Multifactorial T-cell hypofunction that is reversible can limit the efficacy of chimeric antigen receptor-transduced human T cells in solid tumors

Clinical Cancer Research

Volumn 20, Issue 16, 2014, Pages 4262-4273

  Moon, Edmund K ^a   Wang, Liang Chuan ^a   Dolfi, Douglas V ^a   Wilson, Caleph B ^b   Ranganathan, Raghuveer ^a   Sun, Jing ^a   Kapoor, Veena ^a   Scholler, John ^b   Puré, Ellen ^a   Milone, Michael C ^b   June, Carl H ^b   Riley, James L ^a   Wherry, E John ^a   Albelda, Steven M ^a  

^a UNIVERSITY OF PENNSYLVANIA   (United States)

^b UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CANCER VACCINE; CHIMERIC ANTIGEN RECEPTOR; DIACYLGLYCEROL KINASE; FIBROBLAST ACTIVATION PROTEIN; LYMPHOCYTE ANTIGEN RECEPTOR; LYMPHOCYTE RECEPTOR; MESOTHELIN; PROTEIN 3B4; PROTEIN LAG3; PROTEIN PD1; PROTEIN TIM3; PROTEIN TYROSINE PHOSPHATASE SHP 1; SERINE PROTEINASE; UNCLASSIFIED DRUG; GELATINASE; GLYCOSYLPHOSPHATIDYLINOSITOL ANCHORED PROTEIN; MEMBRANE PROTEIN; SEPRASE;

ADOPTIVE TRANSFER; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CANCER CHEMOTHERAPY; CANCER IMMUNOTHERAPY; CANCER INHIBITION; CONTROLLED STUDY; CYTOTOXIC T LYMPHOCYTE; DRUG EFFICACY; FEMALE; HUMAN; HUMAN CELL; LYMPHOCYTE FUNCTION; MITOSIS INHIBITION; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN TARGETING; SIGNAL TRANSDUCTION; SOLID TUMOR; TUMOR MICROENVIRONMENT; UPREGULATION; 3T3 CELL LINE; ADOPTIVE IMMUNOTHERAPY; ANIMAL; CYTOTOXICITY; DRUG SCREENING; GENETICS; IMMUNOLOGY; MESOTHELIOMA; METABOLISM; NONOBESE DIABETIC MOUSE; SCID MOUSE; T LYMPHOCYTE; TUMOR ASSOCIATED LEUKOCYTE; TUMOR CELL CULTURE;

ANIMALS; BALB 3T3 CELLS; CYTOTOXICITY, IMMUNOLOGIC; FEMALE; GELATINASES; GPI-LINKED PROTEINS; HUMANS; IMMUNOTHERAPY, ADOPTIVE; LYMPHOCYTES, TUMOR-INFILTRATING; MEMBRANE PROTEINS; MESOTHELIOMA; MICE; MICE, INBRED NOD; MICE, SCID; RECEPTORS, ANTIGEN, T-CELL; SERINE ENDOPEPTIDASES; SIGNAL TRANSDUCTION; T-LYMPHOCYTES; TUMOR CELLS, CULTURED; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 84905993539     PISSN: 10780432     EISSN: 15573265     Source Type: Journal    
DOI: 10.1158/1078-0432.CCR-13-2627     Document Type: Article

References (59)

1. Escudier B. Emerging immunotherapies for renal cell carcinoma. Ann Oncol 2012;23 Suppl 8:viii35-40.
2. Rosenberg SA, Yang JC, Sherry RM, Kammula US, Hughes MS, Phan GQ, et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res 2011;17:4550-7.
3. Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 2011;365:725-33.
4. Sadelain M, Brentjens R, Riviere I. The basic principles of chimeric antigen receptor design. Cancer Discov 2013;3:388-98.
5. Gilham DE, Debets R, Pule M, Hawkins RE, Abken H. CAR-T cells and solid tumors: tuning T cells to challenge an inveterate foe. Trends Mol Med 2012;18:377-84.
6. Lipowska-Bhalla G, Gilham DE, Hawkins RE, Rothwell DG. Targeted immunotherapy of cancer with CAR T cells: achievements and challenges. Cancer Immunol Immunother 2012;61:953-62.
7. Gajewski TF. Failure at the effector phase: immune barriers at the level of the melanoma tumor microenvironment. Clin Cancer Res 2007;13 (18 Pt 1):5256-61.
8. Mescher MF, Popescu FE, Gerner M, Hammerbeck CD, Curtsinger JM. Activation-induced non-responsiveness (anergy) limits CD8 T cell responses to tumors. Semin Cancer Biol 2007;17:299-308.
9. Powell JD. The induction and maintenance of T cell anergy. Clin Immunol 2006;120:239-46.
10. Russ AJ, Wentworth L, Xu K, Rakhmilevich A, Seroogy CM, Sondel PM, et al. Suppression of T-cell expansion by melanoma is exerted on resting cells. Ann Surg Oncol 2011;18:3848-57.
11. Baitsch L, Fuertes-Marraco SA, Legat A, Meyer C, Speiser DE. The three main stumbling blocks for anticancer T cells. Trends Immunol 2012;33:364-72.
12. Gajewski TF, Woo SR, Zha Y, Spaapen R, Zheng Y, Corrales L, et al. Cancer immunotherapy strategies based on overcoming barriers within the tumor microenvironment. Curr Opin Immunol 2013;25:268-76.
13. Mayer A, Vaupel P. Hypoxia, lactate accumulation, and acidosis: siblings or accomplices driving tumor progression and resistance to therapy? Adv Exp Med Biol 2013;789:203-9.
14. Abate-Daga D, Hanada KI, Davis JL, Yang JC, Rosenberg SA, Morgan RA. Expression profiling of TCR-engineered T cells demonstrates over-expression of multiple inhibitory receptors in persisting lymphocytes. Blood 2013;122:1399-410.
15. Park HJ, Kusnadi A, Lee EJ, Kim WW, Cho BC, Lee IJ, et al. Tumor-infiltrating regulatory T cells delineated by upregulation of PD-1 and inhibitory receptors. Cell Immunol 2012;278:76-83.
16. Zheng Y, Zha Y, Gajewski TF. Molecular regulation of T-cell anergy. EMBO Rep 2008;9:50-55.
17. + lymphocytes inactivates antitumor effector phase. J Immunol 2010;185:7133-40.
18. Crespo J, Sun H, Welling TH, Tian Z, Zou W. T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment. Curr Opin Immunol 2013;25:214-21.
19. Paling NR, Welham MJ. Role of the protein tyrosine phosphatase SHP-1 (Src homology phosphatase-1) in the regulation of interleukin-3-induced survival, proliferation and signalling. Biochem J 2002;368(Pt 3):885-94.
20. Hopewell EL, Zhao W, Fulp WJ, Bronk CC, Lopez AS, Massengill M, et al. Lung tumor NF-kappaB signaling promotes T cell-mediated immune surveillance. J Clin Invest 2013;123:2509-22.
21. Zhong XP, Olenchock BA, Koretzky GA. The role of diacylglycerol kinases in T cell anergy. Ernst Schering Found Symp Proc 2007;3:139-49.
22. Habib-Agahi M, Phan TT, Searle PF. Co-stimulation with 4-1BB ligand allows extended T-cell proliferation, synergizes with CD80/CD86 and can reactivate anergic T cells. Int Immunol 2007;19:1383-94.
23. + cytolytic T lymphocytes in vivo. Blood 2004;103:177-84.
24. Zhang H, Merchant MS, Chua KS, Khanna C, Helman LJ, Telford B, et al. Tumor expression of 4-1BB ligand sustains tumor lytic T cells. Cancer Biol Ther 2003;2:579-86.
25. Wilcox RA, Flies DB, Zhu G, Johnson AJ, Tamada K, Chapoval AI, et al. Provision of antigen and CD137 signaling breaks immunological ignorance, promoting regression of poorly immunogenic tumors. J Clin Invest 2002;109:651-9.
26. Ho M, Feng M, Fisher RJ, Rader C, Pastan I. A novel high-affinity human monoclonal antibody to mesothelin. Int J Cancer 2011;128:2020-30.
27. Carpenito C, Milone MC, Hassan R, Simonet JC, Lakhal M, Suhoski MM, et al. Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains. Proc Natl Acad Sci U S A 2009;106:3360-5.
28. Wang LS, Lo A, Scholler J, Sun J, Majumdar RS, Kapoor V, et al. Targeting fibroblast activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit tumor growth and augment host immunity without severe toxicity. Cancer Immunol Res 2013;2:154-66.
29. Brown JA, Dorfman DM, Ma FR, Sullivan EL, Munoz O, Wood CR, et al. Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production. J Immunol 2003;170:1257-66.
30. Yi T, Pathak MK, Lindner DJ, Ketterer ME, Farver C, Borden EC. Anticancer activity of sodium stibogluconate in synergy with IFNs. J Immunol 2002;169:5978-85.
31. + T cells deficient in diacylglycerol kinases. Cancer Res 2013;73:3566-77.
32. Zhao Y, Moon E, Carpenito C, Paulos CM, Liu X, Brennan AL, et al. Multiple injections of electroporated autologous T cells expressing a chimeric antigen receptor mediate regression of human disseminated tumor. Cancer Res 2010;70:9053-61.
33. Pilon-Thomas S, Mackay A, Vohra N, Mule JJ. Blockade of programmed death ligand 1 enhances the therapeutic efficacy of combination immunotherapy against melanoma. J Immunol 2010;184:3442-9.
34. Brentjens RJ, Davila ML, Riviere I, Park J, Wang X, Cowell LG, et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med 2013;5:177ra138.
35. Radoja S, Frey AB. Cancer-induced defective cytotoxic T lymphocyte effector function: another mechanism how antigenic tumors escape immune-mediated killing. Mol Med 2000;6:465-79.
36. Zippelius A, Batard P, Rubio-Godoy V, Bioley G, Lienard D, Lejeune F, et al. Effector function of human tumor-specific CD8 T cells in melanoma lesions: a state of local functional tolerance. Cancer Res 2004;64:2865-73.
37. Gajewski TF, Meng Y, Blank C, Brown I, Kacha A, Kline J, et al. Immune resistance orchestrated by the tumor microenvironment. Immunol Rev 2006;213:131-45.
38. Mantovani A, Romero P, Palucka AK, Marincola FM. Tumour immunity: effector response to tumour and role of the microenvironment. Lancet 2008;371:771-83.
39. Sakuishi K, Apetoh L, Sullivan JM, Blazar BR, Kuchroo VK, Anderson AC. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med 2010;207:2187-94.
40. Radoja S, Saio M, Schaer D, Koneru M, Vukmanovic S, Frey AB. CD8 (+) tumor-infiltrating T cells are deficient in perforin-mediated cytolytic activity due to defective microtubule-organizing center mobilization and lytic granule exocytosis. J Immunol 2001;167:5042-51.
41. Chappert P, Schwartz RH. Induction of T cell anergy: integration of environmental cues and infectious tolerance. Curr Opin Immunol 2010;22:552-9.
42. Wherry EJ. T cell exhaustion. Nat Immunol 2011;12:492-9.
43. + tumor-infiltrating T cells. Cancer Res 2007;67:11447-54.
44. + T cells that is reversible by pharmacologic intervention. J Immunol 2012;188:5990-6000.
45. Whiteside TL. Signaling defects in T lymphocytes of patients with malignancy. Cancer Immunol Immunother 1999;48:346-52.
46. Rappl G, Riet T, Awerkiew S, Schmidt A, Hombach AA, Pfister H, et al. The CD3-zeta chimeric antigen receptor overcomes TCR hyporesponsiveness of human terminal late-stage T cells. PLoS ONE 2012;7:e30713.
47. Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J Immunol 2004;173:945-54.
48. Fowler CC, Pao LI, Blattman JN, Greenberg PD. SHP-1 in T cells limits the production of CD8 effector cells without impacting the formation of long-lived central memory cells. J Immunol 2010;185:3256-67.
49. Sanjuan MA, Jones DR, Izquierdo M, Merida I. Role of diacylglycerol kinase alpha in the attenuation of receptor signaling. J Cell Biol 2001;153:207-20.
50. + T cell functional responses. J Biol Chem 2010;286:5254-65.
51. + tumor-infiltrating lymphocyte lytic function. J Immunol 2005;174:1830-40.
52. Ahmadzadeh M, Johnson LA, Heemskerk B, Wunderlich JR, Dudley ME, White DE, et al. Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood 2009;114:1537-44.
53. Ngiow SF, von Scheidt B, Akiba H, Yagita H, Teng MW, Smyth MJ. Anti-TIM3 antibody promotes T cell IFN-gamma-mediated antitumor immunity and suppresses established tumors. Cancer Res 2011;71:3540-51.
54. Goldberg MV, Drake CG. LAG-3 in cancer immunotherapy. Curr Top Microbiol Immunol 2011;344:269-78.
55. Chlewicki LK, Velikovsky CA, Balakrishnan V, Mariuzza RA, Kumar V. Molecular basis of the dual functions of 2B4 (CD244). J Immunol 2008;180:8159-67.
56. Nazareth MR, Broderick L, Simpson-Abelson MR, Kelleher RJ Jr, Yokota SJ, Bankert RB. Characterization of human lung tumor-associated fibroblasts and their ability to modulate the activation of tumor-associated T cells. J Immunol 2007;178:5552-62.
57. Chmielewski M, Abken H. CAR T cells transform to trucks: chimeric antigen receptor-redirected T cells engineered to deliver inducible IL-12 modulate the tumour stroma to combat cancer. Cancer Immunol Immunother 2012;61:1269-77.
58. Sun J, Dotti G, Huye LE, Foster AE, Savoldo B, Gramatges MM, et al. T cells expressing constitutively active Akt resist multiple tumor-associated inhibitory mechanisms. Mol Ther 2010;18:2006-17.
59. Iyer S, Wang ZG, Akhtari M, Zhao W, Seth P. Targeting TGFbeta signaling for cancer therapy. Cancer Biol Ther 2005;4:261-6.