Epstein-Barr virus-targeted immunotherapy for nasopharyngeal ...

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ANTI-TUMOUR TREATMENT

Epstein-Barr virus-targeted immunotherapy for nasopharyngeal carcinoma Amine Masmoudi a,*, Nabil Toumi a, Afef Khanfir a, Lamia Kallel-Slimi a, Jamel Daoud b, Hela Karray c, Mounir Frikha a a b c

Department of Medical Oncology, Habib Bourguiba Hospital, Sfax 3029, Tunisia Department of Radiotherapy, Habib Bourguiba Hospital, Sfax 3029, Tunisia Department of Microbiology, Habib Bourguiba Hospital, Sfax 3029, Tunisia

Received 23 January 2007; received in revised form 4 April 2007; accepted 8 April 2007

KEYWORDS Nasopharyngeal cancer; Epstein-Barr virus; Adoptive immunotherapy; Vaccination

Summary Epstein-Barr virus (EBV) is constantly present in undifferentiated and poorly-differentiated nasopharyngeal cancer. Thus, tumour-associated viral antigens are potential targets for immunotherapy. Recently, both preclinical and early clinical studies have shown that various strategies can enhance EBV-specific immunity. Moreover, significant anti-tumour effect has been observed, and was generally correlated with biological response. The present review discusses the rational for EBV-targeted immunotherapy and summarises the latest developments in this area. c 2007 Elsevier Ltd. All rights reserved.



Introduction Nasopharyngeal carcinoma (NPC) is an uncommon neoplasm in most parts of the world, with an annual incidence of less one per 100.000 habitants.1 However, this disease is endemic in southern China and Hong Kong, where incidence rates ranging from 15 to 50 per 100.000 have been reported.2 An intermediate incidence is seen in Alaska, Greenland, North Africa and the Mediterranean basin. In Tunisia, NPC is the most frequent head and neck cancer, with an age-adjusted

* Corresponding author. Tel./fax: +216 74 24 69 13. E-mail address: [email protected] (A. Masmoudi).

incidence of 4.7 per 100.000 in men and 0.9 per 100.000 in women in the Southern region.3 Radiotherapy is the mainstay treatment of non metastatic NPC, achieving local control in 50–90% of cases.1 Recently, on the basis of randomised trials4–7 confirmed by two meta-analysis,8,9 concurrent platinum-based chemo-radiotherapy became the new standard of care, especially in patients with T3–T4 primary tumours and/or lymph node involvement (N1–N2–N3).10 Despite improvements in therapeutic results, local regional failure and distant metastasis are still occurring in a significant number of patients. Moreover, radiotherapy and chemotherapy often result in both acute side effects and long-term sequelae, with the latter being even more severe



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in younger patients.11 Xerostomia, trismus, endocrine dysfunction, cognitive impairment and radiation-induced secondary malignancies are examples of treatment effects which significantly affect patients’ quality of life, if not survival.11–15 Therefore, it seems necessary to develop novel approaches, with the aim of improving outcome for refractory disease and, eventually, deescalating conventional cytotoxic therapies. Epstein-Barr virus (EBV) is uniformly detected in patients with undifferentiated and poorly-differentiated NPC, regardless of geographical origin.16 On the other hand, there is now compelling evidence that cytotoxic T lymphocytes-based immunotherapy is effective in another entity of EBV-linked malignancies, namely post-transplant lymphoproliferative disorders (PTLD).17–19 The success of this therapy has prompted researchers to develop similar strategies for other EBV-positive tumours, such as NPC. We will discuss the rationale for virus-targeted immunotherapy and examine some of the most widely studied approaches in NPC.

Epstein-Barr virus and nasopharyngeal carcinoma EBV is a DNA-virus that belongs to the herpesvirus family. The virus genome comprises more than 85 genes, some of which encodes for proteins that interact and/or have structural homologies with cytokines, cellular transduction signals or anti-apoptotic molecules (Table 1).16 In addition to NPC, EBV is associated to at least four other types of malignancy in human: endemic Burkitt’s lymphoma, nasal T/natural killer cell lymphoma, Hodgkin’s

Table 1

lymphoma (with the exclusion of type 1) and PTLD. The implication of EBV in other neoplasms, such us leiomyosarcomas in immuno-compromised individuals and gastric cancer, is strongly suspected but not yet firmly established.16 Whereas infection of B lymphocytes begins with the attachment of the virus to the CD21 molecule on these cells,20 EBV penetration into nasopharyngeal epithelial cells may be explained by an IgA mediated endocytosis22 or by the presence of a B-cell antigenically-related surface protein.21 All EBV-related malignancies involve the virus latent infection. According to the pattern of viral antigens expression, three types of latency (I, II and III) are described (Table 2). As opposed to type III, characterised by unrestricted expression of latent antigens-together with HLA molecules-, the absence of most EBNAs, all membrane proteins (LMPs) and HLA molecules in type I latency make tumour cells invisible to host anti-EBV immune surveillance. Latency II, associated with NPC (and Hodgkin’s lymphoma), involves a relatively limited expression of viral genes. Functions of latency proteins are summarized in Table 3.16,23,24 Although NPC is associated with global cellular immunity suppression,25 an EBV-specific immune response is well documented. However, the frequency of anti-EBV specific T cells in NPC patients is usually lower than in healthy carriers of the virus. Nonetheless, in patients attaining clinical remission, EBV specific immunity increases to levels similar to those of healthy seropositive individuals, thus supporting a direct role of the tumour in immunity suppression.26 NPC is characterised by a unique histological pattern, where a rich lymphocyte infiltrate is intimately associated to malignant epithelial cells. The function of these

Viral genes with human homologues

EBV gene

Human homologue

Functional homology

Function

BCRF1 BDLF2

Interleukin 10 Cyclin B1

Yes Unknown

Cellular immunity suppression –

BHRF1

Bcl 2

Yes

Inhibition of apoptosis

BARF

CSF-1 receptor ICAM-1 (CD54)

Yes Unknown

T cells suppression –

Table 2

Latency patterns in EBV-related malignancies

Latency type

Viral genes expressed

Cellular gene expression

Tumour

Type I

EBNA-1

CD10, CD77, ICAM2

Endemic Burkitt’s lymphoma

Type II

EBNA-1 LMP-1 LMP-2

CD23, CD80, CD86, CD40, ICAM1, LFA1, LFA3, TAP1, TAP2, HLA class I

Nasopharyngeal carcinoma Hodgkin’s lymphoma Nasal T/NK lymphoma

Type III

All EBNAs (EBNA-1, EBNA-2, EBNA-LP, EBNA-3A, 3B and 3C) LMP-1 LMP-2

CD23, CD80, CD86, ICAM1, ICAM2, LFA1, LFA3, TAP1, TAP2, HLA class I

Lymphoproliferative disorders in immunocompromised individuals (AIDS, transplantation, X-linked lymphoproliferative disorders)

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Function of EBV latency products

Protein

Function

EBNA-1

Maintenance and replication of the viral genome Immortalisation of B cells Immortalisation of B cells Unknown Immortalisation of B cells Immortalisation of B cells Initiation of latent cycle

EBNA-2 EBNA-3A EBNA-3B EBNA-3C LMP-1 LMP-2A and B

tumour-infiltrating lymphocytes remains largely unknown. Although in vitro studies suggested a cytotoxic activity against EBV infected cells, specificity and effectiveness of this function have not been confirmed in vivo.25 Moreover, NPC cells can escape cytotoxic T lymphocytes (CTL) control in vivo, and several mechanisms, such as the expression of Fas ligand,27 have been suggested to explain this immune evasion.

Immunotherapy strategies Two distinct approaches are being developed to treat NPC. Adoptive immunotherapy consists to bypass the antigen presentation step by directly activating effector cells, whereas active immunotherapy aims to enhance tumour antigens recognition by the immune system (Table 4). Table 4

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Adoptive immunotherapy The example of post-transplant lymphoproliferative disorders PTLD represent a heterogeneous group of haematological malignancies of B phenotype that develop in the setting of iatrogenic immunosuppression after bone morrow or solid organ transplantation. These neoplasms have an aggressive clinical behaviour, and are constantly associated with EBV infection. The observation of tumour regression in approximately 25% of patients after simple reduction of immunosuppression gave rational for anti-EBV adoptive immunotherapy. Initial studies included bone morrow recipients, in whom PTLD are generally of donor origin. Papadopoulos et al. first reported complete remission in patients with PTLD who received unmanipulated donor T lymphocytes.17 Subsequently, another group demonstrated the effectiveness of donor EBV-specific lymphocytes infusions for the prevention or the treatment of PTLD.18 By contrast to bone morrow recipients, PTLD arising after solid organ transplantation are of recipient origin, making the safety and efficacy of allogenic therapy uncertain. In this setting, autologous CTLs, generated before transplantation and infused back to the patient during therapeutic immunosuppression, significantly reduce viral genome load and prevent the onset of PTLD.19,23 The procedure for generating EBV specific CTLs is schematically summarised in Figure 1. Thus, PTLD are considered as a model of EBV-related tumours in which virus-targeted immunotherapy is feasible

Immunotherapy strategies for nasopharyngeal carcinoma

Strategy Adoptive immunotherapy Allogenic specific CTLs transfer

Autologous specific CTLs transfer

Active immunotherapy Recombinant viral vector

Tumour antigen-pulsed DCs

Advantages

Limitations

Published data

 Proven efficacy in EBV-related PTLD  Availability of established CTLs lines with various HLA alleles for immediate use

 Need for HLA-matched donor  Short persistence of infused CTLs  Significant mismatch between the repertoire of CTLs and latency II viral antigens

Case report

 Can be readily generated even in heavily pre-treated patients  Favourable safety profile  Immunological and clinical responses reported

 Need for ex vivo cell culture  Time required to expand CTLs  Significant mismatch between the repertoire of CTLs and tumourexpressed viral antigens

Phase I

 Engineered to express defined immunogenic epitope(s)  Can be engineered to co-express immunostimulatory molecules  Encouraging data in animal models

 Risk of generating replicationcompetent virus  Immunodominance of viral antigens over tumour antigens  Preexisiting immunity against the virus may attenuate the therapeutic efficacy

Preclinical

 Use of highly efficient antigenpresenting cells  Immunological and clinical responses documented in NPC  Promising preclinical and pilot clinical studies in other malignancies

 Need for ex vivo cell culture  Time required to generate, activate and expand DCs  Optimal technique for antigen loading (peptide, protein, tumour lystae, etc.) is still undefined

Phase I

Abbreviations: CTLs, cytotoxic T cells; EBV, Epstein-Barr virus; PTLD, post-transplantation lymphoproliferative disease; DCs, dendritic cells.

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Figure 1 Generation of EBV-specific cytotoxic T cells (adapted from Ref. 23, with permission). PBMC, peripheral blood mononuclear cells; LCL, lymphoblastoid cell lines; CTLs, cytotoxic T cells.

and efficient. It is important, however, to underline the high immunogenicity of these neoplasms, mainly due to the expression of EBNA3 antigens. Despite the lack of EBNA3 expression in type II latency, immunotherapy techniques targeting other viral antigens are beginning to show real promise in NPC. Allogenic CTL therapy in nasopharyngeal cancer The first observation suggesting clinical efficacy of this approach was reported by Comoli et al.28 In a heavily pre-treated NPC patient with intra-cranial disease progression, the infusion of EBV-specific CTLs from a HLA-identical sibling resulted in a minor tumour regression followed by a 3-month stabilisation. Simultaneously, peripheral anti-LMP2 specific CTLs increased to a level similar to healthy EBV seropositive controls. Biopsy taken after therapy showed a marked increase in CTLs infiltrate in the tumour, but no allogenic CTLs were detected. Despite this encouraging report, the use of allogenic CTLs has not been further evaluated in NPC, which is in contrast with the extensive study of this approach in bone morrow-related PTLD. Possible reasons for this include: (1) the need for a HLA-matched donor; (2) the risk of CTLs rejection by the patient’s immune system; (3) the short-term persistence of infused allogenic CTLs. Nevertheless, an attractive strategy to circumvent these obstacles would be to use best-matched HLA allogenic CTLs chosen from a frozen bank of well-characterised EBV-specific CTL lines.29 This approach has shown promising results in solid organ transplantation-related PTLD,30 but studies in the setting of NPC are still lacking. Autologous CTL therapy in nasopharyngeal cancer Chua et al. firstly demonstrated the feasibility of autologous EBV-specific CTL transfer in NPC patients.31 The procedure was well tolerated, and CTL transfer significantly increased the frequency of EBV-specific CTL precursors and reduced blood viral load. However, no objective clinical response was documented. More recently, Straathof et al. reported their preliminary experience in 10 NPC patients treated with autologous EBVspecific CTLs.32 Six patients had refractory disease, while the four others received CTLs as adjunctive treatment after

A. Masmoudi et al. attaining clinical remission with chemoradiation for locally advanced NPC. No significant toxicity was observed, except swelling at tumour site in one case, which could not be definitely attributed to therapy. Among six patients with refractory NPC, two had complete responses, and remained in remission over 11–23 months after treatment; one had a partial remission that persisted for 12 months; one has had stable disease for more than 14 months; and two had no response. All four patients treated in remission remained disease free, with a follow-up ranging from 19 to 27 months. While viral genome load was significantly reduced after CTL therapy in six patients, the frequency of peripheral EBV-specific T cells remained unchanged, although a transient increase in LMP2-specific T cells was observed in four patients among eight tested. Thus, no correlation between immunological response and clinical activity could be clearly demonstrated. The authors stipulated that antigens other than LMP2 may have been involved, or that T cells expansion was restricted to sites of tumour antigen presentation. Another feasibility study of CTL therapy was performed by Conoli et al. All 10 included patients were diagnosed with NPC that had progressed after radiotherapy and two or more lines of chemotherapy. In this heavily pre-treated cohort, a partial remission was observed in two patients and a stabilisation in four others, giving an encouraging disease control rate of 60%. Progression-free interval ranged from 3 to 15 months. CTL infusions were well tolerated, with the exception of mild inflammatory reactions at the tumour site in two cases. In contrast to the findings by Strathoof et al., an enhancement in EBV specific immunity was uniformly observed, with a significant increase in LMP-2 specific cells in four patients, of whom three had clinical benefit.33 Perspectives A phase I trial is currently performed under the hospice of Baylor College of Medicine (Houston, TX, USA) in patients diagnosed with relapsed or primarily refractory NPC. In this study, two monoclonal antibodies that are directed to nonoverlapping epitopes on human CD45 (Leukocyte Common Antigen) will be administered with the aim of creating a profound lymphocyte depletion prior to EBV-specific CTL infusions.34 It will be interesting to determine the duration of immunological response and to compare it to previous studies. Considering that viral proteins expressed during latency II are moderately immunogenic, it would be interesting to determine whether EBV specific immunity can be enhanced by the induction of EBV lytic cycle. Preclinical data demonstrated the capacity of gamma-irradiation35 or cytotoxic drugs such as cisplatin and fluorouacil36 to induce EBV lytic cycle, making the combination of CTL therapy with chemotherapy and radiotherapy a potential area of investigation.

Active immunotherapy Active immunotherapy, also known as vaccination, consists to deliver selected tumour-associated antigens to cancer patients in order to induce an immune response that may result in the eradication of malignant cells. Currently, two modalities are being developed in NPC: dendritic cells (DCs) vaccination and viral vectors-introduced peptides.

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FOR HKMA CME MEMBER USE ONLY. DO NOT REPRODUCE OR DISTRIBUTE. Epstein-Barr virus-targeted immunotherapy for nasopharyngeal carcinoma Dendritic cells therapy DCs are professional antigen-presenting cells that have a crucial role in the activation of naive CD4+ and CD8+ T cells. Immature autologous DCs can be generated ex vivo by culturing peripheral blood monocytes in the presence of interleukin-4 and granulocyte–monocyte colony stimulating factor.37 Then, DCs are maturated using tumour necrosis factor-alpha or other agents, pulsed with tumour antigens and finally administered to the patient. A feasibility trial of LMP2 peptide-loaded DCs was reported by Lin et al.38 DCs were given by intranodal inguinal injections in 16 patients with refractory NPC. Therapy was well tolerated, with minor side effects occurring in four patients. Nine (56%) patients showed a significant immune response, as assessed by LMP2-specific CD8+ T cells frequency. Moreover, a radiographically-documented tumour regression was observed in two patients, with a progression-free interval of 10 months and more than 12 months, respectively. In the light of this report, and similar studies in other tumours,39–41 DCs therapy may be considered as one of the most attractive approaches in cancer immunotherapy. Given the moderate immunogenicity of NPC-associated viral antigens, it seems interesting to explore the activity of DCs pulsed with tumour lysates rather than limited epitopes.41 On the other hand, the hypothesis that DCs may be more efficient towards minimal residual disease could not be tested without conducting well-designed randomised trials in patients with early disease. Unfortunately, significant barriers, such as cost and the lack of standardisation, are still limiting the development and the availability of DCs therapy.

Viral-vector introduced peptides Using six HLA A2-restricted epitopes derived from LMP-1, Duraiswamy et al. constructed a recombinant poxvirus that encodes the corresponding protein.42 Human fibroblasts infected with the engineered virus were efficiently recognized by LMP1-specific CTLs from HLA A2 healthy individuals. In HLA A2/Kb transgenic mice, a LMP1-specific T cell immunity was elicited by intraperitoneal injection of the vaccine. Moreover, immunisation significantly afforded protection against LMP1-expressing induced thymoma. Finally, a therapeutic effect could be clearly demonstrated in mice with established tumours: while a complete and sustained remission was observed in recombinant virus-vaccinated mice, all animals that received non engineered poxvirus died rapidly from tumour progression. Considering the potential risks of poxvirus in human, the same group has developed a similar approach using a replication-incompetent adenovirus. In this model, the DNA sequence inserted into virus genoma encoded multiple HLA class I-restricted CTL epitopes from LMP1 and LMP2.43 Similarly to the previous study, the authors reported significant immune responses as well as prophylactic and therapeutic anti-tumour efficiency. Importantly, immunogenic epitopes were restricted through HLA alleles common in different ethnic groups, including NPC endemic regions. Encouraging results with recombinant virus vaccination in patients with colorectal44 and prostate cancer45 have been published, and further evaluation of this approach in NPC is awaited.

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Future needs and challenges As with any cancer, a major obstacle in promoting novel therapies for NPC is the traditional lack of interaction between basic scientists and clinicians. Thus, it is necessary to develop translational research programmes as an integral part of head and neck oncology units. This will permit not only improving current immunotherapy but also tailoring treatment to the patients most likely to benefit. For example, a polyepitope vaccine based on selected immunogenic peptides restricted by each patient’s HLA system would be a promising individualized approach. Since neither specific anti-EBV cells assessment nor cytokine release measurement have been considered as reliable predictors of clinical benefit, alternative tools for monitoring the immune response are required to serve as surrogate markers for immunotherapy efficacy. Finally, a better understanding of cancer cells immune evasion mechanisms and tumour–host interaction at the tumour microenvironment level would help understanding the algorithm of immune responsiveness and design strategies to overcome resistance to therapy. To achieve these goals, there is a need to both sophisticated technology and highly qualified personnel. However, it should be emphasized that more than 90% of all new NPC cases worldwide occur in developing countries.46 Because of restricted resources, research programmes have not been identified as a priority cancer care issue in many high- and intermediate-risk regions. Thus, the establishment of an international collaborative partnership is essential to promote exchange of NPC-related expertise and to facilitate access to populations with higher prevalence of the disease.

Conclusion Despite an abundant preclinical and clinical research, cancer immunotherapy has not yet entered into standard practice. Among head and neck cancer, NPC is characterised by a strong association to EBV, thus giving rationale for viral antigens-targeted immunotherapy. Preliminary clinical data have shown that both CTL and DC-based therapies are well tolerated and can induce significant immune response that is associated with clinical benefits in some patients. Recombinant-virus vaccination has shown promising activity in mouse models, and feasibility studies in NPC patients are planned. Although these data are encouraging, there is still a need for technique standardisation and strategies to circumvent tumour’s immune evasion before large-scale clinical assessment can be undertaken.

References 1. Wei WI, Sham JS. Nasopharyngeal carcinoma. Lancet 2005;365:2041–54. 2. Parkin DM, Whelan SL, Ferlay J, Raymond L, Young J, editors. Cancer incidence in five continents, vol. 7, IARC 143; 1997. p. 814–5. 3. Sellami A, Hsaı¨ri M, Achour N, Jlidi R. Registre du cancer du ´es 1997– Sud Tunisien: incidence des cancers, anne 2000. Tunis: Institut National de la Sante ´ Publique; 2002.

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FOR HKMA CME MEMBER USE ONLY. DO NOT REPRODUCE OR DISTRIBUTE. 504 4. Al-Sarraf M, LeBlanc M, Giri PG, Fu KK, Cooper J, Vuong T, et al. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099. J Clin Oncol 1998;16:1310–7. 5. Lin JC, Jan JS, Hsu CY, Liang WM, Jiang RS, Wang WY. Phase III study of concurrent chemoradiotherapy versus radiotherapy alone for advanced nasopharyngeal carcinoma: positive effect on overall and progression-free survival. J Clin Oncol 2003;21:631–7. 6. Chan AT, Leung SF, Ngan RK, Teo PM, Lau WH, Kwan WH, et al. Overall survival after concurrent cisplatin-radiotherapy compared with radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma. J Natl Cancer Inst 2005;97:536–9. 7. Zhang L, Zhao C, Peng PJ, Lu LX, Huang PY, Han F, et al. Phase III study comparing standard radiotherapy with or without weekly oxaliplatin in treatment of locoregionally advanced nasopharyngeal carcinoma: preliminary results. J Clin Oncol 2005;23:8461–8. 8. Langendijk JA, Leemans CR, Buter J, Berkhof J, Slotman BJ. The additional value of chemotherapy to radiotherapy in locally advanced nasopharyngeal carcinoma: a meta-analysis of the published literature. J Clin Oncol 2004;22:4604–12. 9. Baujat B, Audry H, Bourhis J, Chan AT, Onat H, Chua DT, et al., MAC-NPC Collaborative Group. Chemotherapy in locally advanced nasopharyngeal carcinoma: an individual patient data meta-analysis of eight randomized trials and 1753 patients. Int J Radiat Oncol Biol Phys 2006;64:47–56. 10. American Joint Committee on Cancer. AJCC cancer staging manual. 6th ed. New York, NY: Springer; 2002., pp. 31–46. 11. Daoud J, Toumi N, Bouaziz M, Ghorbel A, Jlidi R, Drira MM, et al. Nasopharyngeal carcinoma in childhood and adolescence: analysis of a series of 32 patients treated with combined chemotherapy and radiotherapy. Eur J Cancer 2003;39: 2349–54. 12. Pow EH, McMillan AS, Leung WK, Wong MC, Kwong DL. Salivary gland function and xerostomia in southern Chinese following radiotherapy for nasopharyngeal carcinoma. Clin Oral Investig 2003;7:230–4. 13. Fang FM, Chiu HC, Kuo WR, Wang CJ, Leung SW, Chen HC, et al. Health-related quality of life for nasopharyngeal carcinoma patients with cancer-free survival after treatment. Int J Radiat Oncol Biol Phys 2002;53:959–68. 14. Cheung MC, Chan AS, Law SC, Chan JH, Tse VK. Impact of radionecrosis on cognitive dysfunction in patients after radiotherapy for nasopharyngeal carcinoma. Cancer 2003;97: 2019–26. 15. Daoud J, Ben Salah H, Kammoun W, Ghorbel A, Frikha M, Jlidi R, et al. Glioblastome et myxome radioinduits apre `s traitement d’un carcinome indiffe ´rencie ´ du nasopharynx. Cancer Radiother 2000;4:469–72. 16. Thompson MP, Kurzrock R. Epstein-Barr virus and cancer. Clin Cancer Res 2004;10:803–21. 17. Papadopoulos EB, Ladanyi M, Emanuel D, Mackinnon S, Boulad MH, Carabasi MH, et al. Infusions of donor leukocytes to treat Epstein-Barr virus-associated lymphoproliferative disorders after allogeneic bone marrow transplantation. N Engl J Med 1994;330:1185–91. 18. Rooney CM, Smith CA, Ng CY, Loftin S, Li C, Krance RA, et al. Use of gene-modified virus-specific T lymphocytes to control Epstein-Barr virus-related lymphoproliferation. Lancet 1995;345:9–13. 19. Comoli P, Labirio M, Basso S, Baldanti F, Grossi P, Furione M, et al. Infusion of autologous Epstein-Barr virus (EBV)-specific cytotoxic T cells for prevention of EBV-related lymphoproliferative disorder in solid organ transplant recipients with evidence of active virus replication. Blood 2002;99:2592–8. 20. Nemerow GR, Wolfert R, McNaughton ME, Cooper NR. Identification and characterization of the Epstein-Barr virus receptor

A. Masmoudi et al.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

on human B lymphocytes and its relationship to the C3d complement receptor (CR2). J Virol 1985;55:347–51. Young LS, Dawson CW, Brown KW, Rickinson AB. Identification of a human epithelial cell surface protein sharing an epitope with the C3d/Epstein-Barr virus receptor molecule of B lymphocytes. Int J Cancer 1989;43:786–94. Lin CT, Lin CR, Tan GK, Chen W, Dee AN, Chan WY. The mechanism of Epstein-Barr virus infection in nasopharyngeal carcinoma cells. Am J Pathol 1997;150:1745–56. Straathof KC, Bollard CM, Rooney CM, Heslop HE. Immunotherapy for Epstein-Barr virus-associated cancers in children. Oncologist 2003;8:83–98. Khanna R, Tellam J, Duraiswamy J, Cooper L. Immunotherapeutic strategies for EBV-associated malignancies. Trends Mol Med 2001;7:270–6. Chan SH, Chew TS, Goh EH, Simons MJ, Shanmugaratnam K. Impaired general cell-mediated immune functions in vivo and in vitro in patients with nasopharyngeal carcinoma. Int J Cancer 1976;18:139–44. Lee SP. Nasopharyngeal carcinoma and the EBV-specific T cell response: prospects for immunotherapy. Semin Cancer Biol 2002;12:463–71. Tsai ST, Fang SY, Jin YT, Su IJ, Yang BC. Analysis of the expression of Fas-L in nasopharyngeal carcinoma tissues. Oral Oncol 1999;35:421–4. Comoli P, De Palma R, Siena S, Nocera A, Basso S, Del Galdo F, et al. Adoptive transfer of allogeneic Epstein-Barr virus (EBV)specific cytotoxic T cells with in vitro antitumor activity boosts LMP2-specific immune response in a patient with EBV-related nasopharyngeal carcinoma. Ann Oncol 2004;15:113–7. Wilkie GM, Taylor C, Jones MM, Burns DM, Turner M, Kilpatrick D, et al. Establishment and characterization of a bank of cytotoxic T lymphocytes for immunotherapy of EpsteinBarr virus-associated diseases. J Immunother 2004;27:309– 16. Haque T, Wilkie GM, Taylor C, Amlot PL, Murad P, Iley A, et al. Treatment of Epstein-Barr-virus-positive posttransplantation lymphoproliferative disease with partly HLA-matched allogenic cytotoxic T cells. Lancet 2002;360:436–42. Chua D, Huang J, Zheng B, Lau SY, Luk W, Kwong DL, et al. Adoptive transfer of autologous Epstein-Barr virus-specific cytotoxic T cells for nasopharyngeal carcinoma. Int J Cancer 2001;94:73–80. Straathof KC, Bollard CM, Popat U, Huls MH, Lopez T, Morriss MC, et al. Treatment of nasopharyngeal carcinoma with Epstein-Barr virus-specific T lymphocytes. Blood 2005;105: 1898–904. Comoli P, Pedrazzoli P, Maccario R, Basso S, Carminati O, Labirio M, et al. Cell therapy of stage IV nasopharyngeal carcinoma with autologous Epstein-Barr virus-targeted cytotoxic T lymphocytes. J Clin Oncol 2005;23:8942–9. National Institutes of Health. EBV-specific CTLs following CD45 antibody to patients with Epstein-Barr virus (EBV) positive nasopharyngeal carcinoma. http://clinicaltrials.gov/ct/show/ NCT00078546?order=1 [accessed 12.11.06]. Westphal EM, Blackstock W, Feng W, Israel B, Kenney SC. Activation of lytic Epstein-Barr virus (EBV) infection by radiation and sodium butyrate in vitro and in vivo: a potential method for treating EBV-positive malignancies. Cancer Res 2000;60:5781–8. Feng WH, Israel B, Raab-Traub N, Busson P, Kenney SC. Chemotherapy induces lytic EBV replication and confers ganciclovir susceptibility to EBV-positive epithelial cell tumors. Cancer Res 2002;62:1920–6. Sallusto F, Lanzavecchia A. Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus inter-

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38.

39.

40.

41.

42.

leukin 4 and downregulated by tumor necrosis factor alpha. J Exp Med 1994;179:1109–18. Lin CL, Lo WF, Lee TH, Ren Y, Hwang SL, Cheng YF, et al. Immunization with Epstein-Barr virus (EBV) peptide-pulsed dendritic cells induces functional CD8+ T-cell immunity and may lead to tumor regression in patients with EBV-positive nasopharyngeal carcinoma. Cancer Res 2002;62:6952–8. Nestle FO, Alijagic S, Gilliet M, Sun Y, Grabbe S, Dummer R, et al. Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. Nat Med 1998;4:328–32. Small EJ, Fratesi P, Reese DM, Strang G, Laus R, Peshwa MV, et al. Immunotherapy of hormone-refractory prostate cancer with antigen-loaded dendritic cells. J Clin Oncol 2000;18: 3894–903. Stift A, Friedl J, Dubsky P, Bachleitner-Hofmann T, Schueller G, Zontsich T, et al. Dendritic cell-based vaccination in solid cancer. J Clin Oncol 2003;21:135–42. Duraiswamy J, Sherritt M, Thomson S, Tellam J, Cooper L, Connolly G, et al. Therapeutic LMP1 polyepitope vaccine for

43.

44.

45.

46.

505

EBV-associated Hodgkin disease and nasopharyngeal carcinoma. Blood 2003;101:3150–6. Duraiswamy J, Bharadwaj M, Tellam J, Connolly G, Cooper L, Moss D, et al. Induction of therapeutic T-cell responses to subdominant tumor-associated viral oncogene after immunization with replication-incompetent polyepitope adenovirus vaccine. Cancer Res 2004;64:1483–9. Harrop R, Connolly N, Redchenko I, Valle J, Saunders M, Ryan MG, et al. Vaccination of colorectal cancer patients with modified vaccinia Ankara delivering the tumor antigen 5T4 (TroVax) induces immune responses which correlate with disease control: a phase I/II trial. Clin Cancer Res 2006;12: 3416–24. Arlen PM, Gulley JL, Parker C, Skarupa L, Pazdur M, Panicali D, et al. A randomized phase II study of concurrent docetaxel plus vaccine versus vaccine alone in metastatic androgen-independent prostate cancer. Clin Cancer Res 2006;12:1260–9. Parkin DM. The burden of cancer in the developing world: 2002. Alexandria: ASCO Educational Book; 2005., 702–18.

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