Anti PD-L1 in Non-small Cell Lung Cancer
The PD-1 pathway may be critical in the immune system’s ability to control cancer. Blocking this pathway with PD-1 and PD-L1 antibodies has led to unprecedented tumor response and control in some patients with NSCLC.
Immunotherapy has had limited success in the treatment of lung cancer, attributed in part to the belief that lung cancer is non-immunogenic.1 Lung cancer cells can evade the immune system for a variety of reasons including the secretion of immunosuppressive cytokines, loss of major histocompatibility complex (MHC) antigen expression and the factors described below.2,3 Most patients who present with advanced disease are immune suppressed, as documented by reports of decreases in peripheral and tumor lymphocyte counts.4,5 In lung cancer patients, regulatory T cells (Tregs-CD4+), which are known to play a role in suppressing tumor immune surveillance, have been found at higher levels than other T cell subsets in both the peripheral blood and tumors.6 Tregs-CD4+ also suppress cytotoxic T lymphocytes (CD8+ T cells), which are responsible for killing tumor cells, tumor immunosurveillance and immune memory.
Another way cancer cells can shield themselves from the immune system is by disabling tumor-specific T cells by host or tumor specific mechanisms.7,8 One such mechanism is to co-opt inhibitory pathways such as the PD-1 pathway. Lung tumor cells have been found to express PD-L1, a known ligand of the PD-1 receptor on T-cells. This allows the tumors to directly suppress anti-tumor cytolytic T cell activity via T cell down-regulation and inhibition.9,10 Blocking the binding of the PD-1 receptor to one of its ligands, PD-L1, via monoclonal antibodies augments the T cell response.1 Two trials of antibodies blocking this pathway have demonstrated preliminary evidence of activity and this pathways’ importance in non-small cell lung cancer (NSCLC) using an anti-PD-1 antibody and an anti-PD-L1 antibody.
Anti PD-L1 monoclonal antibody
The first in human trial of the anti-PD-L1 monoclonal antibody BMS 936559 included a large cohort of patients with advanced NSCLC.12 In this trial, the anti-PD-L1 antibody was given once every two weeks. The maximum tolerated dose was not reached and all dose levels were well tolerated. The most common treatment related adverse events were fatigue, infusion reactions, and diarrhea. After the dose escalation phase was completed, several dose expansion cohorts were included in the trial. Patients with previously treated NSCLC were randomized to 1, 3, and 10 mg/kg dose levels. A total of 207 patients have been enrolled in this trial thus far including 75 NSCLC patients.
Of the 75 patients with NSCLC, 49 patients were evaluable for response. Objective response was seen in five of the 49 patients. Tumor response was seen in squamous (1 of 13 patients, 8%) and non-squamous (4 of 36 patients, 11%) histologies. An additional six (12%) patients had stable disease for at least six months. These results further support the previous BMS 936558 trial of PD-1 findings, implying that blockade of the PD-1 pathway may cause tumor response and control in NSCLC.
Other agents in development
Other PD-L1 antibodies are also in current development (Table 1). An ongoing phase I dose escalation trial of Medi-4736 includes NSCLC patients (NCT#01693562). An ongoing phase I trial of the anti-PD-L1 antibody MPDL-3280A (NCT#01375842) combines MPDL-3280A with bevacizumab. A second phase I trial combines MPDL-3280A with bevacizumab plus chemotherapy (NCT#01633970). Results of these phase I trials are highly anticipated.
Table 1: Clinical Development of Inhibitors of PD-1 Immune Checkpoint
|PD-1||BMS-936558/MDX-1106/ONO-4538||Phase III multiple tumors|
|CT-011||Phase II multiple tumors|
The PD-1 pathway may be critical in the immune system’s ability to control cancer. Blocking this pathway with PD-1 and PD-L1 antibodies has led to unprecedented tumor response and control in some patients with NSCLC. These results have sparked the interest of the lung cancer community and are leading to several trials further investigating this pathway in immune regulation of lung cancer.