IL15 agonists overcome the immunosuppressive effects of MEK inhibitors

Cancer Research

Volumn 76, Issue 9, 2016, Pages 2561-2572

  Allegrezza, Michael J ^a   Rutkowski, Melanie R ^a   Stephen, Tom L ^a   Svoronos, Nikolaos ^a   Tesone, Amelia J ^a   Perales Puchalt, Alfredo ^a   Nguyen, Jenny M ^a   Sarmin, Fahmida ^a   Sheen, Mee R ^b   Jeng, Emily K ^c   Tchou, Julia ^d,e   Wong, Hing C ^c   Fiering, Steven N ^b   Conejo Garcia, Jose R ^a  

^a WISTAR INSTITUTE   (United States)

^b DARTMOUTH MEDICAL SCHOOL   (United States)

^c ALTOR BIOSCIENCE CORPORATION   (United States)

^d UNIVERSITY OF PENNSYLVANIA   (United States)

^e UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALT 803; ANTINEOPLASTIC AGENT; BUPARLISIB; COBIMETINIB; CYTOKINE RECEPTOR AGONIST; INTERLEUKIN 15 AGONIST; MITOGEN ACTIVATED PROTEIN KINASE KINASE INHIBITOR; PHOSPHATIDYLINOSITOL 3 KINASE; TRAMETINIB; UNCLASSIFIED DRUG; ALT-803; INTERLEUKIN 15; PROTEIN; PROTEIN KINASE INHIBITOR; PYRIDONE DERIVATIVE; PYRIMIDINONE DERIVATIVE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; BREAST TUMOR; CELLULAR IMMUNITY; CONTROLLED STUDY; DRUG EFFICACY; DRUG MECHANISM; DRUG POTENTIATION; DRUG TARGETING; FEMALE; HUMAN; HUMAN CELL; IMMUNOREGULATION; IMMUNOSTIMULATION; IN VITRO STUDY; IN VIVO STUDY; MOUSE; NONHUMAN; PRIORITY JOURNAL; SIGNAL TRANSDUCTION; T LYMPHOCYTE ACTIVATION; ANIMAL; C57BL MOUSE; CD8+ T LYMPHOCYTE; DRUG EFFECTS; DRUG SCREENING; EXPERIMENTAL NEOPLASM; FLOW CYTOMETRY; HIGH THROUGHPUT SCREENING; LYMPHOCYTE ACTIVATION; PATHOLOGY; TRANSGENIC MOUSE; TUMOR CELL LINE; WESTERN BLOTTING;

ANIMALS; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; BLOTTING, WESTERN; CD8-POSITIVE T-LYMPHOCYTES; CELL LINE, TUMOR; FLOW CYTOMETRY; HIGH-THROUGHPUT SCREENING ASSAYS; HUMANS; INTERLEUKIN-15; LYMPHOCYTE ACTIVATION; MICE; MICE, INBRED C57BL; MICE, TRANSGENIC; NEOPLASMS, EXPERIMENTAL; PROTEIN KINASE INHIBITORS; PROTEINS; PYRIDONES; PYRIMIDINONES; SIGNAL TRANSDUCTION; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 84969592914     PISSN: 00085472     EISSN: 15387445     Source Type: Journal    
DOI: 10.1158/0008-5472.CAN-15-2808     Document Type: Article

References (44)

1. Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ. Natural innate and adaptive immunity to cancer. Annu Rev Immunol 2011;29: 235-71.
2. Smith-Garvin JE, Koretzky GA, Jordan MS. T cell activation. Annu Rev Immunol 2009;27:591-619.
3. Vella LJ, Pasam A, Dimopoulos N, Andrews M, Knights A, Puaux AL, et al. MEK inhibition, alone or in combination with BRAF inhibition, affects multiple functions of isolated normal human lymphocytes and dendritic cells. Cancer Immunol Res 2014;2:351-60.
4. Yamaguchi T, Kakefuda R, Tanimoto A,Watanabe Y, TajimaN. Suppressive effect of an orally active MEK1/2 inhibitor in two different animal models for rheumatoid arthritis: a comparison with leflunomide. Inflamm Res 2012;61:445-54.
5. Boni A, Cogdill AP, Dang P, Udayakumar D, Njauw CN, Sloss CM, et al. Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function. Cancer Res 2010;70:5213-9.
6. Hu-Lieskovan S, Mok S, Homet Moreno B, Tsoi J, Robert L, Goedert L, et al. Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAF(V600E) melanoma. Sci Transl Med 2015;7:279ra41.
7. Liu L, Mayes PA, Eastman S, Shi H, Yadavilli S, Zhang T, et al. The BRAF and MEK inhibitors dabrafenib and trametinib: effects on immune function and in combination with immunomodulatory antibodies targeting PD-1, PD-L1, and CTLA-4. Clin Cancer Res 2015;21:1639-51.
8. Kono M, Dunn IS, Durda PJ, Butera D, Rose LB, Haggerty TJ, et al. Role of themitogen-activated protein kinase signaling pathway in the regulation of human melanocytic antigen expression. Mol Cancer Res 2006;4:779-92.
9. Bowyer S, Lorigan P. The place of PD-1 inhibitors in melanoma management. Lancet Oncol 2015;16:873-4.
10. Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet 2015;386:444-51.
11. Jackson EL, Willis N, Mercer K, Bronson RT, Crowley D, Montoya R, et al. Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. Genes Dev 2001;15:3243-8.
12. Jonkers J, Meuwissen R, van der GuldenH, Peterse H, van der Valk M, Berns A. Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer. Nat Genet 2001;29:418-25.
13. Scarlett UK, Rutkowski MR, Rauwerdink AM, Fields J, Escovar-Fadul X, Baird J, et al. Ovarian cancer progression is controlled by phenotypic changes in dendritic cells. J Exp Med 2012;209:495-506.
14. Rutkowski MR, Stephen TL, Svoronos N, Allegrezza MJ, Tesone AJ, Perales-Puchalt A, et al. Microbially driven TLR5-dependent signaling governs distal malignant progression through tumor-promoting inflammation. Cancer Cell 2015;27:27-40.
15. Rutkowski MR, Allegrezza MJ, Svoronos N, Tesone AJ, Stephen TL, Perales-Puchalt A, et al. Initiation of metastatic breast carcinoma by targeting of the ductal epithelium with Adenovirus-Cre: a novel transgenic mouse model of breast cancer. J Vis Exp 2014;85:e51171.
16. Roby KF, Taylor CC, Sweetwood JP, Cheng Y, Pace JL, Tawfik O, et al. Development of a syngeneic mouse model for events related to ovarian cancer. Carcinogenesis 2000;21:585-91.
17. Conejo-Garcia JR, Benencia F, Courreges MC, Kang E, Mohamed-Hadley A, Buckanovich RJ, et al. Tumor-infiltrating dendritic cell precursors recruited by a beta-defensin contribute to vasculogenesis under the influence of Vegf-A. Nat Med 2004;10:950-8.
18. Cubillos-Ruiz JR, Engle X, Scarlett UK, Martinez D, Barber A, Elgueta R, et al. Polyethylenimine-based siRNA nanocomplexes reprogram tumor-associated dendritic cells via TLR5 to elicit therapeutic antitumor immunity. J Clin Invest 2009;119:2231-44.
19. Maus MV, Thomas AK, Leonard DG, Allman D, Addya K, Schlienger K, et al. Ex vivo expansion of polyclonal and antigen-specific cytotoxic T lymphocytes by artificial APCs expressing ligands for the T-cell receptor, CD28 and 4-1BB. Nat Biotechnol 2002;20:143-8.
20. Stephen TL, Rutkowski MR, Allegrezza MJ, Perales-Puchalt A, Tesone AJ, Svoronos N, et al. Transforming growth factor b-mediated suppression of antitumor T cells requires FoxP1 transcription factor expression. Immunity 2014;41:427-39.
21. Huarte E, Cubillos-Ruiz JR, Nesbeth YC, Scarlett UK, Martinez DG, Buckanovich RJ, et al. Depletion of dendritic cells delays ovarian cancer progression by boosting antitumor immunity. Cancer Res 2008;68:7684-91.
22. Wargo JA, Cooper ZA, Flaherty KT. Universes collide: combining immunotherapy with targeted therapy for cancer. Cancer Discov 2014;4: 1377-86.
23. Gao N, Flynn DC, Zhang Z, Zhong XS,Walker V, Liu KJ, et al. G1 cell cycle progression and the expression of G1 cyclins are regulated by PI3K/AKT/mTOR/p70S6K1 signaling in human ovarian cancer cells. AmJ PhysiolCell Physiol 2004;287:C281-91.
24. Hou JY, Rodriguez-Gabin A, Samaweera L, Hazan R, Goldberg GL, Horwitz SB, et al. Exploiting MEK inhibitor-mediated activation of ERalpha for therapeutic intervention in ER-positive ovarian carcinoma. PLoS One 2013;8:e54103.
25. Liao W, Lin JX, Leonard WJ. Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy. Immunity 2013;38:13-25.
26. Waldmann TA. The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nat Rev Immunol 2006; 6:595-601.
27. Budagian V, Bulanova E, Paus R, Bulfone-Paus S. IL-15/IL-15 receptor biology: a guided tour through an expanding universe. Cytokine Growth Factor Rev 2006;17:259-80.
28. Ueda Y, Hirai S, Osada S, Suzuki A, Mizuno K, Ohno S. Protein kinase C activates the MEK-ERK pathway in a manner independent of Ras and dependent on Raf. J Biol Chem 1996;271:23512-9.
29. Cantley LC. The phosphoinositide 3-kinase pathway. Science 2002;296: 1655-7.
30. Xu W, Jones M, Liu B, Zhu X, Johnson CB, Edwards AC, et al. Efficacy and mechanism-of-action of a novel superagonist interleukin-15: interleukin-15 receptor alphaSu/Fc fusion complex in syngeneic murine models of multiple myeloma. Cancer Res 2013;73:3075-86.
31. Nesbeth YC, Martinez DG, Toraya S, Scarlett UK, Cubillos-Ruiz JR, Rutkowski MR, et al. CD4+ T cells elicit host immune responses to MHC class II-ovarian cancer through CCL5 secretion and CD40-mediated licensing of dendritic cells. J Immunol 2010;184:5654-62.
32. Rhode PR, Egan JO, Xu W, Hong H, Webb GM, Chen X, et al. Comparison of the superagonist complex, ALT-803, to IL15 as cancer immunotherapeutics in animal models. Cancer Immunol Res 2016;4:49-60.
33. Wee S, Jagani Z, Xiang KX, Loo A, Dorsch M, Yao YM, et al. PI3K pathway activation mediates resistance to MEK inhibitors in KRAS mutant cancers. Cancer Res 2009;69:4286-93.
34. Mirzoeva OK, Das D, Heiser LM, Bhattacharya S, Siwak D, Gendelman R, et al. Basal subtype and MAPK/ERK kinase (MEK)-phosphoinositide 3-kinase feedback signaling determine susceptibility of breast cancer cells to MEK inhibition. Cancer Res 2009;69:565-72.
35. Turke AB, Song Y, Costa C, Cook R, Arteaga CL, Asara JM, et al. MEK inhibition leads to PI3K/AKT activation by relieving a negative feedback on ERBB receptors. Cancer Res 2012;72:3228-37.
36. Drake CG. Combined immune checkpoint blockade. Semin Oncol 2015;42:656-62.
37. Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G. Immunological aspects of cancer chemotherapy. Nat Rev Immunol 2008;8:59-73.
38. Infante JR, Papadopoulos KP, Bendell JC, Patnaik A, Burris HA3rd, Rasco D, et al. A phase 1b study of trametinib, an oral Mitogen-activated protein kinase kinase (MEK) inhibitor, in combination with gemcitabine in advanced solid tumours. Eur J Cancer 2013;49:2077-85.
39. Bedard PL, Tabernero J, Janku F, Wainberg ZA, Paz-Ares L, Vansteenkiste J, et al. A phase Ib dose-escalation study of the oral pan-PI3K inhibitor buparlisib (BKM120) in combination with the oral MEK1/2 inhibitor trametinib (GSK1120212) in patients with selected advanced solid tumors. Clin Cancer Res 2015;21:730-8.
40. Blumenschein GRJr., Smit EF, Planchard D, Kim DW, Cadranel J, De Pas T, et al. A randomized phase II study of the MEK1/MEK2 inhibitor trametinib (GSK1120212) compared with docetaxel in KRAS-mutant advanced nonsmall-cell lung cancer (NSCLC)dagger. Ann Oncol 2015;26:894-901.
41. Mathios D, Park CK, Marcus WD, Alter S, Rhode PR, Jeng EK, et al. Therapeutic administration of IL-15 superagonist complex ALT-803 leads to long-term survival and durable antitumor immune response in a murine glioblastoma model. Int J Cancer 2016;138:187-94.
42. Wong HC, Jeng EK, Rhode PR. The IL-15-based superagonist ALT-803 promotes the antigen-independent conversion of memory CD8 T cells into innate-like effector cells with antitumor activity. Oncoimmunology 2013;2: e26442.
43. Shindo T, Kim TK, Benjamin CL, Wieder ED, Levy RB, Komanduri KV. MEK inhibitors selectively suppress alloreactivity and graft-versushost disease in a memory stage-dependent manner. Blood 2013;121: 4617-26.
44. Engelman JA, Chen L, Tan X, Crosby K, Guimaraes AR, Upadhyay R, et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med 2008;14:1351-6.