Anti-PD-1 antibody significantly increases therapeutic efficacy of Listeria monocytogenes (Lm)-LLO immunotherapy

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• 作者：Mikayel Mkrtichyan (1)
  Namju Chong (2)
  Rasha Abu Eid (1)
  Anu Wallecha (3)
  Reshma Singh (3)
  John Rothman (3)
  Samir N Khleif (1)
  
• 关键词：PD ; 1 ; Immunotherapy ; Listeria ; based vaccine ; Combinational immunotherapy
• 刊名：Journal for Immunotherapy of Cancer
• 出版年：2013
• 出版时间：December 2013
• 年：2013
• 卷：1
• 期：1
• 全文大小：488KB
• 参考文献：1. Pamer EG: Immune responses to Listeria monocytogenes. / Nat Rev Immunol 2004, 4:812鈥?23. CrossRef
  2. Wallecha A, Wood L, Pan ZK, Maciag PC, Shahabi V, Paterson Y: Listeria monocytogenes-derived listeriolysin O has pathogen-associated molecular pattern-like properties independent of its hemolytic ability. / Clin Vaccine Immunol 2013, 20:77鈥?4. CrossRef
  3. Gunn GR, Zubair A, Peters C, Pan ZK, Wu TC, Paterson Y: Two Listeria monocytogenes vaccine vectors that express different molecular forms of human papilloma virus-16 (HPV-16) E7 induce qualitatively different T cell immunity that correlates with their ability to induce regression of established tumors immortalized by HPV-16. / J Immunol 2001, 167:6471鈥?479.
  4. Sewell DA, Shahabi V, Gunn GR 3rd, Pan ZK, Dominiecki ME, Paterson Y: Recombinant Listeria vaccines containing PEST sequences are potent immune adjuvants for the tumor-associated antigen human papillomavirus-16 E7. / Cancer Res 2004, 64:8821鈥?825. CrossRef
  5. Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, Higuchi T, Yagi H, Takakura K, Minato N, / 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 USA 2007, 104:3360鈥?365. CrossRef
  6. Tsushima F, Tanaka K, Otsuki N, Youngnak P, Iwai H, Omura K, Azuma M: Predominant expression of B7-H1 and its immunoregulatory roles in oral squamous cell carcinoma. / Oral Oncol 2006, 42:268鈥?74. CrossRef
  7. Francisco LM, Sage PT, Sharpe AH: The PD-1 pathway in tolerance and autoimmunity. / Immunol Rev 2010, 236:219鈥?42. CrossRef
  8. Agata Y, Kawasaki A, Nishimura H, Ishida Y, Tsubata T, Yagita H, Honjo T: Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. / Int Immunol 1996, 8:765鈥?72. CrossRef
  9. Keir ME, Liang SC, Guleria I, Latchman YE, Qipo A, Albacker LA, Koulmanda M, Freeman GJ, Sayegh MH, Sharpe AH: Tissue expression of PD-L1 mediates peripheral T cell tolerance. / J Exp Med 2006, 203:883鈥?95. CrossRef
  10. Ohigashi Y, Sho M, Yamada Y, Tsurui Y, Hamada K, Ikeda N, Mizuno T, Yoriki R, Kashizuka H, Yane K, / et al.: Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer. / Clin Cancer Res 2005, 11:2947鈥?953. CrossRef
  11. Konishi J, Yamazaki K, Azuma M, Kinoshita I, Dosaka-Akita H, Nishimura M: B7-H1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression. / Clin Cancer Res 2004, 10:5094鈥?100. CrossRef
  12. Nomi T, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro H, Nakamura S, Enomoto K, Yagita H, Azuma M, Nakajima Y: Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. / Clin Cancer Res 2007, 13:2151鈥?157. CrossRef
  13. Thompson RH, Gillett MD, Cheville JC, Lohse CM, Dong H, Webster WS, Krejci KG, Lobo JR, Sengupta S, Chen L, / et al.: Costimulatory B7-H1 in renal cell carcinoma patients: indicator of tumor aggressiveness and potential therapeutic target. / Proc Natl Acad Sci U S A 2004, 101:17174鈥?7179. CrossRef
  14. Ghebeh H, Mohammed S, Al-Omair A, Qattan A, Lehe C, Al-Qudaihi G, Elkum N, Alshabanah M, Bin Amer S, Tulbah A, / et al.: The B7-H1 (PD-L1) T lymphocyte-inhibitory molecule is expressed in breast cancer patients with infiltrating ductal carcinoma: correlation with important high-risk prognostic factors. / Neoplasia 2006, 8:190鈥?98. CrossRef
  15. Thompson RH, Kuntz SM, Leibovich BC, Dong H, Lohse CM, Webster WS, Sengupta S, Frank I, Parker AS, Zincke H, / et al.: Tumor B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term follow-up. / Cancer Res 2006, 66:3381鈥?385. CrossRef
  16. Messal N, Serriari NE, Pastor S, Nunes JA, Olive D: PD-L2 is expressed on activated human T cells and regulates their function. / Mol Immunol 2011, 48:2214鈥?219. CrossRef
  17. Okazaki T, Honjo T: PD-1 and PD-1 ligands: from discovery to clinical application. / Int Immunol 2007, 19:813鈥?24. CrossRef
  18. Curiel TJ, Wei S, Dong H, Alvarez X, Cheng P, Mottram P, Krzysiek R, Knutson KL, Daniel B, Zimmermann MC, / et al.: Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. / Nat Med 2003, 9:562鈥?67. CrossRef
  19. Strome SE, Dong H, Tamura H, Voss SG, Flies DB, Tamada K, Salomao D, Cheville J, Hirano F, Lin W, / et al.: B7-H1 blockade augments adoptive T-cell immunotherapy for squamous cell carcinoma. / Cancer Res 2003, 63:6501鈥?505.
  20. He YF, Zhang GM, Wang XH, Zhang H, Yuan Y, Li D, Feng ZH: Blocking programmed death-1 ligand-PD-1 interactions by local gene therapy results in enhancement of antitumor effect of secondary lymphoid tissue chemokine. / J Immunol 2004, 173:4919鈥?928.
  21. Blank C, Brown I, Peterson AC, Spiotto M, Iwai Y, Honjo T, Gajewski TF: PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. / Cancer Res 2004, 64:1140鈥?145. CrossRef
  22. Mkrtichyan M, Najjar YG, Raulfs EC, Abdalla MY, Samara R, Rotem-Yehudar R, Cook L, Khleif SN: Anti-PD-1 synergizes with cyclophosphamide to induce potent anti-tumor vaccine effects through novel mechanisms. / Eur J Immunol 2011, 41:2977鈥?986. CrossRef
  23. Curran MA, Montalvo W, Yagita H, Allison JP: PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. / Proc Natl Acad Sci U S A 2010, 107:4275鈥?280. CrossRef
  24. Mkrtichyan M, Najjar YG, Raulfs EC, Liu L, Langerman S, Guittard G, Ozbun L, Khleif SN: B7-DC-Ig enhances vaccine effect by a novel mechanism dependent on PD-1 expression level on T cell subsets. / J Immunol 2012, 189:2338鈥?347. CrossRef
  25. Rowe JH, Johanns TM, Ertelt JM, Way SS: PDL-1 blockade impedes T cell expansion and protective immunity primed by attenuated Listeria monocytogenes. / J Immunol 2008, 180:7553鈥?557.
  26. Mkrtichyan M, Ghochikyan A, Davtyan H, Movsesyan N, Loukinov D, Lobanenkov V, Cribbs DH, Laust AK, Nelson EL, Agadjanyan MG: Cancer-testis antigen, BORIS based vaccine delivered by dendritic cells is extremely effective against a very aggressive and highly metastatic mouse mammary carcinoma. / Cell Immunol 2011, 270:188鈥?97. CrossRef
  27. Keir ME, Latchman YE, Freeman GJ, Sharpe AH: Programmed death-1 (PD-1):PD-ligand 1 interactions inhibit TCR-mediated positive selection of thymocytes. / J Immunol 2005, 175:7372鈥?379.
  28. 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鈥?45. CrossRef
  29. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC, / 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鈥?034. CrossRef
  30. Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, Linsley PS, Thompson CB, Riley JL: CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. / Mol Cell Biol 2005, 25:9543鈥?553. CrossRef
  31. Seo SK, Seo HM, Jeong HY, Choi IW, Park YM, Yagita H, Chen L, Choi IH: Co-inhibitory role of T-cell-associated B7-H1 and B7-DC in the T-cell immune response. / Immunol Lett 2006, 102:222鈥?28. CrossRef
  32. Fife BT, Guleria I, Gubbels Bupp M, Eagar TN, Tang Q, Bour-Jordan H, Yagita H, Azuma M, Sayegh MH, Bluestone JA: Insulin-induced remission in new-onset NOD mice is maintained by the PD-1-PD-L1 pathway. / J Exp Med 2006, 203:2737鈥?747. CrossRef
  33. Maciag PC, Radulovic S, Rothman J: The first clinical use of a live-attenuated Listeria monocytogenes vaccine: a phase I safety study of Lm-LLO-E7 in patients with advanced carcinoma of the cervix. / Vaccine 2009, 27:3975鈥?983. CrossRef
  34. Wallecha A, French C, Petit R, Singh R, Amin A, Rothman J: Lm-LLO-based immunotherapies and HPV-associated disease. / J Oncol 2012, 2012:542851. CrossRef
  
• 作者单位：Mikayel Mkrtichyan (1)
  Namju Chong (2)
  Rasha Abu Eid (1)
  Anu Wallecha (3)
  Reshma Singh (3)
  John Rothman (3)
  Samir N Khleif (1)
  
  1. Cancer Center, Georgia Regents University, 1120 15th Street, Augusta, GA, 30192, USA
  2. National Cancer Institute, NIH, Vaccine Branch, Bethesda, MD, 20892, USA
  3. Advaxis Inc., Princeton, NJ, 08540, USA
  
• ISSN：2051-1426

文摘

Background One of the significant tumor immune escape mechanisms and substantial barrier for successful immunotherapy is tumor-mediated inhibition of immune response through cell-to-cell or receptor/ligand interactions. Programmed death receptor-1 (PD-1) interaction with its ligands, PD-L1 and PD-L2, is one of the important strategies that many tumors employ to escape immune surveillance. Upon PD-Ls binding to PD-1, T cell receptor (TCR) signaling is dampened, causing inhibition of proliferation, decreased cytokine production, anergy and/or apoptosis. Thus PD-Ls expression by tumor cells serves as a protective mechanism, leading to suppression of tumor-infiltrating lymphocytes in the tumor microenvironment. Lm-LLO immunotherapies have been shown to be therapeutically effective due to their ability to induce potent antigen-specific immune responses. However, it has been demonstrated that infection with Lm leads to up-regulation of PD-L1 on mouse immune cells that can inhibit effector T cells through PD-1/PD-L1 pathway. Methods Therapeutic and immune efficacy of Listeria-based vaccine (Lm-LLO-E7) in combination with anti-PD-1 antibody was tested in E7 antigen expressing TC-1 mouse tumor model. Tumor growth, survival, as well as peripheral and tumor-infiltrating immune cell profiles after immunotherapy were assessed. Results Here we demonstrate that the combination of an Lm-LLO immunotherapy with anti-PD-1 antibody that blocks PD-1/PD-L1 interaction, significantly improves immune and therapeutic efficacy of treatment in TC-1 mouse tumor model. Importantly, we show that in addition to significant reduction of regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC) in both spleen and tumor microenvironment that are mediated solely by the Lm-LLO immunotherapy, the addition of anti-PD-1 antibody to the treatment results in significant increase of antigen-specific immune responses in periphery and CD8 T cell infiltration into the tumor. As a result, this combinational treatment leads to significant inhibition of tumor growth and prolonged survival/complete regression of tumors in treated animals. We also demonstrate that in vitro infection with Lm results in significant upregulation of surface PD-L1 expression on human monocyte-derived dendritic cells suggesting the translational capacity of this finding. Conclusions Our findings demonstrate that combination of Lm-LLO-based vaccine with blocking of PD-1/PD-L1 interaction is a feasible approach with clinical translation potential that can lead to overall enhancement of the efficacy of anti-tumor immunotherapy.