Application of Lifileucel in Advanced Non-Small Cell Lung Cancer Patients Resistant to Immune Checkpoint Inhibitors

This article, authored by Adam J. Schoenfeld and numerous other top scholars, was published in the 2024 edition of Cancer Discovery. The study is based on a multi-center phase II clinical trial aiming to evaluate the efficacy and safety of Lifileucel (LN-145), an autologous tumor-infiltrating lymphocyte (TIL) monotherapy, in patients with metastatic non-small cell lung cancer (mNSCLC) resistant to immune checkpoint inhibitors (ICI).

Background

In recent years, immunotherapy, including immune checkpoint inhibitors (ICI), has shown significant efficacy in treating advanced non-small cell lung cancer (NSCLC). However, some patients exhibit resistance to ICI, particularly those with negative PD-L1 (programmed death-ligand 1) expression, low tumor mutation burden (TMB), and STK11 mutations. For these patients, there are currently no effective alternative therapies. Therefore, exploring new treatment strategies such as autologous TIL cell therapy is crucial.

Autologous TIL cell therapy, which uses a patient’s own immune cells to combat tumors, initially showed good results in treating malignant melanoma. The feasibility of this therapy in non-small cell lung cancer has not been fully validated. This study aims to examine the application of autologous TIL cell therapy in mNSCLC patients who no longer respond to ICI therapy.

Research Methods and Process

Study Design and Participants

The study was conducted from January 2019 to January 2021, including 39 mNSCLC patients with previous treatment experience. All patients underwent tumor tissue resection, and 28 patients received Lifileucel therapy that met manufacturing specifications. The average age of these patients was 61, with a good performance status (ECOG-PS 0 or 1).

Tumor Tissue Acquisition and TIL Cell Preparation

Patients underwent tumor tissue resection surgeries, usually lung resections. The excised tumor tissues were sent to a centralized GMP (Good Manufacturing Practice) facility for TIL cell expansion in vitro, which took about 22 days per treatment cycle. Patients then received a preparative non-myeloablative lymphodepletion (NMA-LD) chemotherapy regimen, followed by a one-time TIL cell infusion.

Treatment Implementation and Safety

No uncontrollable adverse events related to the surgery occurred during the treatment process. The primary toxic side effects due to chemotherapy, such as leukopenia and thrombocytopenia, recovered in most cases within two weeks. Among the 28 treated patients, two died due to treatment-related adverse events.

Efficacy Evaluation

Efficacy was assessed using RECIST v1.1 (Response Evaluation Criteria in Solid Tumors), with the primary endpoints being objective response rate (ORR) and progression-free survival (PFS). Data analysis up to February 22, 2022, showed an objective response rate of 21.4%, including 1 complete response (CR) and 5 partial responses (PR). Some patients showed a reduction in tumor burden at the initial evaluation.

Results

Safety

The study found that all patients exhibited grade 3 or 4 hematologic abnormalities, including significant reductions in white blood cells, platelets, and hemoglobin levels. Most side effects returned to normal within two weeks post-treatment. Two patients died due to treatment-related adverse events.

Efficacy

Among the 28 patients, the objective response rate was 21.4%. One patient achieved a complete metabolic response (CR) at 6.4 months, and five patients achieved partial responses (PR). These responses included tumors that were PD-L1 negative, had low TMB, and contained STK11 mutations, demonstrating the potential efficacy of TIL cell therapy in these immune-resistant patients.

The study also showed that TIL cell therapy could be successfully prepared and applied across different types of tumor tissues (e.g., lungs, liver, lymph nodes), demonstrating its broad applicability.

Key Findings and Discussion

This is the first multi-center phase II clinical trial to demonstrate the feasibility and efficacy of an autologous TIL therapy in mNSCLC patients who progressed after ICI treatment. Despite a high proportion of patients with liver and/or brain metastases, indicating more severe and challenging conditions, Lifileucel still showed good efficacy.

Although the study results indicate good efficacy of Lifileucel in traditionally ICI-insensitive tumors, further research is needed to explore its potential mechanisms, particularly the combined use of TIL cell therapy and immune checkpoint inhibitors (ICI).

Conclusion

This study is the first to demonstrate the feasibility and efficacy of autologous TIL cell therapy in mNSCLC patients whose conditions had progressed after ICI treatment, suggesting the potential of TIL therapy as a treatment option for these patients. Although further research is needed to explore TIL therapy in different tumor types, this study provides a solid foundation for expanding the clinical application of TIL therapy.

The successful implementation of the study not only shows the potential efficacy of TIL therapy for immune-resistant tumors but also provides direction for future exploratory clinical trials, particularly the combined use of TIL therapy with other treatments to achieve better efficacy.

Research Significance

This study provides a new treatment option for mNSCLC patients resistant to ICI, demonstrating the feasibility and efficacy of TIL cell therapy in these patients and offering new ideas for future treatment strategies. The study also emphasizes the broad applicability and potential value of TIL therapy, particularly in patients with high tumor burdens, low PD-L1 expression, and complex genetic mutation types.

The research not only provides valuable data and experience for the application of TIL cell therapy in non-small cell lung cancer but also offers new directions and potential for treating various types of tumors in the future. This has significant implications for advancing cancer treatment and improving patient survival rates.