Chimeric Antigen Receptor (CAR) T-Cell Therapy for Patients with Lung Cancer: Current Perspectives

Abstract

Immunotherapy using chimeric antigen receptor (CAR)-engineered T-cells has achieved unprecedented efficacy in selected hematological cancers. However, solid tumors such as lung cancer impose several additional challenges to the attainment of clinical success using this emerging therapeutic modality. Lung cancer is the biggest cause of cancer-related mortality worldwide, accounting for approximately 1.8 million deaths worldwide each year. Obstacles to the development of CAR T-cell immunotherapy for lung cancer include the selection of safe tumor-selective targets, accounting for the large number of candidates that have been evaluated thus far. Tumor heterogeneity is also a key hurdle, meaning that single target-based approaches are susceptible to therapeutic failure through the emergence of antigen null cancers. There is also a need to enable CAR T-cells to traffic efficiently to sites of disease, to infiltrate tumor deposits and to operate within the hostile tumor microenvironment formed by solid tumors, resisting the onset of exhaustion. Multiple immune, metabolic, physical and chemical barriers operate at the core of malignant lesions, with potential for further heterogeneity and evolution in the face of selective therapeutic pressures. Although the extraordinarily adaptable nature of lung cancers has recently been unmasked, immunotherapy using immune checkpoint blockade can achieve long-term disease control in a small number of patients, establishing clinical proof of concept that immunotherapies can control advanced lung carcinomas. This review summarizes pre-clinical CAR T-cell research that is specifically focused on lung cancer in addition to published and ongoing clinical trial activity. A number of advanced engineering strategies are also described which are designed to bridge the gap to the attainment of meaningful efficacy using genetically engineered T-cells.

Challenges and considerations in the immunotherapy of DLL3-positive small-cell lung cancer using IL-18 armoured chimeric antigen receptor T-cells

“…Second-generation (2G) CAR designs incorporated one co-stimulatory domain to augment and sustain T-cell activation, most notably CD28-CD3ζ and 4-1BB-CD3ζ. Building upon these advancements, third-generation CARs further refined this architecture by integrating multiple co-stimulatory domains ( 1 ). Given this extensive development, immunotherapy using CAR-engineered T-cells has achieved remarkable success in treating haematological malignancies.…”

“…Given this extensive development, immunotherapy using CAR-engineered T-cells has achieved remarkable success in treating haematological malignancies. However, effectiveness in combating solid tumours such as small-cell lung cancer (SCLC) has been notably limited thus far ( 1 ). SCLC represents approximately 15% of lung cancers and is characterized by a rapid rate of proliferation, a strong propensity for early metastasis, and an unfavourable prognosis ( 2 ).…”

“…Delta-like ligand 3 (DLL3) is an inhibitory Notch ligand which has emerged as an attractive tumour-specific target that is overexpressed on the cell surface of SCLC cells ( 10 ). By contrast, expression in normal tissues is largely restricted to intracellular membranes, most notably the Golgi apparatus ( 1 ). Various strategies for targeting DLL3 are currently under investigation, both in the pre-clinical and clinical settings.…”

The role of CD4+ CAR T cells in cancer immunotherapy

“…Additionally, highly impressive efficacy has recently been reported in patients with the paediatric solid tumour, neuroblastoma ( 2 ). Nonetheless, common adult cancer types such as lung cancer largely remain stubbornly resistant to CAR T cell immunotherapy ( 3 , 4 ). To address this, it is widely acknowledged that there is a need for more effective CAR T cell trafficking and infiltration of solid tumours, selection of more tumour specific targets, improved CAR T cell persistence, enhanced performance within the immunosuppressive tumour microenvironment (TME) and prevention of life-threatening CAR T cell-associated toxicities ( 3 ).…”