T-cell therapy for EBV-associated nasopharyngeal carcinoma: preparative lymphodepleting chemotherapy does not improve clinical results.

BACKGROUND We and others have demonstrated that adoptive cell therapy with Epstein-Barr virus (EBV)-specific autologous cytotoxic T lymphocytes (CTLs) may control disease progression in patients with EBV-associated nasopharyngeal carcinoma (NPC). With the aim of favoring in vivo T-cell expansion, we optimized our cell therapy approach by administering higher doses of EBV-specific CTLs, following lymphodepleting chemotherapy. PATIENTS AND METHODS Eleven patients with EBV-related NPC in whom conventional treatment failed have been enrolled. Patients received nonmyeloablative lymphodepleting chemotherapy consisting of cyclophosphamide and fludarabine. Two doses of autologous EBV-specific CTLs were subsequently infused, 2 weeks apart. Study end points were feasibility and clinical outcome. RESULTS All patients enrolled completed the treatment and were assessable for analysis. The median dose of CTLs per infusion was 3.7 × 10(8). Therapy was well tolerated, with no severe adverse events ascribable to either chemotherapy or cell therapy. Disease control (defined as either tumor regression or disease stabilization lasting >4 months) was obtained in 6 of 11 patients, in keeping with previously published results. CONCLUSIONS Our data confirm that EBV-specific CTL therapy is safe and associated with antitumor activity in patients with advanced NPC. The use of lymphodepleting chemotherapy before high-dose CTL infusion did not enhance the clinical benefit observed in our previous series.

[1]  C. Rooney,et al.  Treatment of Epstein–Barr Virus Infections: Chemotherapy, Antiviral Therapy, and Immunotherapy , 2013 .

[2]  H. Heslop,et al.  Enhancing the in vivo expansion of adoptively transferred EBV-specific CTL with lymphodepleting CD45 monoclonal antibodies in NPC patients. , 2009, Blood.

[3]  E. Felip,et al.  Nasopharyngeal cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. , 2008, Annals of oncology : official journal of the European Society for Medical Oncology.

[4]  S. Rosenberg,et al.  Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[5]  F. Baldanti,et al.  Kinetics of Epstein-Barr Virus DNA Load in Different Blood Compartments of Pediatric Recipients of T-Cell-Depleted HLA-Haploidentical Stem Cell Transplantation , 2008, Journal of Clinical Microbiology.

[6]  Jianhong Cao,et al.  Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. , 2008, The New England journal of medicine.

[7]  S. Rosenberg,et al.  Adoptive cell transfer: a clinical path to effective cancer immunotherapy , 2008, Nature Reviews Cancer.

[8]  F. Marincola,et al.  Tumour immunity: effector response to tumour and role of the microenvironment , 2008, The Lancet.

[9]  Chung-Che Chang,et al.  Complete responses of relapsed lymphoma following genetic modification of tumor-antigen presenting cells and T-lymphocyte transfer. , 2007, Blood.

[10]  Yang Zhang,et al.  Phase II clinical study of gemcitabine in the treatment of patients with advanced nasopharyngeal carcinoma after the failure of platinum-based chemotherapy , 2007, Cancer Chemotherapy and Pharmacology.

[11]  Franco Locatelli,et al.  Cell therapy of stage IV nasopharyngeal carcinoma with autologous Epstein-Barr virus-targeted cytotoxic T lymphocytes. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  G. Botti,et al.  Treatment of EBV‐Related Post‐Renal Transplant Lymphoproliferative Disease with a Tailored Regimen Including EBV‐Specific T Cells , 2005, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[13]  S. Rosenberg,et al.  Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  Adrian P Gee,et al.  Treatment of nasopharyngeal carcinoma with Epstein-Barr virus--specific T lymphocytes. , 2005, Blood.

[15]  C. Thng,et al.  Paclitaxel, carboplatin, and gemcitabine in metastatic nasopharyngeal carcinoma , 2005, Cancer.

[16]  K. Knutson,et al.  Adoptive T cell therapy of solid cancers , 2005, Cancer Immunology, Immunotherapy.

[17]  J. Berkhof,et al.  The additional value of chemotherapy to radiotherapy in locally advanced nasopharyngeal carcinoma: a meta-analysis of the published literature. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  George Coukos,et al.  Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival , 2004, Nature Medicine.

[19]  P. Kourilsky,et al.  Foxp3 Expressing CD4+CD25high Regulatory T Cells Are Overrepresented in Human Metastatic Melanoma Lymph Nodes and Inhibit the Function of Infiltrating T Cells1 , 2004, The Journal of Immunology.

[20]  Yau-Huei Wei,et al.  Quantification of plasma Epstein-Barr virus DNA in patients with advanced nasopharyngeal carcinoma. , 2004, The New England journal of medicine.

[21]  A. Garden,et al.  A Phase II study of docetaxel and carboplatin as neoadjuvant therapy for nasopharyngeal carcinoma with early T status and advanced N status , 2004, Cancer.

[22]  P. Pedrazzoli,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. , 2004, Annals of oncology : official journal of the European Society for Medical Oncology.

[23]  A. Davis,et al.  Generating CTLs against the subdominant Epstein-Barr virus LMP1 antigen for the adoptive immunotherapy of EBV-associated malignancies. , 2003, Blood.

[24]  J. Thompson,et al.  Adoptive T cell therapy using antigen-specific CD8+ T cell clones for the treatment of patients with metastatic melanoma: In vivo persistence, migration, and antitumor effect of transferred T cells , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[25]  H. Heslop,et al.  Adenoviral gene transfer into dendritic cells efficiently amplifies the immune response to LMP2A antigen: A potential treatment strategy for Epstein‐Barr virus–positive Hodgkin's lymphoma , 2001, International journal of cancer.

[26]  D. Chua,et al.  A phase II study of ifosfamide, 5-fluorouracil and leucovorin in patients with recurrent nasopharyngeal carcinoma previously treated with platinum chemotherapy. , 2000, European journal of cancer.

[27]  J. Armand,et al.  Long-term disease-free survivors in metastatic undifferentiated carcinoma of nasopharyngeal type. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[28]  M. van Glabbeke,et al.  New guidelines to evaluate the response to treatment in solid tumors , 2000, Journal of the National Cancer Institute.

[29]  M Van Glabbeke,et al.  New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. , 2000, Journal of the National Cancer Institute.

[30]  Simon C Watkins,et al.  Dendritic Cells Transduced with an Adenovirus Vector Encoding Epstein-Barr Virus Latent Membrane Protein 2B: a New Modality for Vaccination , 1999, Journal of Virology.

[31]  J. Armand,et al.  Phase II trial of chemotherapy with 5‐fluorouracil, bleomycin, epirubicin, and cisplatin for patients with locally advanced, metastatic, or recurrent undifferentiated carcinoma of the nasopharyngeal type , 1999, Cancer.

[32]  D. Srivastava,et al.  Infusion of cytotoxic T cells for the prevention and treatment of Epstein-Barr virus-induced lymphoma in allogeneic transplant recipients. , 1998, Blood.

[33]  R. Krance,et al.  Use of gene-modified virus-specific T lymphocytes to control Epstein-Barr-virus-related lymphoproliferation , 1995, The Lancet.

[34]  P. Ang,et al.  A phase II trial of 5-fluorouracil and cisplatinum in recurrent or metastatic nasopharyngeal carcinoma. , 1994, Annals of oncology : official journal of the European Society for Medical Oncology.

[35]  R. Weber,et al.  Effectiveness of combined induction chemotherapy and radiotherapy in advanced nasopharyngeal carcinoma. , 1993, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[36]  U. Nater,et al.  Epstein-Barr virus. , 1991, The Journal of family practice.

[37]  Pelayo Vilar,et al.  Nasopharyngeal Carcinoma , 1966 .

[38]  Ch'en Ch'in-Ts'ai,et al.  NASOPHARYNGEAL CARCINOMA , 1959 .