Cellular-based immunotherapy in Epstein-Barr virus induced nasopharyngeal cancer

Highlights

• Up to 20% NPC patients developed relapse following definitive chemo-radiotherapy.

• Presence of EBV-associated tumor antigens allows potential targeting using CBI.

• CBI reported enhanced EBV-specific antitumor immune response with some benefit.

• Immune priming via CBI may diminish previous acquired resistance to failed therapy.

• Developments of novel CBI with combination therapy may improve cancer outcomes.

Abstract

Undifferentiated Nasopharyngeal carcinoma (NPC) is ubiquitously identified with the Epstein-Barr virus (EBV), making this cancer a suitable candidate for cellular-based immunotherapy (CBI) due to its expression of potentially targetable tumor-associated viral antigens. Various preclinical and clinical studies have explored the use of cytotoxic T cells (CTLs), tumor-infiltrating lymphocytes (TILs), natural killer (NK) cells, and dendritic cells (DCs) in the treatment of both refractory and locally advanced NPC with some success. Notably, immune-mediated antitumor effects were observed even in heavily pre-treated NPC patients, suggesting potential clinical benefit of CBI in this group of patients. These immune anti-tumor effects may be even more clinically evident when used as a first-line treatment, since there may not be an intense immunosuppressive environment which is typically encountered in refractory cancer patients. Additionally, CBI may exert an effect in priming the immune system and diminishing the cancer’s acquired resistance to exert a more robust response to previously failed chemotherapy. Although these results are encouraging, further refinements of clinical protocols to boost anti-tumor response and benefit a larger subset of patients proved necessary. Herein, we aim to review the rational of developing CBI in EBV-induced NPC and summarize its current applications in clinical studies.

Introduction

Nasopharyngeal carcinoma (NPC) occurs worldwide with approximately 87,000 incident cases and 51,000 deaths annually, representing about 0.7% of the global cancer burden [1]. A distinct racial and geographical variation is evident with a higher incidence rate in both southern China and Southeast Asia. This geographic predisposition is suggestive of both genetic and environmental risk factors in its pathogenesis. For instance, several at risk HLA genes such as the HLA-A subtype; and exposure to nitrosamines and nitrosamine precursors in the diet have been reported as risk factors of developing NPC. [2], [3], [4]. Polymorphisms in certain genes, such as CYP2E1, XRCC1, and hOGG1, have also been associated with an altered risk of developing NPC [5], [6]. For instance, CYP2E1 belongs to the cytochrome P450 family and is involved in the metabolic activation of nitrosamines and other pro-carcinogens into reactive intermediates capable of inducing DNA damage. Polymorphisms in CYP2E1, particularly the c2 variant (present in 20–25% of Asians as compared to less than 10% of Caucasians), results in a polymorphic base substitution which up-regulates CYP2E1 expression [5]. Conversely, XRCC1 and hOGG1 are DNA repair genes which play a role in the base excision repair (BER) pathway, and polymorphic variants of both XRCC1 (codon 194, 280 and 399) and hOGG1 (codon 326) have demonstrated decreased capacity for repair of DNA damage caused by nitrosamine compounds and oxidative stress [6], [7], [8]. Taken together, an individual with polymorphism in all three genes may succumb to greater DNA damage, thus increasing the risk of developing NPC.

Due to its radiosensitive nature, radiotherapy is the primary treatment modality for all stages of non-metastatic NPC; with concurrent chemo-radiotherapy being administered for locally advanced cases. This treatment paradigm attained more than 85% chance of loco-regional control and 80% survival [9], [10]. Despite positive clinical outcomes, a significant number of patients developed local regional failure (approximately 18%) or distant metastasis (approximately 17%), necessitating new treatment paradigms in this cancer [11]. Additionally, the close anatomical proximity of the nasopharynx to several critical structures including the brainstem, optic nerves, inner ears, and temporomandibular joint, precluded surgical salvage or radical re-radiation since severe radiation associated adverse effects like temporal lobe brain necrosis or carotid blow-out syndrome can occur [12], [13]. Therefore, there is a critical need for novel treatment modalities so as to minimize treatment-associated complications and to improve current survival rates in this cancer.