Cytotoxic T Cell Adoptive Immunotherapy as a Treatment for Nasopharyngeal Carcinoma

Abstract

c Epstein-Barr virus (EBV) is associated with nasopharyngeal carcinoma (NPC). We assess the safety and tolerability of adoptive transfer of autologous cytotoxic T lymphocytes (CTLs) specific for the EBV latent membrane protein (LMP) in a patient with recurrent NPC. After infusion, the majority of pulmonary lesions were no longer evident, although the primary tumor did not regress. CASE REPORT In 2002, a middle-aged man (42 years old) was diagnosed with stage IV (T4 N2c M1) Epstein-Barr virus (EBV)-positive undifferentiated carcinoma with all of the pathological characteristics of nasopharyngeal carcinoma (NPC). This NPC patient (HLA A11, B60, B62) presented with multiple pulmonary metastases. He underwent a course of chemotherapy (3 cycles of induction cisplatin and fluorouracil [5FU]) and high-dose palliative radiotherapy to the nasopharynx and upper (60 Gy in 30 fractions over 6 weeks) and lower (50 Gy) cervical nodes, followed by 3 more cycles of cisplatin and 5FU. This treatment resulted in a complete radiological regression of pulmonary metastases and partial regression of NPC at the primary site. Three years later, the pulmonary metastases became radiologically apparent again and were treated with six cycles of carboplatin and 5FU. Following this, six cycles of gemcitabine were administered. In each case, while a complete regression of the lung metastases was seen, the lesion subsequently recurred, prompting a further nine cycles of gemcitabine. However, despite this, his disease progressed, suggesting resistance to gemcitabine. Carboplatin was added for another nine cycles in late 2006; radiological evidence demonstrated disease progression and resistance to chemotherapy.In September 2007, the patient commenced adoptive immunotherapy, for which he received six infusions (on a fortnightly basis, during a 3-month period) of autologous EBV-specific cytotoxic T lymphocytes (CTLs) directed toward the latent membrane protein (LMP) of this virus (1). This treatment resulted in regression of the majority of pulmonary metastases. To generate these LMP-specific cells, autologous peripheral blood mononuclear cells (PBMCs) were screened for reactivity to two different HLAcompatible LMP 1-and 2-specific CTL epitopes. A response against the LMP 2 peptide epitope SSCSSCPLSK (SSC) (1) was detected in this patient. Subsequently, autologous PBMCs were stimulated with SSC-coated autologous lymphoblastoid cell lines (LCLs) and expanded to yield large numbers of LMP-specific CTL cultures (see the legend to Fig. 1 for details). These cultures were screened for specificity by 51 Cr release assays and for phenotype by flow cytometry after 21 days. In the functional 51 Cr release studies, a single LMP 2 response to the HLA A11-restricted peptide (SSC) was detected (2), as measured by specific 51 Cr release of autologous phytohemagglutinin (PHA) target cells coated with SSC or another LMP-specific peptide epitope, IEDPPFNSL (IED) (Fig. 1) (1). Flow cytometry revealed that these patient-derived CTLs contained a high percentage o...

Therapeutic vaccine targeting Epstein-Barr virus latent protein, LMP1, suppresses LMP1-expressing tumor growth and metastasis in vivo

“…The fact that EBV-specific CTL from peripheral blood of NPC patients can be reactivated ex vivo brings up a trend of adoptive autologous CTL therapy [6, 28]. Although adoptive CTL therapy in NPC gained effectiveness in phase II clinical trial [28], the specificity of CTLs activated by EBV-transformed lymphoblastoid cell lines (LCLs) are still under evaluation.…”

“…The strong association of NPC with EBV makes viral antigen-targeted immunotherapy an attractive treatment modality [5]. Adoptive transfer of autologous EBV-specific CTL has proven effective in metastatic or locally recurrent NPC patients [6]. Meanwhile, efficacies of DNA vaccines carrying various combination of EBV antigens are also under evaluation [7–9].…”

Adoptive Therapy for EBV-Induced Cancers: Driving Success with Post-Transplant Lymphoproliferative Disorder to Other EBV-Derived Tumors

“…The most straightforward approach has used defined HLA-restricted synthetic peptide epitopes to generate CTL either using a single stimulation with peptide or following repeated stimulation with peptide coated LCL [59]. In Phase I clinical studies this approach has shown some evidence of disease regression with a recent case report demonstrating clearance of pulmonary lesions following CTL infusion, although no impact on the primary tumor was detectable [60]. To broaden the HLA coverage in these targeted approaches other clinical studies have employed recombinant vectors to deliver either whole antigen or polyepitope constructs designed to provide broad HLA coverage while restricting the potential risks associated with the oncogenicity of the LMP antigens [61,62].…”

Cytotoxic T cells and Cancer Therapy

“…Moreover, when the plasma samples of the patients have been collected a peak in the EBV DNA have been observed which is the proof of the fact that the NPC cells have undergone lysis by the action of these infused CTLs. It is also interesting to note that there is possibility that the CTLs have better access to lungs when infused (Abbas et al, 2007;Kenter et al, 2008;Kenter et al, 2009;Lutzky et al, 2014).…”