the development of new agents targeting important cellular pathways involved in cancer progression , although promising , has so far resulted in relatively short - term benefits for the majority of patients with advanced malignancy .
cell therapy can be numbered among the novel biologic therapeutics that will increase our ability to cure human disease in the years to come . despite the great potential ,
t cell therapy for cancer still has a marginal role in the management of patients with neoplasia .
this is due to limitations inherent to the technologies and products employed , and , more importantly , to the financial and structural requirements that are associated with cell therapy 1 - 3 .
clinical application was first attempted by rosenberg and colleagues in 1985 by using lak cells , infused with il-2 into patients with different advanced malignancies 4 : response was observed in four kinds of solid tumors , thus paving the way to further investigations . afterwards , several experimental and clinical studies were conducted : cell types tested included cik cells 5 , tumor infiltrating lymphocytes ( tils ) 6,7,8 and other t - cells variously manipulated 1,3,9 - 11 , which were used in different settings , from solid cancers to the transplantation field . among the factors that so far limited a wider use of t cell therapy for human tumors
may be the very low frequency of tumor - specific lymphocytes circulating in patients with cancer , or the limited ability to induce t cell lines with protective antitumor activity with current knowledge and available technology . with the exception of til therapy in melanoma ,
the only other human solid cancer setting in which tumor - specific t cells have been employed with success is virus - related tumors . indeed ,
when the frequency of circulating t cells against the target antigen on a tumour is high , as is the case for viral antigens , t cell therapy can be very effective in destroying large tumours in humans . in this context
, ebv - positive malignancies provide an optimal model system to test and ameliorate cellular therapies : the first very encouraging results were reached with prophylaxis and treatment of posttransplant lymphoproliferative disease 9 - 11 ; the success of this approach has fostered research in other , more complex areas , such as ebv - related solid tumors .
nasopharyngeal carcinoma ( npc ) is a rare cancer in the western hemisphere where its incidence is approximately 1 case per 100,000 individuals ; conversely there are some areas , such as southern china , southeast asia , the mediterranean basin and alaska , where it reaches 80 per 100,000 individuals : moreover in the western hemisphere the tumor histology differs from the endemic form 12 .
all these differences suggest that an important role in the pathogenesis is played by genetic and environmental factors .
the current who classification defines nasopharyngeal cancer a carcinoma that shows light microscopic or ultrastructural evidence of squamous differentiation .
it encompasses squamous cell carcinoma , associated with behavioural risk factors such as alcohol and tobacco use , non keratinizing carcinoma ( differentiated and undifferentiated ) and basaloid squamous cell carcinoma 13 .
the most common pediatric nasopharyngeal carcinoma is the non - keratinizing undifferentiated carcinoma 14 and is associated with ebv in practically 100% of cases 13 . although npc is serologically and biologically associated with epstein - barr virus , npc cells express only a limited pattern of ebv genes ( the so - called latency ii pattern ) which comprises non - coding rnas ( ebers , barts ) , the nuclear antigen ebna1 and surface antigens lmp1 and lmp2 15 , immunogens that are weak , albeit capable of inducing a t - lymphocyte response . in most cases
the tumor presents as a painless mass in the upper neck , with possible cervical lymphadenopathy .
the most common pattern of tumor diffusion is local infiltration which , given the limitrophe structures , may cause serous otitis , hearing difficulties , nasal obstruction , epistaxis , dysphasia , dysphonia and dysphagia .
npc can metastatize to lung , bone , mediastinum , bone marrow and visceral organs 13,16,17 .
paraneoplastic syndromes may also be present , in most cases related to tumor dissemination or relapse , such as hypertrophic osteoarthropathy , leukemoid reaction , fuo , dermatomyositis , and inappropriate adh secretion syndrome 18 .
the extent of the tumor at diagnosis is described by the tnm classification of the american joint committee on cancer ; in children , as in adults , the tnm stage at the time of diagnosis correlates with outcome 19 .
however , with more advanced and improved treatments , while the presence of metastases continues to be associated with poor outcome , t and n staging are losing prognostic significance 20 , 21 .
radiotherapy is a cornerstone of first line therapy and it is the standard treatment for early - stage npc ( t1 - 2a ; n0 ; m0 ) : patients with local disease can be adequately treated with radiation alone , with a 5-years control ranging from 80 to 95% of cases 22 - 25 .
treatment strategies for locally advanced npc consists mainly of platinum based chemotherapy in conjunction with radiotherapy , and yields an overall response rate of about 90% , with complete response ranging from 20 to 50% 26 - 28 .
induction treatment is able to improve local regional control , which translates into long - term specific survival benefits . in local - regional recurrent nasopharyngeal cancer
not amenable for reirradiation , combination cisplatin - based chemotherapy is a standard first line treatment , with response rates of 40 - 80% , mainly depending on the site of lesions , previous treatment , disease free interval 28,29 .
no standard second - line chemotherapy has been defined , but a recent study reported an 11% response rate in recurrent and metastatic disease by combining target therapy ( cetuximab ) to carboplatin 30 .
second line therapies in refractory / relapsing patients usually have little effect on the natural history of the disease , and there is therefore a need to develop additional forms of treatment , particularly ones that lack overlapping toxicities with radiochemotherapy 31,32 .
in the last 15 years , a number of reports demonstrated the effectiveness of atct directed against ebv antigens for the treatment of ebv - related hematological malignancies in the immunocompromised host 3,9 - 11,33 .
ebv - related posttransplant lymphoproliferative disease ( ptld ) constitutes a highly immunogenic lymphoproliferation whose onset is greatly favoured by the host immunodeficiency status .
thus , t cell therapy in this setting is expected to have a great chance of success .
adoptive transfer of polyclonal ctls specific for viral latency antigens in the context of ebv - associated malignancies arising in the immunocompetent host , such as nasopharyngeal carcinoma ( npc ) , is hampered by a number of factors 34 .
ebv - specific ctls are dominated by reactivity against viral proteins not expressed by these tumors .
moreover , the transferred ctls have to compete with endogenous lymphocytes for cytokines and biological niches , and , once ctls reach the tumor site , they have to overcome the inhibitory barriers exerted by the tumor environment .
notwithstanding these limitations , the results of the clinical cell therapy trials conducted so far in npc patients demonstrate that administration of an avid anti - tumour t cell targeting a highly expressed antigen can result in cancer regression 35,36 . to date , a total of 57 patients with npc were treated within phase i - ii clinical trials 35 - 41 . in a phase i study , comoli et al .
35 enrolled 10 patients with stage iv npc in progression after conventional radiotherapy and chemotherapy .
patients underwent multiple ( from 2 to 23 ) infusions of autologous ebv - specific ctls with a dose ranging from 2 to 8x10 cells /m , accompanied by administration of low - dose ( 1x10u ) recombinant il-2 with the purpose of prolonging t - lymphocyte life - span .
there were no major adverse events , although two patients suffered from moderate inflammatory reactions at the tumor site .
control of disease progression was obtained in six of ten patients ( two with partial response and four with stable disease ) .
more importantly , it was demonstrated that tumor control related to cell therapy did occur , and was associated to the emergence or increase in lmp2-specific responses in the peripheral blood . in the same year , straathof and colleagues 36 published data from 10 patients with advanced npc . in a recent update 37
louis added 13 new patients to the previous 10 ( whose follow - up was extended ) , for a total of 23 patients treated . of these patients ( all but one with stage iii - iv npc ) eight were in disease remission at the time of the first infusion and 15 had active disease
they were treated with a mean of 2 infusions with a dose ranging from 2x10 cells / m to 2x10 cells /m
the therapy was well tolerated : only one patient experienced marked swelling at the tumor site requiring a tracheostomy .
of the eight patients treated in remission five remained disease - free for 25 to 82 months and three suffered from disease relapse . of the other 15 patients treated with active disease ten showed control of the disease ( 5 with complete response , 2 with partial response , 3 with stable disease ) , while the other five progressed .
prior to these two studies , one pilot study in china showed that the adoptive transfer of autologous ebv - targeted ctls induced antiviral responses but no clinical responses in 4 npc patients 40 , while adoptive transfer of allogeneic ebv - specific ctl induced a clinical response in a patient with advanced - stage npc , likely associated to a boost in endogenous lmp2-specific response 41 .
the data obtained with these early studies prompted further efforts aimed at enhancing the expansion potential of infused t - cells , by means of a lymphodepleting treatment prior to ctl infusion , as demonstrated in the context of t - cell therapy for melanoma 42,43 . in a pilot study , 8 patients with loco - regional or metastatic refractory / recurrent npc were given anti - cd45 monoclonal antibody treatment , followed by escalating doses of polyclonal ebv - specific ctl .
after transitory lymphodepletion , and increase in the circulating levels of il-15 , 3 objective responses were seen , in the patients who showed higher increase in their peripheral blood frequency of ebv - specific t cells after ctl infusion 38 .
secondino and colleagues 39 enrolled 11 heavily pre - treated patients with active stage iv npc , who received non - myeloablative lymphodepleting chemotherapy consisting of cyclophosphamide and fludarabine : two doses of autologous ebv - specific ctls ( median dose of 3.7x10cells ) were subsequently infused , two weeks apart , supported by low - dose il-2 .
control of disease was obtained in six of eleven patients ( 3 with stable disease , 2 with partial response and one with minor response ) .
two patients experienced mild to moderate swelling at the disease site . notwithstanding the encouraging preliminary results ,
the use of lymphodepleting preparative regimens as a mean to overcome the inhibitory checkpoints devised by the tumor cells is a strategy that needs further optimization .
to summarize , data collected from a total of 57 patients receiving polyclonal , ebv - polyspecific ctl were as follows : of 30 patients with advanced , active npc , treated with autologous or allogeneic , polyclonal ebv - specific ctl infusions , 17 ( 56% ) achieved control of the disease ( defined as either tumor regression or disease stabilization)of 19 patients with advanced , active npc , treated with autologous , polyclonal ebv - specific ctl infusions preceded by a lymphodepleting regimen 9 ( 47% ) achieved control of the diseaseof 8 patients treated in disease remission , although at great risk of relapse , at the time of the first infusion , 5 ( 62% ) remained disease - free for 25 to 82 months and 3 suffered from relapsing disease of 30 patients with advanced , active npc , treated with autologous or allogeneic , polyclonal ebv - specific ctl infusions , 17 ( 56% ) achieved control of the disease ( defined as either tumor regression or disease stabilization ) of 19 patients with advanced , active npc , treated with autologous , polyclonal ebv - specific ctl infusions preceded by a lymphodepleting regimen 9 ( 47% ) achieved control of the disease of 8 patients treated in disease remission , although at great risk of relapse , at the time of the first infusion , 5 ( 62% ) remained disease - free for 25 to 82 months and 3 suffered from relapsing disease t cell therapy , although now frequently used in the hematopoietic transplantation setting , has not yet been widely introduced in the clinical oncologic field and is currently limited to research protocols in highly - specialized centres . for solid tumors , the majority of the literature available nowadays refers to treatment of melanoma 42 .
the phase i - ii studies of ebv - targeted t cell therapy for npc , taken together , provide one of the larger series for non - melanoma solid malignancies .
these studies provide new perspectives on the optimal treatment for metastatic or recurrent disease ; indeed , to date , cisplatin - based chemotherapy is considered the preferred regimen for such patients : response rates are above 50% and median survival is approximately 12 months 26 .
however , the choice for second - line regimens in patients with unsatisfactory responses to a platinum - based treatment remains unclear 32 .
in the cell therapy trials described , the patients enrolled were a heavily pre - treated cohort with a very poor prognosis .
in these patients , further conventional treatment would likely lead to a very high risk of toxicity , ranging from 26% after re - irradiation with high dose radiotherapy 44 to 89% after conventional cytotoxic protocols 45 . in the cohort treated with ctls , there were only five out of 52 patients ( less than 10% ) who suffered from swelling at the tumor site ; of these , four had mild to moderate inflammatory reactions 35 , 39 and only one had a major complication 36 .
in particular this patient , who presented bulky disease and pre - existing facial swelling , two days after the first infusion , developed marked worsening of the tumefaction requiring a tracheostomy : the authors performed a needle biopsy which showed tumor cells , but not inflammatory cells , suggesting tumor progression rather than an inflammatory reaction .
thus the safety and the feasibility of this approach , even at the highest doses reached , is more than a supposition . the second point to take into consideration
is the efficacy of this therapy : taken grossly together all these data show a response rate ranging from 47 to 64% , thus perfectly in line with other types of second- , third- or more advanced therapy 32 . for the patients treated in remission ,
given the small size of the cohort , the role of infused ctls remains unclear .
but , more importantly , these data raise a number of questions , which remains , to date , unresolved .
first of all , what is the role and the best timing of adoptive t - cell therapy in npc ?
the studies published to date indicate that ctls could possibly be administered earlier the course of treatment and in combination with conventional therapies ( for example as consolidation treatment after achieving response to second line therapy ) 39 .
furthermore , immune escape can occur even in instances when polyclonal antigen - specific t cells are infused 46 : gottschalk et al reported a patient with ebv - positive lymphoproliferative disease , who failed ebv - specific t - cell therapy , in which the tumor virus had deleted immunodominant ebv epitopes 47 .
a strategy to overcome this phenomenon , and to increase clinical efficacy through better targeting , could be to ameliorate the quality of the cell product .
in this perspective , efforts are being made towards augmenting the pool of t - cells specific for the subdominant antigens expressed on ebv latency ii tumor cells within the infused product , with the aim of increasing t cell therapy efficacy . in detail , the subdominant component of the ebv - specific immune response directed towards latent membrane proteins lmp1 and lmp2 has been shown to expand , by stimulation with dendritic cells or ebv - lcl genetically modified to express the antigens 48 - 50 . in a pilot study enrolling ebv - positive hodgkin or non - hodgkin lymphoma , 5 of 6 patients with active relapsed disease showed a tumor response after infusion of autologous lmp2-specific ctl 51 .
a barrier to the function of infused ebv - specific ctls in immunocompetent hosts is the display of tumor - mediated immune evasion strategies 52 . to improve the resistance of ctls to tumor - derived inhibitory cytokines , bollard et al .
have shown that ebv - specific ctl made transgenic for a dominant - negative tgf- receptor , in which the intracellular signaling domain is truncated , are rendered resistant to the devastating effects of tgf- , secreted by hodgkin tumor cells 53 .
likewise , treatment failure due to lack or loss of ebv antigen expression by neoplastic cell subpopulations may be avoided through redirecting ebv - specific ctls to target other tumor antigens .
it has been shown that ebv - specific ctls expressing a chimeric antigen receptor ( car ) specific for cd30 , a molecule highly and consistently expressed on malignant hodgkin reed - sternberg cells , while retaining their original specificity , are also able to target cd30 + neoplastic cells , and mediate activity against ebv-/cd30 + tumors in a xenograft model 54 .
in the last 15 years , a number of reports demonstrated the effectiveness of atct directed against ebv antigens for the treatment of ebv - related hematological malignancies in the immunocompromised host 3,9 - 11,33 .
ebv - related posttransplant lymphoproliferative disease ( ptld ) constitutes a highly immunogenic lymphoproliferation whose onset is greatly favoured by the host immunodeficiency status .
thus , t cell therapy in this setting is expected to have a great chance of success .
adoptive transfer of polyclonal ctls specific for viral latency antigens in the context of ebv - associated malignancies arising in the immunocompetent host , such as nasopharyngeal carcinoma ( npc ) , is hampered by a number of factors 34 .
ebv - specific ctls are dominated by reactivity against viral proteins not expressed by these tumors .
moreover , the transferred ctls have to compete with endogenous lymphocytes for cytokines and biological niches , and , once ctls reach the tumor site , they have to overcome the inhibitory barriers exerted by the tumor environment .
notwithstanding these limitations , the results of the clinical cell therapy trials conducted so far in npc patients demonstrate that administration of an avid anti - tumour t cell targeting a highly expressed antigen can result in cancer regression 35,36 . to date , a total of 57 patients with npc were treated within phase i - ii clinical trials 35 - 41 . in a phase i study , comoli et al .
35 enrolled 10 patients with stage iv npc in progression after conventional radiotherapy and chemotherapy .
patients underwent multiple ( from 2 to 23 ) infusions of autologous ebv - specific ctls with a dose ranging from 2 to 8x10 cells /m , accompanied by administration of low - dose ( 1x10u ) recombinant il-2 with the purpose of prolonging t - lymphocyte life - span .
there were no major adverse events , although two patients suffered from moderate inflammatory reactions at the tumor site .
control of disease progression was obtained in six of ten patients ( two with partial response and four with stable disease ) .
more importantly , it was demonstrated that tumor control related to cell therapy did occur , and was associated to the emergence or increase in lmp2-specific responses in the peripheral blood . in the same year , straathof and colleagues 36 published data from 10 patients with advanced npc . in a recent update 37
louis added 13 new patients to the previous 10 ( whose follow - up was extended ) , for a total of 23 patients treated . of these patients ( all but one with stage iii - iv npc ) eight were in disease remission at the time of the first infusion and 15 had active disease
they were treated with a mean of 2 infusions with a dose ranging from 2x10 cells / m to 2x10 cells /m
the therapy was well tolerated : only one patient experienced marked swelling at the tumor site requiring a tracheostomy .
of the eight patients treated in remission five remained disease - free for 25 to 82 months and three suffered from disease relapse . of the other 15 patients treated with active disease ten showed control of the disease ( 5 with complete response , 2 with partial response , 3 with stable disease ) , while the other five progressed .
prior to these two studies , one pilot study in china showed that the adoptive transfer of autologous ebv - targeted ctls induced antiviral responses but no clinical responses in 4 npc patients 40 , while adoptive transfer of allogeneic ebv - specific ctl induced a clinical response in a patient with advanced - stage npc , likely associated to a boost in endogenous lmp2-specific response 41 .
the data obtained with these early studies prompted further efforts aimed at enhancing the expansion potential of infused t - cells , by means of a lymphodepleting treatment prior to ctl infusion , as demonstrated in the context of t - cell therapy for melanoma 42,43 . in a pilot study , 8 patients with loco - regional or metastatic refractory / recurrent npc were given anti - cd45 monoclonal antibody treatment , followed by escalating doses of polyclonal ebv - specific ctl .
after transitory lymphodepletion , and increase in the circulating levels of il-15 , 3 objective responses were seen , in the patients who showed higher increase in their peripheral blood frequency of ebv - specific t cells after ctl infusion 38 .
secondino and colleagues 39 enrolled 11 heavily pre - treated patients with active stage iv npc , who received non - myeloablative lymphodepleting chemotherapy consisting of cyclophosphamide and fludarabine : two doses of autologous ebv - specific ctls ( median dose of 3.7x10cells ) were subsequently infused , two weeks apart , supported by low - dose il-2 .
control of disease was obtained in six of eleven patients ( 3 with stable disease , 2 with partial response and one with minor response ) .
two patients experienced mild to moderate swelling at the disease site . notwithstanding the encouraging preliminary results ,
the use of lymphodepleting preparative regimens as a mean to overcome the inhibitory checkpoints devised by the tumor cells is a strategy that needs further optimization .
to summarize , data collected from a total of 57 patients receiving polyclonal , ebv - polyspecific ctl were as follows : of 30 patients with advanced , active npc , treated with autologous or allogeneic , polyclonal ebv - specific ctl infusions , 17 ( 56% ) achieved control of the disease ( defined as either tumor regression or disease stabilization)of 19 patients with advanced , active npc , treated with autologous , polyclonal ebv - specific ctl infusions preceded by a lymphodepleting regimen 9 ( 47% ) achieved control of the diseaseof 8 patients treated in disease remission , although at great risk of relapse , at the time of the first infusion , 5 ( 62% ) remained disease - free for 25 to 82 months and 3 suffered from relapsing disease of 30 patients with advanced , active npc , treated with autologous or allogeneic , polyclonal ebv - specific ctl infusions , 17 ( 56% ) achieved control of the disease ( defined as either tumor regression or disease stabilization ) of 19 patients with advanced , active npc , treated with autologous , polyclonal ebv - specific ctl infusions preceded by a lymphodepleting regimen 9 ( 47% ) achieved control of the disease of 8 patients treated in disease remission , although at great risk of relapse , at the time of the first infusion , 5 ( 62% ) remained disease - free for 25 to 82 months and 3 suffered from relapsing disease
t cell therapy , although now frequently used in the hematopoietic transplantation setting , has not yet been widely introduced in the clinical oncologic field and is currently limited to research protocols in highly - specialized centres . for solid tumors , the majority of the literature available nowadays refers to treatment of melanoma 42 .
the phase i - ii studies of ebv - targeted t cell therapy for npc , taken together , provide one of the larger series for non - melanoma solid malignancies .
these studies provide new perspectives on the optimal treatment for metastatic or recurrent disease ; indeed , to date , cisplatin - based chemotherapy is considered the preferred regimen for such patients : response rates are above 50% and median survival is approximately 12 months 26 .
however , the choice for second - line regimens in patients with unsatisfactory responses to a platinum - based treatment remains unclear 32 .
in the cell therapy trials described , the patients enrolled were a heavily pre - treated cohort with a very poor prognosis . in these patients , further conventional treatment would likely lead to a very high risk of toxicity , ranging from 26% after re - irradiation with high dose radiotherapy 44 to 89% after conventional cytotoxic protocols 45 . in the cohort treated with ctls
, there were only five out of 52 patients ( less than 10% ) who suffered from swelling at the tumor site ; of these , four had mild to moderate inflammatory reactions 35 , 39 and only one had a major complication 36 .
in particular this patient , who presented bulky disease and pre - existing facial swelling , two days after the first infusion , developed marked worsening of the tumefaction requiring a tracheostomy : the authors performed a needle biopsy which showed tumor cells , but not inflammatory cells , suggesting tumor progression rather than an inflammatory reaction .
thus the safety and the feasibility of this approach , even at the highest doses reached , is more than a supposition . the second point to take into consideration is the efficacy of this therapy : taken grossly together all these data show a response rate ranging from 47 to 64% , thus perfectly in line with other types of second- , third- or more advanced therapy 32 . for the patients treated in remission ,
given the small size of the cohort , the role of infused ctls remains unclear .
but , more importantly , these data raise a number of questions , which remains , to date , unresolved .
first of all , what is the role and the best timing of adoptive t - cell therapy in npc ? the studies published to date indicate that ctls could possibly be administered earlier the course of treatment and in combination with conventional therapies ( for example as consolidation treatment after achieving response to second line therapy ) 39 .
furthermore , immune escape can occur even in instances when polyclonal antigen - specific t cells are infused 46 : gottschalk et al reported a patient with ebv - positive lymphoproliferative disease , who failed ebv - specific t - cell therapy , in which the tumor virus had deleted immunodominant ebv epitopes 47 . in the setting of npc immune escape
a strategy to overcome this phenomenon , and to increase clinical efficacy through better targeting , could be to ameliorate the quality of the cell product . in this perspective
, efforts are being made towards augmenting the pool of t - cells specific for the subdominant antigens expressed on ebv latency ii tumor cells within the infused product , with the aim of increasing t cell therapy efficacy . in detail , the subdominant component of the ebv - specific immune response directed towards latent membrane proteins lmp1 and lmp2 has been shown to expand , by stimulation with dendritic cells or ebv - lcl genetically modified to express the antigens 48 - 50 . in a pilot study enrolling ebv - positive hodgkin or non - hodgkin lymphoma , 5 of 6 patients with active relapsed disease showed a tumor response after infusion of autologous lmp2-specific ctl 51 .
a barrier to the function of infused ebv - specific ctls in immunocompetent hosts is the display of tumor - mediated immune evasion strategies 52 . to improve the resistance of ctls to tumor - derived inhibitory cytokines , bollard et al .
have shown that ebv - specific ctl made transgenic for a dominant - negative tgf- receptor , in which the intracellular signaling domain is truncated , are rendered resistant to the devastating effects of tgf- , secreted by hodgkin tumor cells 53 .
likewise , treatment failure due to lack or loss of ebv antigen expression by neoplastic cell subpopulations may be avoided through redirecting ebv - specific ctls to target other tumor antigens .
it has been shown that ebv - specific ctls expressing a chimeric antigen receptor ( car ) specific for cd30 , a molecule highly and consistently expressed on malignant hodgkin reed - sternberg cells , while retaining their original specificity , are also able to target cd30 + neoplastic cells , and mediate activity against ebv-/cd30 + tumors in a xenograft model 54 .
the management of human cancer with radio - chemotherapy is still suboptimal , due to persistence of refractory / relapsing disease , and the increased toxicity observed with increased efficacy of therapeutic regimens .
targeted therapies may offer equal or increased efficacy , coupled with a considerable decrease in overall toxicity . among these novel approaches ,
cell therapy offers a unique opportunity to restore antitumor immune surveillance , and it is therefore conceivable that application of this strategy will increase in the next few years 55 . in particular , for patients with relapsed or refractory npc which express ebv antigens , autologous , polyclonal , ebv - specific ctl therapy is safe , feasible , with low complication rates and a significant clinical response .
 among the novel biologic therapeutics that will increase our ability to cure human cancer in the years to come , t cell therapy is one of the most promising approaches . 
 however , with the possible exception of tumor - infiltrating lymphocytes therapy for melanoma , clinical trials of adoptive t - cell therapy for solid tumors have so far provided only clear proofs - of - principle to build on with further development . 
 epstein - barr virus ( ebv)-associated malignancies offer a unique model to develop t cell - based immune therapies , targeting viral antigens expressed on tumor cells . in the last two decades , ebv - specific cytotoxic t - lymphocytes ( ctl ) 
 have been successfully employed for the prophylaxis and treatment of ebv - related lymphoproliferative disorders in immunocompromised hosts . 
 more recently , this therapeutic approach has been applied to the setting of ebv - related solid tumors , such as nasopharyngeal carcinoma . 
 the results are encouraging , although further improvements to the clinical protocols are clearly necessary to increase anti - tumor activity . 
 promising implementations are underway , including harnessing the therapeutic potential of ctls specific for subdominant ebv latent cycle epitopes , and delineating strategies aimed at targeting immune evasion mechanisms exerted by tumor cells . 
Introduction
Nasopharyngeal carcinoma
Cell therapy for NPC
Clinical results
Considerations on clinical data and on future strategies to ameliorate outcome
Conclusions