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JNCI Monographs 1998 1998(23):89-93;
© 1998 by Oxford University Press
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Journal of the National Cancer Institute Monographs, No. 23, 89-93, 1998
© 1998 Oxford University Press

Immunotherapy for Epstein-Barr Virus-Associated Cancers

Cliona M. Rooney, Marie A. Roskrow, Colton A. Smith, Malcolm K. Brenner, Helen E. Heslop*

* Affiliations of authors: C. M. Rooney, M. A. Roskrow, C. A. Smith (Department of Virology and Molecular Biology), M. K. Brenner, H. E. Heslop (Department of Hematology and Oncology), St. Jude Children's Research Hospital, Memphis, TN.

Correspondence to: Cliona M. Rooney, Ph.D., Department of Pediatrics-Hematology/Oncology, Texas Children's Hospital, Baylor College of Medicine, 6621 Fannin St., Houston, TX 77030-2399. E-mail: cmrooney{at}msmail.his.tch.tmc.edu


   Abstract
Top
 Abstract
Introduction
 Methods
 Results and Discussion
 References
 
Epstein-Barr virus (EBV)-associated lymphoproliferative disease (EBV-LPD) is a frequently fatal complication of organ transplantation and human immunodeficiency virus (HIV) infection. We have studied the safety and efficacy of adoptively transferred, gene-marked virus-specific cytotoxic T lymphocytes (CTLs) as prophylaxis and treatment of EBV-LPD in recipients of T-cell-depleted allogeneic bone marrow. In 42 patients treated prophylactically, no toxicity was experienced. None of these patients developed EBV-LPD, in contrast with eight of 53 (15%) patients who did not receive prophylactic CTL. Three patients who had not received CTL developed aggressive disease and received CTL as treatment. Gene-marked CTL homed to tumor sites and selective accumulation of marker gene was detected in tumor tissues. Tumors regressed completely in two patients, but the third died of respiratory failure. Infused CTLs persisted for up to 3 years in vivo, they rapidly reconstituted EBV-specific immune responses to levels seen in normal individuals, and they reduced high viral titers by two to three logs. We are now using autologous EBV-specific CTL to treat patients with relapsed EBV-positive Hodgkin's disease and we are developing methods for the generation of antigen-specific lines. This approach could be applied to patients with HIV who develop EBV-LPD, using CTL derived early in the course of HIV infection.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results and Discussion
 References
 
More than 90% of individuals are infected with Epstein-Barr virus (EBV). Primary infection occurs through the oropharynx, where the virus replicates in epithelial cells and infects circulating B lymphocytes (1,2). The virus then persists for the life of the infected individual, in epithelial cells and B lymphocytes. EBV can efficiently transform B lymphocytes in vitro into permanently growing lymphoblastoid cell lines (LCLs) if immune T cells are first removed or inactivated (1). Similarly, in the absence of T-cell function in vivo, EBV may transform B cells causing lymphoproliferative disease (EBV-LPD) or lymphoma (3). Recipients of stem cells from human leukocyte antigen (HLA)-mismatched family members or unrelated donors are particularly at risk of developing this complication if T cells are removed from the allograft to prevent graft-versus-host disease (GvHD) (4,5).

Unlike disease caused by herpesviruses, such as CMV and HSV, EBV-LPD is associated with the latent phase of the virus. Therefore, drugs such as acyclovir, which target the viral DNA polymerase, are ineffective in prevention or treatment. The nine latency-associated EBV proteins expressed in the tumor cells provide potent antigenic targets for immunotherapeutic approaches (1). Donor T cells have been used effectively to treat EBV-LPD (6,7), but are associated with GvHD and when used to treat active disease, they can cause significant pathology due to inflammation. We show here that donor-derived, EBV-specific cytotoxic T lymphocytes (CTLs) can safely be given prophylactically and will prevent EBV-LPD without causing GvHD.

EBV is also found in the malignant cells of 50% of patients with Hodgkin's disease (HD) (8-10), offering another potential target for CTL therapy. Although the long-term survival for the majority of patients with HD is good, the outlook for the 10% who fail initial therapy is poor. Furthermore, primary therapy for HD is aggressive and the incidence of second cancers and other long-term treatment-related toxic effects is high. Targeted immunotherapy may provide a less toxic alternative primary treatment, which should improve the quality of life of survivors and could offer salvage therapy to those who fail conventional therapy. Although EBV gene expression in the malignant cells of HD is more limited than in immunoblastic lymphoma cells, the three latency-associated proteins that are expressed (EBNA1, LMP1, and LMP2a) should provide antigenic targets for immunotherapeutic approaches (2,11). We are currently analyzing the potential of EBV-specific CTL as therapy for relapsed HD.


   Methods
Top
 Abstract
 Introduction
 Methods
Results and Discussion
 References
 
Generation of EBV-Transformed B-Cell Lines

LCLs were prepared from bone marrow donors or patients with HD by infection of peripheral blood mononuclear cells (PBMCs) with concentrated viral supernatant from the B95-8 cell line (12). Cells were cultured in flat-bottomed wells in the presence of 1 µg/mL of cyclosporin A until clumps of virus-transformed cells began to expand. After establishment, LCLs were maintained in acyclovir to prevent the production of infectious virus in the cultures (12).

CTL Generation

EBV-specific CTL lines were generated by co-culture of 2 x 106 PBMCs with 5 x 104 irradiated autologousEBV-transformed B cells in 2-mL wells. CTLs were expanded by weekly restimulation with the irradiated autologous LCL and twice weekly stimulation with 20 U/mL of recombinant interleukin 2 after day 14. CTLs were gene marked with a retrovirus vector containing the bacterial neomycin resistance (neo) gene as described previously (12).

Safety Testing of CTL Lines

When sufficient CTL numbers were achieved, the line was safety tested and frozen. Release criteria mandated that the line should possess the donor HLA type; should contain less than 1% B cells; should be free of contaminating bacteria, fungi, and mycoplasma; should have low endotoxin; and should have minimal cytotoxic activity against recipient-derived phytohemagglutinin-induced lymphoblasts (PHA blasts), a measure of potential GvHD activity. Supernatants from gene-marked lines were saved to test for replication-competent retrovirus.

CTL Assay

Target cells, which included autologous HLA class I-mismatched LCLs, a lymphokine-activated killer-sensitive Tcell lymphoma, HSB-2, and PHA blasts derived from the recipients prior to bone marrow transplant (BMT), were labeled with 100 mCi 51Cr in a small volume of medium for 1 hour at 37 °C. They were then washed extensively and incubated with CTLs at the required effector : target ratio for 5 hours. Half the supernatant was then removed from each well and counted. The percent specific lysis was calculated using the standard formula,


PCR for neo and EBV

DNA was prepared from PBMC using QIAmp Blood PCR kits (Qiagen, Chatsworth, CA). For quantitation of EBV, dilutions of DNA from 1 to 0.1 µg were subjected to a 25-cycle polymerase chain reaction (PCR) using 25 mM MgCl2, 1 µM of each primer, and 200 µM deoxynucleotides. The primers, first described by Boyle et al. (13), amplified a unique region of the EBNA2 gene that distinguishes between the two strains of EBV. The amplified products were electrophoresed on a 2.5% agarose gel, transferred to nylon MSI membranes, and detected by DNA hybridization using nonradiolabeled EBV probes according to the GENIUS (Boehringer Mannheim Corp, Indianapolis, IN) system (14). Quantitation of neo sequences was carried out as described previously (15). PCR products were electrophoresed, Southern blotted and probed with a radiolabeled neospecific probe. PCR products were compared with known standards and the sensitivity of detection was 0.01% neomarked cells.

Precursor CTL Assay

Patient PBMCs were plated in flat-bottomed 96-well plates at six to ten doubling dilutions from 5 x 105 cells per well with 104 cells from the irradiated autologous LCL and 105 irradiated autologous PBMC as feeders. Replicates ranged from 6 to 12 depending on the PBMC numbers available. Cells were restimulated weekly with the autologous irradiated LCL and fed twice weekly with 20 U per mL of interleukin 2 from day 14. Cytotoxicity against the autologous and an HLA-mismatched LCL was tested after 6 weeks of culture.

Dendritic Cell Preparation

Dendritic cells (DC) were enriched from peripheral blood by adhering 106 PBMC to 2 mL culture wells in 1 mL of medium for 2 hours. Nonadherent cells were removed gently and 1 mL of medium containing 800 U per mL granulocyte-macrophage colony-stimulating factor (GM-CSF) and 500 U per mL interleukin 4 was added to the adherent cells (16). These cells were cultured for 3-5 days with the addition of extra GM-CSF on day 3. Between 20% and 50% of these cells had DC morphology and phenotype (CD3-, CD14-, CD19-, DR+, and CD1a+). The crude population was used for transduction.

Dendritic Cell Transduction

Cells (106) that were enriched for DC were transduced with a retrovirus vector containing the LMP2a gene, using a flow-through transduction method. Retrovirus supernatant (20-40 mL) was concentrated on an Anocell 25 membrane by applying a pressure of 40-60 mm Hg. DC in 1 mL were then gently adhered to the virus on the membrane by applying a pressure of 20 mm Hg for 5-10 minutes. The membrane was then placed in a 6-mL well and cultured in 5 mL of complete medium containing GM-CSF for 16 hours before analysis for retrovirus integration or for irradiation and use as stimulator cells.


   Results and Discussion
Top
 Abstract
 Introduction
 Methods
 Results and Discussion
References
 
Safety

Forty-five recipients of T-cell-depleted marrow have received donor-derived, EBV-specific CTL, generated by stimulation of donor PBMC with the autologous irradiated, EBV-transformed B cell line. Twenty-six EBV-specific CTL lines were gene marked prior to infusion to determine the in vivo fate of the infused cell line. All patients were treated on protocols approved locally by our Institutional Review Board and federally by the Recombinant DNA Advisory Committee of the National Institutes of Health and the Food and Drug Administration (17).

CTL as prophylaxis. Forty-two patients received EBV-specific CTL as prophylaxis and in these patients there was no short- or long-term toxicity. Eleven patients died, eight from relapse of the original leukemia, two from bacterial sepsis unrelated to CTL infusion, and one from pneumonitis. One patient developed a recurrence of GvHD, with no accumulation of marked T cells in biopsy tissue, and three developed skin rashes attributed to drug sensitivity.

CTL as treatment. Three patients who did not receive prophylactic CTL (two were ineligible and one refused prophylaxis) received CTL as treatment for fulminant disease (5,18). Disease regressed completely in two patients, one without incident, but one with severe morbidity as a result of the inflammatory response to his bulky and extensive disease. The third patient died of overwhelming disease, 25 days after CTL infusion.

Persistence

Twenty-six patients received CTL that had been gene marked with efficiencies ranging from 0.1% to 10%. Marked cells could be tracked by PCR analysis of peripheral blood DNA prepared from patients for up to 18 weeks after CTL infusion (Fig. 1)Go (19). Semiquantitative analysis of marker DNA indicated an expansion of CTL in vivo of up to three logs in some patients. If EBV-specific CTLs were selectively expanded from patients, marked T cells could be detected for up to 3 years postinfusion (19). The generation of an immune response to the marker gene and resultant destruction of marked cells did not appear to be a problem in our patient group, since marked cells persisted long term in all but two assessable patients.



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  		Fig. 1. Marked cells detected for up to 17 months in patient-derived EBV-specific CTL lines. Southern blot of neospecific PCR of DNA prepared from EBV-specific CTL lines initiated from patient UPN 214 at the indicated times after CTL infusion. Signals are compared with control cells in which from 0.01% to 10% of the cells contain one copy of the marker gene.

 
Immune Reconstitution

Evidence for immune reconstitution came from comparisons of the precursor frequency of EBV-specific T cells before CTL infusion and 1 and 4 weeks after. In 15 patients, there was a 35-fold median increase in precursor frequency (range, 1.5 to >500-fold) (19). An example of the increase in precursor frequency is demonstrated in Fig. 2.Go



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  		Fig. 2. The frequency of EBV-specific CTL precursors increases after CTL infusion. Here shown is an example of one patient in whom CTL precursors that kill the autologous LCL increase over the 4 weeks following infusion of one dose of 2 x 107 CTL/m2. Dotted line shows the number of precursors that kill the autologous LCL and solid line shows killing of an HLA class I-mismatched LCL.

 
Antiviral Effects

We had previously shown that in stem cell transplant recipients, more than 2000 EBV genomes per 106 peripheral blood mononuclear cells were highly predictive of EBV-LPD (14). Seven of 63 individuals who had high EBV DNA levels and did not receive CTL prophylaxis developed EBV-LPD. By contrast, while six patients in the prophylaxis group also developed high EBV DNA, in all of these individuals, EBV DNA levels dropped by two to four logs within 3 weeks of infusion, and none subsequently developed lymphoma (19).

Antitumor Effects

Three lines of evidence indicated that infused EBV-specific CTLs had antitumor effects. First, none of 42 patients who received prophylactic CTL developed EBV-LPD compared with seven of 63 who did not receive CTL (either because they were transplanted before the study opened or because they were ineligible or refused). Second, none of the patients who developed high EBV DNA and received CTL developed EBV-LPD. The third line of evidence came from patients who responded to infusion of EBV-specific CTL as treatment for bulky disease. In one of these patients, we obtained biopsy specimens and found evidence for accumulation or expansion of infused CTL in tumor biopsy tissue. In this case, in situ PCR analysis demonstrated marked cells in tumor tissue biopsied 10 days after CTL infusion. Comparative analysis of the marker gene in peripheral blood and tumor tissue demonstrated selective accumulation or amplification of marked cells in the tumor tissue. About 1% of cells in the tumor tissue were marked by comparison with less than 0.01% in peripheral blood. Although this patient recovered completely and has been disease free for more than 1 year, he had severe morbidity as a result of the CTL-mediated inflammatory response to his diffusely invasive disease.

Prophylaxis is Better Than Cure

Although we successfully treated two of three patients with extensive lymphoma, a third patient who received CTL as treatment of advanced pulmonary disease died of respiratory failure with overwhelming tumor burden. Together with the morbidity experienced by the second patient, our results show that, while prophylactic use of EBV-specific CTL is safe and effective, treatment of this rapidly progressive and invasive disease by infusion of EBV-specific CTL can cause damage and may be ineffective in advanced cases.

Treatment of EBV-Positive HD

To expand on this successful prevention of EBV-lymphoma in allogeneic stem cell transplant recipients, we decided to apply CTL to a second EBV-associated tumor, HD. Two protocols were designed and approved, one for the treatment of patients who have relapsed after therapy and have active disease and the second as adjuvant therapy for patients who receive autologous BMT as treatment for relapsed disease. EBV-specific CTL lines were activated and expanded in vitro, using the patient-derived EBV-transformed B cell line as antigen-presenting cells. CTLs were derived successfully from 9 of 13 patients, although lines grew more slowly from patients with HD than from normal donors and usually required additional mitogenic stimulation (20).

A drawback to the approach of using LCL as the antigen-presenting cell for the generation of CTL for HD is that these CTL may not contain clones with specificity for the three EBV proteins expressed in Hodgkin's tumor cells. These three, EBNA-1, LMP1, and LMP2, are poorly immunogenic by comparison with EBNAs 3a, 3b, and 3c, which are immunodominant on the majority of HLA backgrounds (2,11). Fig. 3Go shows that CTLs generated by co-culture with LCL contain clones with specificity for a limited range of EBV proteins. If the CTL lines generated from patients with HD contained no clones with specificity for EBNA1, LMP1, or LMP2, then they would have no effect on disease.



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  		Fig. 3. EBV-specific CTLs generated by co-culture with the autologous EBV-transformed B cell line have limited antigen specificity. The specificity of the TU CTL line was tested against the autologous TU LCL and an HLA-mismatched LCL (MM LCL). The antigen specificity was tested using autologous TU fibroblasts that had been infected with vaccinia recombinants expressing the eight known EBV latency-associated proteins that are expressed in LCL. Only fibroblasts expressing EBNAs 3b and 3c are recognized. There is no significant killing of fibroblasts expressing EBNA1, LMP1, or LMP2a.

 
To generate CTL with specificity for the proteins expressed in HD tumor cells from patients in whom these proteins may be poorly immunogenic, we are using DCs to present proteins individually. DCs are the most potent antigen-presenting cells known and have been shown both to induce primary immune responses in vitro and to overcome nonresponsiveness to tumor antigens (21). Since EBNA1 is not processed appropriately for class I recognition (22) and LMP1 is heterogeneous between EBV isolates (23), we have chosen to express LMP2a in DC for stimulation of autologous CTLs, using retrovirus vector containing the LMP2a complementary DNA. As shown in Fig. 4,Go LMP2a-transduced DCs are able to induce autologous CTLs that kill not only autologous fibroblasts expressing LMP2a from a vaccinia virus vector but also the autologous LCL that is a biologic target for EBV. Future studies will assess the efficacy of LMP2a-specific CTL in the treatment of EBV-positive HD.



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  		Fig. 4. CTLs induced by stimulation with autologous dendritic cells transduced with a retrovirus-LMP2a construct kill fibroblasts infected with a vaccinia LMP2a recombinant. Autologous fibroblasts are also killed strongly. HLA-mismatched LCL and fibroblasts infected vaccinia recombinants expressing LMP1 or ß-galactosidase are not killed.

 
In summary, we provide clinical evidence that infusion of EBV-specific CTL provides safe and effective prophylaxis for EBV-associated lymphoproliferative disease in stem cell transplant recipients. CTLs persist for up to 3 years in vivo, they rapidly restore cellular immune responses to EBV, and they reduce high EBV load to nonthreatening levels. As treatment for advanced and rapidly progressive disease, CTL may be less effective and may cause pathology. However, our studies provide good rationale for applying cellular immunotherapy to other cancers with identifiable target antigens.


   Acknowledgments
 
Supported in part by Public Health Service grants CA21765, CA81364, and CA71426 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services; by the Assisi Foundation of Memphis; and by the American Lebanese Syrian Associated Charities.


   References
Top
 Abstract
 Introduction
 Methods
 Results and Discussion
 References
 

1 Rickinson AB, Kieff E. Epstein-Barr virus. In: Fields BN, Knipe DM, Howley PM, editors. Fields virology. Philadelphia: Lippincott-Raven, 1996, pp 2397-446.

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7 Heslop HE, Brenner MK, Rooney CM. Donor T cells to treat EBV-associated lymphoma. N Engl J Med 1994;331:679-80.[Free Full Text]

8 Herbst H, Steinbrecher E, Niedobitek G, Young L, Brooks L, Muller-Lantzsch N, et al. Distribution and phenotype of Epstein-Barr virus-harboring cells in Hodgkin's disease. Blood 1992;80:484-91.[Abstract/Free Full Text]

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11 Khanna R, Burrows SR, Moss DJ. Immune regulation in Epstein-Barr virus-associated diseases. Microbiolog Rev 1995;59:387-405.[Abstract/Free Full Text]

12 Smith CA, Ng CY, Heslop HE, Holladay MS, Richardson S, Turner EV, et al. Production of genetically modified EBV-specific cytotoxic T cells for adoptive transfer to patients at high risk of EBV-associated lymphoproliferative disease. J Hematother 1995;4:73-9.[Medline]

13 Boyle MJ, Sewell WA, Sculley TB, Apolloni A, Turner JJ, Swanson CE, et al. Subtypes of Epstein-Barr virus in human immunodeficiency virus-associated non-Hodgkin lymphoma. Blood 1991;78:3004-11.[Abstract/Free Full Text]

14 Rooney CM, Loftin SK, Holladay MS, Brenner MK, Krance RA, Heslop HE. Early identification of Epstein-Barr virus-associated post-transplant lymphoproliferative disease. Br J Haematol 1995;89:98-103.[Web of Science][Medline]

15 Brenner MK, Rill DR, Holladay MS, Heslop HE, Moen RC, Buschle M, et al. Gene marking to determine whether autologous marrow infusion restores long-term haemopoiesis in cancer patients. Lancet 1993;342: 1134-7.[CrossRef][Web of Science][Medline]

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17 Heslop HE, Brenner MK, Rooney CM, Krance RA, Roberts WM, Rochester R, et al. Administration of neomycin-resistance-gene-marked EBV-specific cytotoxic T lymphocytes to recipients of mismatched-related or phenotypically similar unrelated donor marrow grafts. Hum Gene Ther 1994;5:381-97.[Web of Science][Medline]

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23 Khecht H, Bachmann E, Brousset P, Sandvej K, Nadal D, Bachmann F, et al. Deletions within the LMP1 oncogene of Epstein-Barr virus are clustered in Hodgkin's disease and identical to those observed in nasopharyngeal carcinoma. Blood 1993;82:2937-42.[Abstract/Free Full Text]


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