MAP Kinase Inhibition Promotes T Cell and Anti-tumor Activity in Combination with PD-L1 Checkpoint Blockade

Immunity

Volumn 44, Issue 3, 2016, Pages 609-621

  Ebert, Peter J R ^a   Cheung, Jeanne ^a   Yang, Yagai ^a   McNamara, Erin ^a   Hong, Rebecca ^a   Moskalenko, Marina ^a   Gould, Stephen E ^a   Maecker, Heather ^a,b   Irving, Bryan A ^a,c   Kim, Jeong M ^a   Belvin, Marcia ^a   Mellman, Ira ^a  

^a GENENTECH INC   (United States)

^b Gilead   (United States)

^c CytomX Therapeutics Inc   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

MITOGEN ACTIVATED PROTEIN KINASE; PROGRAMMED DEATH 1 LIGAND 1; AZETIDINE DERIVATIVE; GDC-0973; MONOCLONAL ANTIBODY; PIPERIDINE DERIVATIVE;

ANTIGEN SPECIFICITY; ANTINEOPLASTIC ACTIVITY; ARTICLE; CD8+ T LYMPHOCYTE; CYTOTOXICITY; DEATH; ENZYME ACTIVITY; ENZYME INHIBITION; HUMAN; IMMUNOTHERAPY; NEOPLASM; NONHUMAN; PHENOTYPE; PRIORITY JOURNAL; T LYMPHOCYTE; TUMOR REGRESSION; ANIMAL; APOPTOSIS; BAGG ALBINO MOUSE; CANCER TRANSPLANTATION; CARCINOMA; CELL CYCLE CHECKPOINT; COLONIC NEOPLASMS; COMBINATION DRUG THERAPY; DRUG EFFECTS; DRUG POTENTIATION; DRUG THERAPY; IMMUNOLOGY; LYMPHOCYTE ACTIVATION; MOLECULARLY TARGETED THERAPY; MOUSE; TUMOR CELL LINE;

ANIMALS; ANTIBODIES, MONOCLONAL; ANTIGENS, CD274; APOPTOSIS; AZETIDINES; CARCINOMA; CD8-POSITIVE T-LYMPHOCYTES; CELL CYCLE CHECKPOINTS; CELL LINE, TUMOR; COLONIC NEOPLASMS; DRUG SYNERGISM; DRUG THERAPY; DRUG THERAPY, COMBINATION; EXTRACELLULAR SIGNAL-REGULATED MAP KINASES; HUMANS; IMMUNOTHERAPY; LYMPHOCYTE ACTIVATION; MICE; MICE, INBRED BALB C; MOLECULAR TARGETED THERAPY; NEOPLASM TRANSPLANTATION; PIPERIDINES;

EID: 84960450202     PISSN: 10747613     EISSN: 10974180     Source Type: Journal    
DOI: 10.1016/j.immuni.2016.01.024     Document Type: Article

References (57)

1. Akinleye A., Furqan M., Mukhi N., Ravella P., Liu D. MEK and the inhibitors: from bench to bedside. J. Hematol. Oncol. 2013, 6:27.
2. Ali K., Soond D.R., Piñeiro R., Hagemann T., Pearce W., Lim E.L., Bouabe H., Scudamore C.L., Hancox T., Maecker H., et al. Inactivation of PI(3)K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer. Nature 2014, 510:407-411.
3. Angelosanto J.M., Blackburn S.D., Crawford A., Wherry E.J. Progressive loss of memory T cell potential and commitment to exhaustion during chronic viral infection. J. Virol. 2012, 86:8161-8170.
4. Anichini A., Molla A., Vegetti C., Bersani I., Zappasodi R., Arienti F., Ravagnani F., Maurichi A., Patuzzo R., Santinami M., et al. Tumor-reactive CD8+ early effector T cells identified at tumor site in primary and metastatic melanoma. Cancer Res. 2010, 70:8378-8387.
5. Barber D.L., Wherry E.J., Masopust D., Zhu B., Allison J.P., Sharpe A.H., Freeman G.J., Ahmed R. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 2006, 439:682-687.
6. Bollag G., Hirth P., Tsai J., Zhang J., Ibrahim P.N., Cho H., Spevak W., Zhang C., Zhang Y., Habets G., et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 2010, 467:596-599.
7. Borghaei H., Paz-Ares L., Horn L., Spigel D.R., Steins M., Ready N.E., Chow L.Q., Vokes E.E., Felip E., Holgado E., et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N. Engl. J. Med. 2015, 373:1627-1639.
8. Burgess M.R., Hwang E., Firestone A.J., Huang T., Xu J., Zuber J., Bohin N., Wen T., Kogan S.C., Haigis K.M., et al. Preclinical efficacy of MEK inhibition in Nras-mutant AML. Blood 2014, 124:3947-3955.
9. Chen D.S., Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity 2013, 39:1-10.
10. Chen D., Heath V., O'Garra A., Johnston J., McMahon M. Sustained activation of the raf-MEK-ERK pathway elicits cytokine unresponsiveness in T cells. J. Immunol. 1999, 163:5796-5805.
11. D'Souza W.N., Chang C.F., Fischer A.M., Li M., Hedrick S.M. The Erk2 MAPK regulates CD8 T cell proliferation and survival. J. Immunol. 2008, 181:7617-7629.
12. DeSilva D.R., Jones E.A., Favata M.F., Jaffee B.D., Magolda R.L., Trzaskos J.M., Scherle P.A. Inhibition of mitogen-activated protein kinase kinase blocks T cell proliferation but does not induce or prevent anergy. J. Immunol. 1998, 160:4175-4181.
13. Djeu J.Y., Jiang K., Wei S. A view to a kill: signals triggering cytotoxicity. Clin. Cancer Res. 2002, 8:636-640.
14. Dooley A.J., Gupta A., Bhattacharyya M., Middleton M.R. Intermittent dosing with vemurafenib in BRAF V600E-mutant melanoma: review of a case series. Ther. Adv. Med. Oncol. 2014, 6:262-266.
15. Engelman J.A., Chen L., Tan X., Crosby K., Guimaraes A.R., Upadhyay R., Maira M., McNamara K., Perera S.A., Song Y., et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat. Med. 2008, 14:1351-1356.
16. Ferris R.L., Lu B., Kane L.P. Too much of a good thing? Tim-3 and TCR signaling in T cell exhaustion. J. Immunol. 2014, 193:1525-1530.
17. Flaherty K.T., Puzanov I., Kim K.B., Ribas A., McArthur G.A., Sosman J.A., O'Dwyer P.J., Lee R.J., Grippo J.F., Nolop K., Chapman P.B. Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl. J. Med. 2010, 363:809-819.
18. Fujii Y., Matsuda S., Takayama G., Koyasu S. ERK5 is involved in TCR-induced apoptosis through the modification of Nur77. Genes Cells 2008, 13:411-419.
19. Grimaldi A.M., Simeone E., Ascierto P.A. The role of MEK inhibitors in the treatment of metastatic melanoma. Curr. Opin. Oncol. 2014, 26:196-203.
20. + tumor-reactive repertoire infiltrating human tumors. J. Clin. Invest. 2014, 124:2246-2259.
21. Gupta S., Weiss A., Kumar G., Wang S., Nel A. The T-cell antigen receptor utilizes Lck, Raf-1, and MEK-1 for activating mitogen-activated protein kinase. Evidence for the existence of a second protein kinase C-dependent pathway in an Lck-negative Jurkat cell mutant. J. Biol. Chem. 1994, 269:17349-17357.
22. Hatzivassiliou G., Haling J.R., Chen H., Song K., Price S., Heald R., Hewitt J.F., Zak M., Peck A., Orr C., et al. Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers. Nature 2013, 501:232-236.
23. Herbst R.S., Soria J.C., Kowanetz M., Fine G.D., Hamid O., Gordon M.S., Sosman J.A., McDermott D.F., Powderly J.D., Gettinger S.N., et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 2014, 515:563-567.
24. Hodi F.S., O'Day S.J., McDermott D.F., Weber R.W., Sosman J.A., Haanen J.B., Gonzalez R., Robert C., Schadendorf D., Hassel J.C., et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 2010, 363:711-723.
25. Hoeflich K.P., Merchant M., Orr C., Chan J., Den Otter D., Berry L., Kasman I., Koeppen H., Rice K., Yang N.Y., et al. Intermittent administration of MEK inhibitor GDC-0973 plus PI3K inhibitor GDC-0941 triggers robust apoptosis and tumor growth inhibition. Cancer Res. 2012, 72:210-219.
26. Johnston R.J., Comps-Agrar L., Hackney J., Yu X., Huseni M., Yang Y., Park S., Javinal V., Chiu H., Irving B., et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. Cancer Cell 2014, 26:923-937.
27. Jordan K.R., McMahan R.H., Kemmler C.B., Kappler J.W., Slansky J.E. Peptide vaccines prevent tumor growth by activating T cells that respond to native tumor antigens. Proc. Natl. Acad. Sci. USA 2010, 107:4652-4657.
28. Larkin J., Ascierto P.A., Dréno B., Atkinson V., Liszkay G., Maio M., Mandalà M., Demidov L., Stroyakovskiy D., Thomas L., et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N. Engl. J. Med. 2014, 371:1867-1876.
29. Lazarevic V., Glimcher L.H., Lord G.M. T-bet: a bridge between innate and adaptive immunity. Nat. Rev. Immunol. 2013, 13:777-789.
30. Lebbé C., Weber J.S., Maio M., Neyns B., Harmankaya K., Hamid O., O'Day S.J., Konto C., Cykowski L., McHenry M.B., Wolchok J.D. Survival follow-up and ipilimumab retreatment of patients with advanced melanoma who received ipilimumab in prior phase II studies. Ann. Oncol. 2014, 25:2277-2284.
31. Lee P.P., Yee C., Savage P.A., Fong L., Brockstedt D., Weber J.S., Johnson D., Swetter S., Thompson J., Greenberg P.D., et al. Characterization of circulating T cells specific for tumor-associated antigens in melanoma patients. Nat. Med. 1999, 5:677-685.
32. Li G., Yang Q., Zhu Y., Wang H.R., Chen X., Zhang X., Lu B. T-Bet and Eomes regulate the balance between the effector/central memory T cells versus memory stem like T cells. PLoS ONE 2013, 8:e67401.
33. Liu X., Gibbons R.M., Harrington S.M., Krco C.J., Markovic S.N., Kwon E.D., Dong H. Endogenous tumor-reactive CD8(+) T cells are differentiated effector cells expressing high levels of CD11a and PD-1 but are unable to control tumor growth. OncoImmunology 2013, 2:e23972.
34. Liu L., Mayes P.A., Eastman S., Shi H., Yadavilli S., Zhang T., Yang J., Seestaller-Wehr L., Zhang S.Y., Hopson C., 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, 21:1639-1651.
35. McArthur G.A., Ribas A. Targeting oncogenic drivers and the immune system in melanoma. J. Clin. Oncol. 2013, 31:499-506.
36. Ott P.A., Bhardwaj N. Impact of MAPK pathway activation in BRAF(V600) melanoma on T cell and dendritic cell function. Front. Immunol. 2013, 4:346.
37. Page D.B., Postow M.A., Callahan M.K., Allison J.P., Wolchok J.D. Immune modulation in cancer with antibodies. Annu. Rev. Med. 2014, 65:185-202.
38. Paley M.A., Kroy D.C., Odorizzi P.M., Johnnidis J.B., Dolfi D.V., Barnett B.E., Bikoff E.K., Robertson E.J., Lauer G.M., Reiner S.L., Wherry E.J. Progenitor and terminal subsets of CD8+ T cells cooperate to contain chronic viral infection. Science 2012, 338:1220-1225.
39. Pardoll D.M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 2012, 12:252-264.
40. Parish I.A., Rao S., Smyth G.K., Juelich T., Denyer G.S., Davey G.M., Strasser A., Heath W.R. The molecular signature of CD8+ T cells undergoing deletional tolerance. Blood 2009, 113:4575-4585.
41. Powles T., Eder J.P., Fine G.D., Braiteh F.S., Loriot Y., Cruz C., Bellmunt J., Burris H.A., Petrylak D.P., Teng S.L., et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 2014, 515:558-562.
42. Putz E.M., Prchal-Murphy M., Simma O.A., Forster F., Koenig X., Stockinger H., Piekorz R.P., Freissmuth M., Müller M., Sexl V., Zebedin-Brandl E. PI3Kδ is essential for tumor clearance mediated by cytotoxic T lymphocytes. PLoS ONE 2012, 7:e40852.
43. Rahman A. Vemurafenib and cobimetinib in BRAF-mutated melanoma. Lancet Oncol. 2014, 15:e535.
44. Robert C., Schachter J., Long G.V., Arance A., Grob J.J., Mortier L., Daud A., Carlino M.S., McNeil C., Lotem M., et al. Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med. 2015, 372:2521-2532. KEYNOTE-006 investigators.
45. Rosen, L.S., LoRusso, P., Ma, W.W., Goldman, J., Weise, A., Colevas, A.D., Adjei, A., Yazji, S., Shen, A., Johnston, S., et al. (2011). Abstract 4716: A first-in-human phase I study to evaluate the MEK1/2 inhibitor GDC-0973 administered daily in patients with advanced solid tumors. In Proceed. 102nd Ann. Meet. AACR 71, . doi:10.1158/1538-7445.
46. Schietinger A., Greenberg P.D. Tolerance and exhaustion: defining mechanisms of T cell dysfunction. Trends Immunol. 2014, 35:51-60.
47. Shindo T., Kim T.K., Benjamin C.L., Wieder E.D., Levy R.B., Komanduri K.V. MEK inhibitors selectively suppress alloreactivity and graft-versus-host disease in a memory stage-dependent manner. Blood 2013, 121:4617-4626.
48. Solit D.B., Rosen N. Resistance to BRAF inhibition in melanomas. N. Engl. J. Med. 2011, 364:772-774.
49. Speiser D.E., Utzschneider D.T., Oberle S.G., Münz C., Romero P., Zehn D. T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?. Nat. Rev. Immunol. 2014, 14:768-774.
50. Su B., Cheng J., Yang J., Guo Z. MEKK2 is required for T-cell receptor signals in JNK activation and interleukin-2 gene expression. J. Biol. Chem. 2001, 276:14784-14790.
51. Tan N., Wong M., Nannini M.A., Hong R., Lee L.B., Price S., Williams K., Savy P.P., Yue P., Sampath D., et al. Bcl-2/Bcl-xL inhibition increases the efficacy of MEK inhibition alone and in combination with PI3 kinase inhibition in lung and pancreatic tumor models. Mol. Cancer Ther. 2013, 12:853-864.
52. Terheyden P., Schrama D., Pedersen L.O., Andersen M.H., Kämpgen E., thor Straten P., Becker J.C. Longitudinal analysis of MART-1/HLA-A2-reactive T cells over the course of melanoma progression. Scand. J. Immunol. 2003, 58:566-571.
53. Topalian S.L., Sznol M., McDermott D.F., Kluger H.M., Carvajal R.D., Sharfman W.H., Brahmer J.R., Lawrence D.P., Atkins M.B., Powderly J.D., et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J. Clin. Oncol. 2014, 32:1020-1030.
54. Wang A., Rud J., Olson C.M., Anguita J., Osborne B.A. Phosphorylation of Nur77 by the MEK-ERK-RSK cascade induces mitochondrial translocation and apoptosis in T cells. J. Immunol. 2009, 183:3268-3277.
55. Weiss A., Littman D.R. Signal transduction by lymphocyte antigen receptors. Cell 1994, 76:263-274.
56. Wolchok J.D., Kluger H., Callahan M.K., Postow M.A., Rizvi N.A., Lesokhin A.M., Segal N.H., Ariyan C.E., Gordon R.A., Reed K., et al. Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 2013, 369:122-133.
57. Zhu Y., Ju S., Chen E., Dai S., Li C., Morel P., Liu L., Zhang X., Lu B. T-bet and eomesodermin are required for T cell-mediated antitumor immune responses. J. Immunol. 2010, 185:3174-3183.