Integrating novel therapeutic monoclonal antibodies into the management of head and neck cancer

Cancer

Volumn 120, Issue 5, 2014, Pages 624-632

  Bauman, Julie E ^a   Ferris, Robert L ^a  

^a UNIVERSITY OF PITTSBURGH CANCER INSTITUTE   (United States)

Author keywords

angiogenesis; antibodies; cytokines; growth factors; immune escape; immunity

Indexed keywords

BEVACIZUMAB; CD16 ANTIGEN; CETUXIMAB; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; FICLATUZUMAB; FRESOLIMUMAB; INTERLEUKIN 10; INTERLEUKIN 6; IPILIMUMAB; MONOCLONAL ANTIBODY; PROGRAMMED DEATH 1 RECEPTOR; TRANSFORMING GROWTH FACTOR BETA1; TUMOR ANTIGEN; TUMOR NECROSIS FACTOR RECEPTOR; VASCULOTROPIN;

CANCER IMMUNOTHERAPY; DRUG RESPONSE; DRUG TARGETING; HEAD AND NECK SQUAMOUS CELL CARCINOMA; HUMAN; PRIORITY JOURNAL; PROTEIN FUNCTION; PROTEIN TARGETING; REVIEW; TREATMENT OUTCOME; TUMOR ESCAPE;

ANGIOGENESIS; ANTIBODIES; CYTOKINES; GROWTH FACTORS; IMMUNE ESCAPE; IMMUNITY;

ANTIBODIES, MONOCLONAL; ANTIBODIES, MONOCLONAL, HUMANIZED; ANTIBODY-DEPENDENT CELL CYTOTOXICITY; ANTIGENS, NEOPLASM; ANTINEOPLASTIC AGENTS; CARCINOMA, SQUAMOUS CELL; CYTOKINES; HEAD AND NECK NEOPLASMS; HUMANS; IMMUNOGLOBULIN G; IMMUNOTHERAPY; RECEPTORS, TUMOR NECROSIS FACTOR; T-LYMPHOCYTES, CYTOTOXIC;

EID: 84896726042     PISSN: 0008543X     EISSN: 10970142     Source Type: Journal    
DOI: 10.1002/cncr.28380     Document Type: Review

References (98)

1. Kamangar F, Dores GM, Anderson WF,. Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol. 2006; 24: 2137-2150.
2. Allen C, Duffy S, Teknos T, et al. Nuclear factor-kappaB-related serum factors as longitudinal biomarkers of response and survival in advanced oropharyngeal carcinoma. Clin Cancer Res. 2007; 13: 3182-3190.
3. Leibowitz MS, Andrade Filho PA, Ferrone S, Ferris RL,. Deficiency of activated STAT1 in head and neck cancer cells mediates TAP1-dependent escape from cytotoxic T lymphocytes. Cancer Immunol Immunother. 2011; 60: 525-535.
4. Kuss I, Hathaway B, Ferris RL, Gooding W, Whiteside TL,. Decreased absolute counts of T lymphocyte subsets and their relation to disease in squamous cell carcinoma of the head and neck. Clin Cancer Res. 2004; 10: 3755-3762.
5. Whiteside TL,. Immunobiology of head and neck cancer. Cancer Metastasis Rev. 2005; 24: 95-105.
6. Hoffmann TK, Dworacki G, Tsukihiro T, et al. Spontaneous apoptosis of circulating T lymphocytes in patients with head and neck cancer and its clinical importance. Clin Cancer Res. 2002; 8: 2553-2562.
7. Dasgupta S, Bhattacharya-Chatterjee M, O'Malley BW Jr, Chatterjee SK,. Inhibition of NK cell activity through TGF-beta 1 by down-regulation of NKG2D in a murine model of head and neck cancer. J Immunol. 2005; 175: 5541-5550.
8. Bauernhofer T, Kuss I, Henderson B, Baum AS, Whiteside TL,. Preferential apoptosis of CD56dim natural killer cell subset in patients with cancer. Eur J Immunol. 2003; 33: 119-124.
9. Young MR, Wright MA, Lozano Y, Matthews JP, Benefield J, Prechel MM,. Mechanisms of immune suppression in patients with head and neck cancer: influence on the immune infiltrate of the cancer. Int J Cancer. 1996; 67: 333-338.
10. Baruah P, Lee M, Odutoye T, et al. Decreased levels of alternative co-stimulatory receptors OX40 and 4-1BB characterise T cells from head and neck cancer patients. Immunobiology. 2012; 217: 669-675.
11. Lopez-Albaitero A, Nayak JV, Ogino T, et al. Role of antigen-processing machinery in the in vitro resistance of squamous cell carcinoma of the head and neck cells to recognition by CTL. J Immunol. 2006; 176: 3402-3409.
12. Ferris RL, Whiteside TL, Ferrone S,. Immune escape associated with functional defects in antigen-processing machinery in head and neck cancer. Clin Cancer Res. 2006; 12: 3890-3895.
13. Chaturvedi AK, Engels EA, Anderson WF, Gillison ML,. Incidence trends for human papillomavirus-related and -unrelated oral squamous cell carcinomas in the United States. J Clin Oncol. 2008; 26: 612-619.
14. Chaturvedi AK, Engels EA, Pfeiffer RM, et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol. 2011; 29: 4294-4301.
15. Mehanna H, Beech T, Nicholson T, et al. Prevalence of human papillomavirus in oropharyngeal and nonoropharyngeal head and neck cancer-systematic review and meta-analysis of trends by time and region. Head Neck. 2013; 35: 747-755.
16. Hadden J, Verastegui E, Barrera JL, et al. A trial of IRX-2 in patients with squamous cell carcinomas of the head and neck. Int Immunopharmacol. 2003; 3: 1073-1081.
17. De Stefani A, Forni G, Ragona R, et al. Improved survival with perilymphatic interleukin 2 in patients with resectable squamous cell carcinoma of the oral cavity and oropharynx. Cancer. 2002; 95: 90-97.
18. Urba SG, Forastiere AA, Wolf GT, Amrein PC,. Intensive recombinant interleukin-2 and alpha-interferon therapy in patients with advanced head and neck squamous carcinoma. Cancer. 1993; 71: 2326-2331.
19. Srivastava RM, Lee SC, Andrade Filho PA, et al. Cetuximab-activated natural killer and dendritic cells collaborate to trigger tumor antigen-specific T-cell immunity in head and neck cancer patients. Clin Cancer Res. 2013; 19: 1858-1872.
20. Ferris RL, Jaffee EM, Ferrone S,. Tumor antigen-targeted, monoclonal antibody-based immunotherapy: clinical response, cellular immunity, and immunoescape. J Clin Oncol. 2010; 28: 4390-4399.
21. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012; 366: 2455-2465.
22. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012; 366: 2443-2454.
23. Albers AE, Ferris RL, Kim GG, Chikamatsu K, DeLeo AB, Whiteside TL,. Immune responses to p53 in patients with cancer: enrichment in tetramer+ p53 peptide-specific T cells and regulatory T cells at tumor sites. Cancer Immunol Immunother. 2005; 54: 1072-1081.
24. Schuler PJ, Boeckers P, Engers R, et al. EGFR-specific T cell frequencies correlate with EGFR expression in head and neck squamous cell carcinoma. J Transl Med. 2011; 9: 168.
25. Albers A, Abe K, Hunt J, et al. Antitumor activity of human papillomavirus type 16 E7-specific T cells against virally infected squamous cell carcinoma of the head and neck. Cancer Res. 2005; 65: 11146-11155.
26. Ferris RL, Hunt JL, Ferrone S,. Human leukocyte antigen (HLA) class I defects in head and neck cancer: molecular mechanisms and clinical significance. Immunol Res. 2005; 33: 113-133.
27. Grandis JR, Tweardy DJ,. Elevated levels of transforming growth factor alpha and epidermal growth factor receptor messenger RNA are early markers of carcinogenesis in head and neck cancer. Cancer Res. 1993; 53: 3579-3584.
28. Ang KK, Berkey BA, Tu X, et al. Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res. 2002; 62: 7350-7356.
29. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006; 354: 567-578.
30. Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008; 359: 1116-1127.
31. Grandis JR, Tweardy DJ,. TGF-alpha and EGFR in head and neck cancer. J Cell Biochem Suppl. 1993; 17F: 188-191.
32. Vermorken JB, Herbst RS, Leon X, Amellal N, Baselga J,. Overview of the efficacy of cetuximab in recurrent and/or metastatic squamous cell carcinoma of the head and neck in patients who previously failed platinum-based therapies. Cancer. 2008; 112: 2710-2719.
33. Licitra L, Storkel S, Kerr KM, et al. Predictive value of epidermal growth factor receptor expression for first-line chemotherapy plus cetuximab in patients with head and neck and colorectal cancer: Analysis of data from the EXTREME and CRYSTAL studies. Eur J Cancer. 2013; 49: 1161-1168.
34. Licitra L, Mesia R, Rivera F, et al. Evaluation of EGFR gene copy number as a predictive biomarker for the efficacy of cetuximab in combination with chemotherapy in the first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck: EXTREME study. Ann Oncol. 2011; 22: 1078-1087.
35. Martins RG, Parvathaneni U, Bauman JE, et al. Cisplatin and radiotherapy with or without erlotinib in locally advanced squamous cell carcinoma of the head and neck: a randomized phase II Trial. J Clin Oncol. 2013; 31: 1415-1421.
36. Argiris A, Ghebremichael M, Gilbert J, et al. Phase III randomized, placebo-controlled trial of docetaxel with or without gefitinib in recurrent or metastatic head and neck cancer: an Eastern Cooperative Oncology Group Trial. J Clin Oncol. 2013; 31: 1405-1414.
37. Lango MN, Shin DM, Grandis JR,. Targeting growth factor receptors: integration of novel therapeutics in the management of head and neck cancer. Curr Opin Oncol. 2001; 13: 168-175.
38. Lee SC, Srivastava RM, Lopez-Albaitero A, Ferrone S, Ferris RL,. Natural killer (NK): dendritic cell (DC) cross talk induced by therapeutic monoclonal antibody triggers tumor antigen-specific T cell immunity. Immunol Res. 2011; 50: 248-254.
39. Kondadasula SV, Roda JM, Parihar R, et al. Colocalization of the IL-12 receptor and FcgammaRIIIa to natural killer cell lipid rafts leads to activation of ERK and enhanced production of interferon-gamma. Blood. 2008; 111: 4173-4183.
40. Zhang W, Gordon M, Schultheis AM, et al. FCGR2A and FCGR3A polymorphisms associated with clinical outcome of epidermal growth factor receptor expressing metastatic colorectal cancer patients treated with single-agent cetuximab. J Clin Oncol. 2007; 25: 3712-3718.
41. Kim DH, Jung HD, Kim JG, et al. FCGR3A gene polymorphisms may correlate with response to frontline R-CHOP therapy for diffuse large B-cell lymphoma. Blood. 2006; 108: 2720-2725.
42. Varchetta S, Gibelli N, Oliviero B, et al. Elements related to heterogeneity of antibody-dependent cell cytotoxicity in patients under trastuzumab therapy for primary operable breast cancer overexpressing Her2. Cancer Res. 2007; 67: 11991-11999.
43. Lopez-Albaitero A, Lee SC, Morgan S, et al. Role of polymorphic Fc gamma receptor IIIa and EGFR expression level in cetuximab mediated, NK cell dependent in vitro cytotoxicity of head and neck squamous cell carcinoma cells. Cancer Immunol Immunother. 2009; 58: 1853-1864.
44. Schneider-Merck T, Lammerts van Bueren JJ, Berger S, et al. Human IgG2 antibodies against epidermal growth factor receptor effectively trigger antibody-dependent cellular cytotoxicity but, in contrast to IgG1, only by cells of myeloid lineage. J Immunol. 2010; 184: 512-520.
45. Vermorken JB, Stohlmacher-Williams J, Davidenko I, et al. Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial. Lancet Oncol. 2013; 14: 697-710.
46. Giralt J, Trigo J, Nuyts S, et al. Phase 2, randomized trial (CONCERT02) of panitumumab plus radiotherapy compared with chemoradiotherapy in patients with unresected, locally advanced squamous cell carcinoma of the head and neck. Ann Oncol. 2012; 23 (suppl 9): ix334-ix347.
47. Wheeler DL, Huang S, Kruser TJ, et al. Mechanisms of acquired resistance to cetuximab: role of HER (ErbB) family members. Oncogene. 2008; 27: 3944-3956.
48. Scheuer W, Friess T, Burtscher H, Bossenmaier B, Endl J, Hasmann M,. Strongly enhanced antitumor activity of trastuzumab and pertuzumab combination treatment on HER2-positive human xenograft tumor models. Cancer Res. 2009; 69: 9330-9336.
49. Glisson BS, Tseng JE, Marur S, et al. Randomized phase II trial of cixutumumab alone or with cetuximab for refractory recurrent/metastatic squamous cancer of head and neck. Abstract A6030. J Clin Oncol. 2013; 29.
50. Bekaii-Saab TS, Roda JM, Guenterberg KD, et al. 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: 2983-2991.
51. van Herpen CM, Looman M, Zonneveld M, et al. Intratumoral administration of recombinant human interleukin 12 in head and neck squamous cell carcinoma patients elicits a T-helper 1 profile in the locoregional lymph nodes. Clin Cancer Res. 2004; 10: 2626-2635.
52. Gorden KB, Gorski KS, Gibson SJ, et al. Synthetic TLR agonists reveal functional differences between human TLR7 and TLR8. J Immunol. 2005; 174: 1259-1268.
53. Schnurr M, Chen Q, Shin A, et al. Tumor antigen processing and presentation depend critically on dendritic cell type and the mode of antigen delivery. Blood. 2005; 105: 2465-2472.
54. Hart OM, Athie-Morales V, O'Connor GM, Gardiner CM,. TLR7/8-mediated activation of human NK cells results in accessory cell-dependent IFN-gamma production. J Immunol. 2005; 175: 1636-1642.
55. Lu H, Dietsch GN, Matthews MA, et al. VTX-2337 is a novel TLR8 agonist that activates NK cells and augments ADCC. Clin Cancer Res. 2012; 18: 499-509.
56. Stephenson RM, Lim CM, Matthews M, Dietsch G, Hershberg R, Ferris RL,. TLR8 stimulation enhances cetuximab-mediated natural killer cell lysis of head and neck cancer cells and dendritic cell cross-priming of EGFR-specific CD8+ T cells. Cancer Immunol Immunother. 2013; 62: 1347-1357.
57. Wang T, Niu G, Kortylewski M, et al. Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med. 2004; 10: 48-54.
58. Johnston PA, Grandis JR,. STAT3 signaling: anticancer strategies and challenges. Mol Interv. 2011; 11: 18-26.
59. Siveen KS, Kuttan G,. Role of macrophages in tumour progression. Immunol Lett. 2009; 123: 97-102.
60. Kortylewski M, Kujawski M, Wang T, et al. Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat Med. 2005; 11: 1314-1321.
61. Lee JC, Lee KM, Kim DW, Heo DS,. Elevated TGF-beta1 secretion and down-modulation of NKG2D underlies impaired NK cytotoxicity in cancer patients. J Immunol. 2004; 172: 7335-7340.
62. Huang B, Pan PY, Li Q, et al. Gr-1+CD115+ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-bearing host. Cancer Res. 2006; 66: 1123-1131.
63. Leef G, Thomas SM,. Molecular communication between tumor-associated fibroblasts and head and neck squamous cell carcinoma. Oral Oncol. 2013; 49: 381-386.
64. Singhal E, Sen P,. Hepatocyte growth factor-induced c-Src- phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin pathway inhibits dendritic cell activation by blocking IkappaB kinase activity. Int J Biochem Cell Biol. 2011; 43: 1134-1146.
65. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006; 355: 2542-2550.
66. Kyzas PA, Stefanou D, Batistatou A, Agnantis NJ,. Prognostic significance of VEGF immunohistochemical expression and tumor angiogenesis in head and neck squamous cell carcinoma. J Cancer Res Clin Oncol. 2005; 131: 624-630.
67. Lionello M, Staffieri A, Marioni G,. Potential prognostic and therapeutic role for angiogenesis markers in laryngeal carcinoma. Acta Otolaryngol. 2012; 132: 574-582.
68. Argiris A, Kotsakis AP, Hoang T, et al. Cetuximab and bevacizumab: preclinical data and phase II trial in recurrent or metastatic squamous cell carcinoma of the head and neck. Ann Oncol. 2013; 24: 220-225.
69. Sun S, Wang Z,. Head neck squamous cell carcinoma c-Met(+) cells display cancer stem cell properties and are responsible for cisplatin-resistance and metastasis. Int J Cancer. 2011; 129: 2337-2348.
70. Knowles LM, Stabile LP, Egloff AM, et al. HGF and c-Met participate in paracrine tumorigenic pathways in head and neck squamous cell cancer. Clin Cancer Res. 2009; 15: 3740-3750.
71. De Bacco F, Luraghi P, Medico E, et al. Induction of MET by ionizing radiation and its role in radioresistance and invasive growth of cancer. J Natl Cancer Inst. 2011; 103: 645-661.
72. Bedi A, Chang X, Noonan K, et al. Inhibition of TGF-beta enhances the in vivo antitumor efficacy of EGF receptor-targeted therapy. Mol Cancer Ther. 2012; 11: 2429-2439.
73. Rossi JF, Negrier S, James ND, et al. A phase I/II study of siltuximab (CNTO 328), an anti-interleukin-6 monoclonal antibody, in metastatic renal cell cancer. Br J Cancer. 2010; 103: 1154-1162.
74. Melero I, Hirschhorn-Cymerman D, Morales-Kastresana A, Sanmamed MF, Wolchok JD,. Agonist antibodies to TNFR molecules that costimulate T and NK cells. Clin Cancer Res. 2013; 19: 1044-1053.
75. Sathawane D, Kharat RS, Halder S, et al. Monocyte CD40 expression in head and neck squamous cell carcinoma (HNSCC). Hum Immunol. 2013; 74: 1-5.
76. Vonderheide RH, Glennie MJ,. Agonistic CD40 antibodies and cancer therapy. Clin Cancer Res. 2013; 19: 1035-1043.
77. Posner MR, Cavacini LA, Upton MP, Tillman KC, Gornstein ER, Norris CM Jr,. Surface membrane-expressed CD40 is present on tumor cells from squamous cell cancer of the head and neck in vitro and in vivo and regulates cell growth in tumor cell lines. Clin Cancer Res. 1999; 5: 2261-2270.
78. Cao W, Cavacini LA, Tillman KC, Posner MR,. CD40 function in squamous cell cancer of the head and neck. Oral Oncol. 2005; 41: 462-469.
79. Vonderheide RH, Dutcher JP, Anderson JE, et al. Phase I study of recombinant human CD40 ligand in cancer patients. J Clin Oncol. 2001; 19: 3280-3287.
80. Vonderheide RH, Flaherty KT, Khalil M, et al. Clinical activity and immune modulation in cancer patients treated with CP-870,893, a novel CD40 agonist monoclonal antibody. J Clin Oncol. 2007; 25: 876-883.
81. Vonderheide RH, Burg JM, Mick R, et al. Phase I study of the CD40 agonist antibody CP-870,893 combined with carboplatin and paclitaxel in patients with advanced solid tumors. Oncoimmunology. 2013; 2: e23033.
82. Beatty GL, Chiorean EG, Fishman MP, et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science. 2011; 331: 1612-1616.
83. Gramaglia I, Jember A, Pippig SD, Weinberg AD, Killeen N, Croft M,. The OX40 costimulatory receptor determines the development of CD4 memory by regulating primary clonal expansion. J Immunol. 2000; 165: 3043-3050.
84. Kitamura N, Murata S, Ueki T, et al. OX40 costimulation can abrogate Foxp3+ regulatory T cell-mediated suppression of antitumor immunity. Int J Cancer. 2009; 125: 630-638.
85. Weinberg AD, Rivera MM, Prell R, et al. Engagement of the OX-40 receptor in vivo enhances antitumor immunity. J Immunol. 2000; 164: 2160-2169.
86. Hirschhorn-Cymerman D, Rizzuto GA, Merghoub T, et al. OX40 engagement and chemotherapy combination provides potent antitumor immunity with concomitant regulatory T cell apoptosis. J Exp Med. 2009; 206: 1103-1116.
87. Pollok KE, Kim YJ, Zhou Z, et al. Inducible T cell antigen 4-1BB. Analysis of expression and function. J Immunol. 1993; 150: 771-781.
88. So T, Lee SW, Croft M,. Immune regulation and control of regulatory T cells by OX40 and 4-1BB. Cytokine Growth Factor Rev. 2008; 19: 253-262.
89. Kohrt HE, Houot R, Goldstein M, et al. Targeting CD137 to enhance the antitumor efficacy of cetuximab by stimulation of innate and adaptive immunity. Abstract A3015. J Clin Oncol. 2013; 31.
90. Badoual C, Hans S, Merillon N, et al. PD-1-expressing tumor-infiltrating T cells are a favorable prognostic biomarker in HPV-associated head and neck cancer. Cancer Res. 2013; 73: 128-138.
91. Strauss L, Bergmann C, Gooding W, Johnson JT, Whiteside TL,. The frequency and suppressor function of CD4+CD25highFoxp3+ T cells in the circulation of patients with squamous cell carcinoma of the head and neck. Clin Cancer Res. 2007; 13: 6301-6311.
92. Peggs KS, Quezada SA, Chambers CA, Korman AJ, Allison JP,. Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. J Exp Med. 2009; 206: 1717-1725.
93. Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010; 363: 711-723.
94. Dewan MZ, Galloway AE, Kawashima N, et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res. 2009; 15: 5379-5388.
95. Quezada SA, Peggs KS,. Exploiting CTLA-4, PD-1 and PD-L1 to reactivate the host immune response against cancer. Br J Cancer. 2013; 108: 1560-1565.
96. Cho YA, Yoon HJ, Lee JI, Hong SP, Hong SD,. Relationship between the expressions of PD-L1 and tumor-infiltrating lymphocytes in oral squamous cell carcinoma. Oral Oncol. 2011; 47: 1148-1153.
97. Lyford-Pike S, Peng S, Young GD, et al. Evidence for a role of the PD-1:PD-L1 pathway in immune resistance of HPV-associated head and neck squamous cell carcinoma. Cancer Res. 2013; 73: 1733-1741.
98. Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002; 8: 793-800.