In this issue

Director's Corner by David G. Poplack, M.D.

New Therapies in Pediatric Cancer
by Stacey Berg, M.D.

Ependymoma: A Review
by Patricia Baxter, M.D. and Murali Chintagumpala, M.D.

HIV-Related Malignancies
by Parth Mehta, M.D. and Brigitta U. Mueller, M.D.

Nasopharyngeal Carcinoma
by Chrystal U. Louis, M.D., M.P.H., Helen E. Heslop, M.D. and Stephen Gottschalk, M.D.
 

The annual incidence of nasopharyngeal carcinoma (NPC) varies from 50 per 100,000 in southern China, Southeast Asia, and the Mediterranean basin to 1 per 100,000 in the rest of the world. Although NPC is a rare form of childhood cancer in the United States and Europe, it accounts for approximately 40 percent to 50 percent of childhood malignancies in the nasopharynx.^1,2

Pathogenesis
NPC arises from the epithelial cells of the nasopharynx and almost all nonkeratinizing and undifferentiated forms of this tumor are associated with Epstein-Barr virus (EBV).³ Besides EBV, genetic as well as environmental factors play an important role in the pathogenesis of NPC. For example, many tumors have somatic chromosome deletions resulting in loss of tumor suppressor genes, and in endemic areas first-degree relatives of NPC patients have an increased risk of developing NPC, highlighting the contribution of genetic risk factors. Environmental factors also play a role, including the consumption of salted fish and Chinese herbs.^1,2

Clinical Presentation
The most common clinical presentation of NPC is a painless mass in the upper neck, followed by signs and symptoms of nasal obstruction, hearing loss and headache. In addition, patients may present with dysphagia or signs of nerve compression including ptosis, vision loss, and taste abnormalities. Differential diagnoses include upper respiratory tract infection and other malignancies including lymphomas, brain tumors and rhabdomyosarcoma.

Screening, Diagnosis and Staging
In endemic NPC areas like Southeast Asia mass screening is an attractive option to diagnose patients with early stage disease, resulting in improved treatment outcome. Most screening strategies take advantage of the presence of EBV in the malignant NPC cells and measure the immune response to EBV antigen and/or the EBV-DNA load in the peripheral blood of patients.^4,5 While these screening tests might also assist in the diagnosis of NPC, at present a tumor biopsy is considered standard of care to confirm the diagnosis. Once the diagnosis is established, patients require a thorough diagnostic work up, including Magnetic Resonance Imaging (MRI), Computed Tomogram (CT) and bone scan, to determine the extend of the disease.² This is critical since disease status determines treatment and outcome. The use of Positron Emission Tomography (PET) has shown promise to follow disease status and response to therapy, however its role in staging has to be determined in future studies.

Standard Therapy and Outcome
In general, NPC is considered an unresectable tumor, due to its complex anatomical location. NPC is a very radiosensitive tumor and radiotherapy has been used as a single agent for patients with confined primary lesions with excellent outcomes. However, the majority of patients who present with locally advanced disease relapse after radiation therapy. To reduce the risk of recurrence over the last two decades treatment regimens have been successfully developed that combine chemotherapy and radiation.^1,2,6 As in adults, current treatment strategies for pediatric NPC patients with locally-advanced disease include platinum-based chemotherapy and high-dose radiation therapy resulting in overall survival rates of greater 70 percent.⁷ However, long-term survivors suffer from an array of complications including hypothyroidism, xerostomia, dental disease, and hearing loss.^8,9 Thus, current efforts to reduce side effects of conventional therapies are focused on using intensity modulated radiotherapy (IMRT) and cytoprotective agents such as amifostine.

Patients with recurrent disease often present with metastatic disease and the outcome for this patient population remains poor. New targeted therapies are therefore needed that could improve disease-free survival for patients with metatstatic disease and that might ultimately reduce the incidence of long-term treatment-related complications in all patients. Immunotherapies hold the promise of fulfilling both of these needs and several groups, including ours, are actively developing immunotherapies for NPC that target the EBV antigens expressed in NPC tumors.

Immunotherapies for NPC
The strong association of NPC with EBV makes immunotherapy targeting EBV antigens an attractive therapeutic option. Although EBV-positive NPC cells do not express immunodominant EBV antigens, expression of the subdominant EBV antigens LMP1 and/or LMP2 provides target antigens for EBV-specific cytotoxic T cells (CTL).¹⁰ In addition, NPC cells express the EBV antigens EBNA1, which is recognized by non-cytotoxic EBV-specific T cells (helper T cells). Since NPC patients have T cells specific for LMP2, EBNA1, and to lesser extent for LMP1 in their peripheral blood, immunotherapeutic approaches are currently focused on activating and expanding these specific T-cell responses.

A dendritic cell LMP2 vaccine has been evaluated in 16 NPC patients and was shown to be safe, but the antitumor activity was limited.¹¹ At present a group of researchers in England and Hong Kong are testing a vaccinia virus based vaccine that targets EBNA1 and LMP2. Another strategy to enhance the immune response to EBV is the use of T-cell therapies. T-cell therapies for malignancies consist of taking blood from patients, activating and expanding antigen-specific T cells in the laboratory, and infusing the T cells back into the patient. Our group has pioneered this strategy to prevent and treat EBV-positive malignancies post stem cell transplantation with EBV-specific CTL, and more recently for EBV-positive lymphomas and NPC.^12-14 So far three groups of investigators have reported on the use of EBV-specific CTL for the adoptive immunotherapy of patients with recurrent/refractory NPC.^14-16 We have evaluated the safety and efficacy of EBV-specific CTL in two Phase I clinical trials and have treated a total of 33 patients with advanced-stage NPC. Prior to CTL infusion transfer, eight patients were in remission, 23 had active disease, and two had abnormal imaging studies of unknown significance. Seven of eight patients in remission remain in remission 6 to 64 months post CTL infusion. For the remaining 25 patients, the best overall response rate was 50 percent with six complete responses, which have been sustained for 2 to 4 years in four patients, while 2 patients relapsed more than 2 years post CTL.^14,17 We are currently devising strategies to improve the anti-NPC activity of infused EBV-specific CTL and are conducting 2 Phase I clinical studies at our center in which a T-cell product is infused that has an increased frequency of T cells that are specific for the LMP1 and LMP2 antigens expressed in NPC. In preclinical models, we are also actively pursuing genetic approaches to increase the anti-tumor activity of infused EBV-specific T cells.¹⁸

Conclusions
NPC is a rare pediatric tumor and almost all tumors are EBV positive. NPC has been a very instructive model on how viruses, the environment and genetic factors interact in contributing to the malignant transformation of normal cells. Patient with limited local disease have an excellent outcome with combined radiation and chemotherapy, however the prognosis for patients with metastatic/recurrent disease remains poor. Immunotherapies for NPC are being developed that target EBV antigens and initial clinical results are encouraging. While current immunotherapies are reserved for patients who fail conventional therapies, immunotherapies have the potential of being incorporated into front line therapy in the future. If successful, such an approach could be adapted to other pediatric malignancies for which tumor antigens have been identified.
 

About the Authors

Chrystal U. Louis, M.D., M.P.H., is an instructor of Pediatrics at Baylor College of Medicine and completed her fellowship at the Texas Children’s Cancer Center in June 2007. She is a member of the Bone Marrow Transplant and Solid Tumor Teams and her research interests are in the area of immunotherapy for solid tumors.

Stephen Gottschalk, M.D., is an associate professor of Pediatrics at Baylor College of Medicine and completed his fellowship at the Texas Children’s Cancer Center in June 2001 He is a member of the Bone Marrow Transplant and Neuro-Oncology Teams and his research interests are in the area of immunotherapy for solid tumors and brain tumors.

Helen E Heslop, M.D., is a professor of Pediatrics, Medicine and Center for Cell and Gene Therapy at Baylor College of Medicine and serves as Director of the Adult Bone Marrow and Stem Cell Transplant Program, Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital. Dr. Heslop’s research interests are in the area of adoptive immunotherapy for viral infections and cancer.

References

1. Chan,A.T., Teo,P.M. & Huang,D.P. Pathogenesis and treatment of nasopharyngeal carcinoma. Semin. Oncol. 31, 794-801 (2004).
2. Ayan,I., Kaytan,E. & Ayan,N. Childhood nasopharyngeal carcinoma: from biology to treatment. Lancet Oncol 4, 13-21 (2003).
3. Raab-Traub,N. Epstein-Barr virus in the pathogenesis of NPC. Semin. Cancer Biol. 12, 431-441 (2002).
4. Chien,Y.C. et al. Serologic markers of Epstein-Barr virus infection and nasopharyngeal carcinoma in Taiwanese men. N Engl J Med 345, 1877-1882 (2001).
5. Chan,K.C. & Lo,Y.M. Circulating EBV DNA as a tumor marker for nasopharyngeal carcinoma. Semin. Cancer Biol. 12, 489-496 (2002).
6. Mould,R.F. & Tai,T.H. Nasopharyngeal carcinoma: treatments and outcomes in the 20th century. Br J Radiol. 75, 307-339 (2002).
7. Polychronopoulou,S. et al. Nasopharyngeal carcinoma in childhood and adolescence: a single institution's experience with treatment modalities during the last 15 years. Pediatr Hematol Oncol 21, 393-402 (2004).
8. Louis,C.U. et al. A Single Institution Experience With Pediatric Nasopharyngeal Carcinoma: High Incidence of Toxicity Associated With Platinum-based Chemotherapy Plus IMRT. J. Pediatr. Hematol. Oncol. 29, 500-505 (2007).
9. Mertens,R. et al. Treatment of nasopharyngeal carcinoma in children and adolescents: definitive results of a multicenter study (NPC-91-GPOH). Cancer 104, 1083-1089 (2005).
10. Hislop,A.D., Taylor,G.S., Sauce,D. & Rickinson,A.B. Cellular responses to viral infection in humans: lessons from Epstein-Barr virus. Annu. Rev. Immunol. 25, 587-617 (2007).
11. Lin,C.L. 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 62, 6952-6958 (2002).
12. Rooney,C.M. et al. Infusion of cytotoxic T cells for the prevention and treatment of Epstein-Barr virus-induced lymphoma in allogeneic transplant recipients. Blood 92, 1549-1555 (1998).
13. Bollard,C.M. et al. Cytotoxic T Lymphocyte Therapy for Epstein-Barr Virus+ Hodgkin's Disease. J. Exp. Med. 200, 1623-1633 (2004).
14. Straathof,K.C. et al. Treatment of Nasopharyngeal Carcinoma with Epstein-Barr Virus-specific T Lymphocytes. Blood 105, 1898-1904 (2005).
15. Chua,D. et al. Adoptive transfer of autologous Epstein-Barr virus-specific cytotoxic T cells for nasopharyngeal carcinoma. Int. J Cancer 94, 73-80 (2001).
16. Comoli,P. et al. Cell therapy of stage IV nasopharyngeal carcinoma with autologous Epstein-Barr virus-targeted cytotoxic T lymphocytes. J. Clin. Oncol. 23, 8942-8949 (2005).
17. Louis,C.U. et al. Treatment of Epstein Barr Virus-positive Nasopharyngeal Carcinoma with adoptively transferred cytotoxic T cells. 97th AACR Annual Meeting Abstract 4000 (2006).
18. Dotti,G. et al. Human cytotoxic T lymphocytes with reduced sensitivity to Fas-induced apoptosis. Blood 105, 4677-4684 (2005).