Examining the Potential of CAR-T Cell Therapy in Lung Cancer

In a new review published in Thoracic Cancer, researchers outlined common tumor-associated antigens (TAA) in clinical trials of chimeric antigen receptor-modified T (CAR-T) cell therapy for lung cancer to help identify new approaches to pre-clinical experiments and clinical trials for this patient population.

Currently, over 90% of lung cancer cases are diagnosed at an advanced stage with 5-year survival estimated at 10% to 20%. The combination of surgical resection and adjuvant therapy remains the main treatment strategy for the disease; however “only 20% of patients are suitable for surgery, and 80% of patients experience recurrence and eventually die after surgery,” authors wrote.

Although immunotherapy and the use of monoclonal-antibody targeted drugs for lung cancer have gained popularity in recent years, these treatments have limitations, providing a window of opportunity for CAR-T cell therapy.

In addition, CAR-T cell therapy has proven beneficial in drug-resistant B-cell malignancies and relapsed and refractory acute B-lymphocytic leukemia.

“CAR-T cells are genetically engineered to isolate the patient's T cells outside the body and expressed single-chain antibodies that specifically recognize and bind to antigens (e.g., CD19) on cancer cells,” researchers explained.

Depending on their intracellular signaling structural domains, CAR-T cells are classified into 5 generations. Specific co-stimulatory molecules account for the main differences between generations. The safety and efficacy of 5th generation CARs are currently under investigation, while the 2nd generation CAR-T is the most widely used and offers more stable effects.

It is difficult to select the optimal TAA for CAR-T cells in solid tumors but based on past clinical trials, researchers identified a list that includes: epidermal growth factor receptor (EGFR); mesothelin (MSLN); mucin 1 (MUC 1); inactive tyrosine-protein kinase transmembrane receptor (ROR1); carcinoembryonic antigen (CEA); human epidermal growth factor receptor 2 (HER2); programmed death-ligand 1 (PD-L1); and B7-H3, among others.

EGFR belongs to a family of tyrosine kinases associated with tumor angiogenesis, metastasis and recurrence, while its expression has been shown to be upregulated in the tissue of patients with non-small cell lung cancer (NSCLC). MSLN overexpression has been positively correlated with high tumor aggressiveness and poor prognosis in patients with lung cancer.

“Previous studies have confirmed that the expression of MUC1 was significantly higher in lung cancer tissues than in normal lung tissues,” authors noted. One study has also showed treatment with anti-ROR1 CAR-T cells can effectively kill NSCLC cells in a 3-dimensional tumor model.

Despite these and numerous other studies pointing to the potential benefits of targeting additional TAA, the study of CAR-T cell therapy for lung cancer is generally still in an early exploration stage.

Additional challenges are present in this patient population including on-target/off-tumor toxicity, TAA heterogeneity, immunosuppressive tumor microenvironment (TME), neurological toxicity, and cytokine release syndrome.

Taking the heterogeneity of malignant solid tumors and limitations of preclinical experiments into account, researchers suggested caution when determining the clinical applications of CAR-T cells for solid tumors.

They recommend:

• Finding more stably expressed and specific target antigens
• Modifying the structure of CAR to enhance the efficacy, specificity, and survival time of CAR-T cells
• Reducing the toxicity of CAR-T cells
• Optimizing CAR-T cells that target the TME of lung cancer
• Exploring combination therapies, such as combining immune checkpoint inhibitors, PD-1 inhibitors, or dual-CAR-T
• Establishing natural ligand-receptor-based CAR-T cells

“Although research on CAR-T cell immunotherapy against solid tumors is still in its infancy, the beneficial results of preliminary trials provide a theoretical foundation for their application in the subsequent clinical treatment of solid tumors,” authors wrote.

“With the continuous innovation of CAR-T design ideas and treatment protocols, CAR-T cell immunotherapy is expected to become a major “tool” for lung cancer treatment,” they concluded.

Reference

Chen L, Chen F, Li J, et al CAR-T cell therapy for lung cancer: potential and perspective. Thorac Cancer. Published online March 15, 2022. doi:10.1111/1759-7714.14375