.
   PubMed Web of Science ®Google Scholar
• Thaker PH, Bradley WH, Leath CA, Gunderson Jackson C, Borys N, Anwer K, Musso L, Matsuzaki J, Bshara W, et al. GEN-1 in combination with neoadjuvant chemotherapy for patients with advanced epithelial ovarian cancer: a phase I dose-escalation study. Clin Cancer Res. 2021;27(20):5536–5545. doi:10.1158/1078-0432.CCR-21-0360.
   PubMed Web of Science ®Google Scholar
• Cirella A, Luri-Rey C, Di Trani CA, Teijeira A, Olivera I, Bolaños E, Castañón E, Palencia B, Brocco D, et al. Novel strategies exploiting interleukin-12 in cancer immunotherapy. Pharmacol Ther. 2022;239:108–189. doi:10.1016/j.pharmthera.2022.108189.
   Web of Science ®Google Scholar