Anti-PD-(L)1 immunotherapy for brain metastases in non-small cell lung cancer: Mechanisms, advances, and challenges
Shujie Zhou1, Jingjing Xie2, Zhaoqin Huang3
1Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China; Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China.
Abstract:
The brain is one of the most common metastatic sites in non-small cell lung cancer (NSCLC), which is associated with an extremely poor prognosis. Despite the availability of several therapeutic options, the treatment efficacy remains unsatisfactory for NSCLC brain metastases. Anti-programmed cell death-1 (PD-1) and its ligand (PD-L1) monoclonal antibodies have reshaped therapeutic strategies in advanced NSCLC. Preliminary evidence has shown that anti-PD-(L)1 monotherapy is also effective in NSCLC patients with brain metastases. However, the traditional view asserted that these therapeutic antibodies were incapable of crossing the blood-brain barrier (BBB) with large molecular size, thus most patients with brain metastases were excluded from most studies on anti-PD-(L)1 immunotherapy. Therefore, the efficacy and its mechanisms of action of anti-PD-(L)1 immunotherapy against brain metastases in NSCLC have not been clarified. In this review, we will survey the underlying mechanisms and current clinical advances of anti-PD-(L)1 immunotherapy in the treatment of brain metastases in NSCLC. The trafficking of activated cytotoxic T cells that are mainly derived from the primary tumor and deep cervical lymph nodes is critical for the intracranial response to anti-PD-(L)1 immunotherapy, which is driven by interferon-γ (IFN-γ). Additionally, promising combined strategies with the rationale in the treatment of brain metastases will be presented to provide future directions for clinical study design. Several significant challenges in the preclinical and clinical studies of brain metastases, as well as potential solutions, will also be discussed.
Insights
Anti-programmed cell death-1 (PD-1) immunotherapy shows promise for non-small cell lung cancer (NSCLC) brain metastases. T cell trafficking, driven by interferon-gamma, is key to its effectiveness against these challenging tumors.
Area of Science:
- Oncology
- Immunology
- Neurology
Background:
- Brain metastases are common in non-small cell lung cancer (NSCLC), leading to a poor prognosis.
- Current treatments for NSCLC brain metastases have limited efficacy.
- Anti-programmed cell death-1 (PD-1) and its ligand (PD-L1) immunotherapies have advanced NSCLC treatment but face challenges in brain metastases due to the blood-brain barrier (BBB).
Purpose of the Study:
- To review the mechanisms and clinical progress of anti-PD-(L)1 immunotherapy for NSCLC brain metastases.
- To explore the role of T cell trafficking and interferon-gamma (IFN-γ) in intracranial anti-PD-(L)1 responses.
- To discuss combined strategies, challenges, and solutions for treating NSCLC brain metastases with immunotherapy.
Main Methods:
- Review of existing literature on anti-PD-(L)1 immunotherapy in NSCLC brain metastases.
- Analysis of mechanisms involving cytotoxic T cell trafficking and IFN-γ.
- Discussion of preclinical and clinical study challenges and potential solutions.
Main Results:
- Preliminary evidence suggests anti-PD-(L)1 monotherapy is effective in NSCLC patients with brain metastases.
- Activated cytotoxic T cell trafficking from primary tumors and lymph nodes, mediated by IFN-γ, is crucial for intracranial response.
- The BBB was previously thought to limit antibody penetration, excluding many patients from trials.
Conclusions:
- Anti-PD-(L)1 immunotherapy holds significant potential for treating NSCLC brain metastases.
- Understanding T cell trafficking and IFN-γ pathways is vital for optimizing intracranial efficacy.
- Further research and combined strategies are needed to overcome challenges and improve outcomes for NSCLC patients with brain metastases.
