Revolutionizing the treatment for nasopharyngeal cancer: the impact, challenges and strategies of stem cell and genetically engineered cell therapies

Abstract

Nasopharyngeal carcinoma (NPC) is a distinct malignancy of the nasopharynx and is consistently associated with the Epstein-Barr virus (EBV) infection. Its unique anatomical location and complex aetiology often result in advanced-stage disease at first diagnosis. While radiotherapy (RT) and chemotherapy have been the mainstays of treatment, they often fail to prevent tumour recurrence and metastasis, leading to high rates of treatment failure and mortality. Recent advancement in cell-based therapies, such as chimeric antigen receptor (CAR)-T cell therapy, have shown great promise in hematological malignancies and are now being investigated for NPC. However, challenges such as targeting specific tumour antigens, limited T cell persistence and proliferation, and managing treatment-related toxicities must be addressed. Extensive research is needed to enhance the effectiveness and safety of these therapies, paving the way for their integration into standard clinical practice for better management of NPC and a better quality of life for human health.

Keywords: chimeric antigen receptor (CAR)-T cell; engineered T cell receptor-T (TCR-T) cell; nasopharyngeal carcinoma; natural killer (Nk) cell; stem cell; tumour-infiltrating lymphocytes (TIL).

Figure 1

Chimeric antigen receptor (CAR) structure and its evolution from first to fifth generation. The first-generation of CARs consists of an antigen-binding domain, typically a single-chain variable fragment (scFv), followed by a hinge, a transmembrane domain, and an intracellular region, commonly the T cell receptor (TCR) signalling component CD3ζ. In the second and third CAR generations, one or two co-stimulatory domains are added, respectively, enhancing T cell activation and proliferation. Fourth-generation CARs, also known as T cell redirected for universal cytokine-mediated killing (TRUCKs), combine a second-generation CAR construct with additional functional elements, such as cytokine secretion modules. These modules enable CAR-engineered cells to secrete cytokines such as IL-12, which recruit immune cells to the tumour microenvironment (TME) upon antigen recognition, enhancing antitumour activity. The fifth-generation CAR-T cells, also referred to as the next generation, contain a truncated IL-2 receptor β (IL-2Rβ)-chain domain with a motif for binding transcription factors such as STAT3. This can lead to JAK/STAT activation and subsequent cytotoxic responses.

Figure 2

Chimeric antigen receptor (CAR)-T challenges in solid tumours. CAR-T cell immunotherapy has emerged as a promising therapeutic strategy for haematological malignancies, but its application in solid tumours presents several challenges and limitations that need to be addressed. Firstly, the heterogenous nature of tumour cells results in various genetic mutations and antigen expression patterns, making it difficult for CAR-T cells to effectively target all tumour cells. Additionally, tumour cells may undergo antigen escape, where they downregulate or lose the target antigen recognised by the CAR-T cells, allowing them to evade immune detection and destruction. Secondly, the clinical efficacy of CAR-T cell therapy is limited by the inability of CAR-T cells to traffic and infiltrate the tumour due to increased extracellular matrix (ECM) density and abnormal vasculature, ultimately hindering CAR-T cell diffusion and expansion. Thirdly, solid tumours often harbour a complex and highly immunosuppressive microenvironment, which can compromise the effectiveness of CAR-T cell therapy by dampening the immune response and promoting tumour growth. Moreover, higher surface expression of immune checkpoint molecules such as programmed death 1 (PD-1) on CAR-T cells can induce an exhausted phenotype, characterised by reduced cytokine production, proliferation, and cytotoxicity, limiting their capacity to control tumour growth. Lastly, CAR-T cells targeting tumour cells can induce the release of cytokines such as interferon (IFN)-γ and tumour necrosis factor (TNF)-α, activating other immune cells including dendritic cells (DCs), natural killer (NK) cells, monocytes, macrophages, and T cells. These cells further release pro-inflammatory cytokines, triggering a cascade reaction and ultimately contributing to the onset of cytokine release syndrome (CRS), a potentially severe and systemic inflammatory response.