"B7 family ligands and CD28 family receptors" by The Immunologist
Kill switches are built into lawnmowers, treadmills and industrial machinery as essential safety devices. Immune system cells mobilized to attack infections or tumors also have a kill switch called PD-1 that stops errant immune cell attacks on healthy tissues and organs.
However, new research has shown that tumor cells can hack the PD-1 kill switch, thereby avoiding an immune attack. Tumor cells’ immune-evading tactic comes in the form of a surface protein called PD-L1. This protein meshes perfectly with the PD-1 protein of an immune system cell sent to the tumor to kill it. The specific protein interaction activates the PD-1 kill switch, sometimes called the PD-1 checkpoint, which enables the tumor to continue to multiply.
Several pharmaceutical companies have developed monoclonal antibodies that block the PD-1/PD-L1 interaction to let immune cells do their job. Monoclonal antibody treatments that block the PD-1/PD-L1 interaction have shown significant positive effects in clinical trials against several types of cancer. However, the most successful trials include patients selected because their tumor cells express the PD-L1 protein.
Detecting PD-L1 in Circulating Tumor Cells
Excisional tissue biopsies provide only a snapshot in time of the presence of PD-L1 in tumors. Repeated excisional biopsies are often impossible to perform, especially in lung cancer patients. As dynamic genetic and phenotypic changes occur in tumors, some of the cells are continually shed into the bloodstream. Liquid biopsy, or blood sample tests, under development by Epic Sciences can generate real time information on the presence of PD-L1 protein in tumors by analyzing circulating tumor cells (CTCs).
Epic Sciences will give a poster presentation on Nov. 19, 2014, at the 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain, on a new assay the company developed to detect PD-L1 protein in CTCs in blood. The presentation is an analysis of CTCs from non-small cell lung cancer (NSCLC) patients. Epic developed the new assay in recognition of the extremely short supply of tissue from excisional tumor biopsies in many cancer patients.
Identifying patients with PD-L1-expressing tumor cells is essential for the new generation of cancer immunotherapies rapidly progressing in clinical trials. Those monoclonal antibody therapies target PD-L1-expressing tumors.
Detecting PD-L1 Yields ‘Important Insights’
Healthy mammalian cells produce PD-L1 and the related PD-L2 protein, both of which bind to the PD-1. Cells in many types of human tumors and nearly all mouse and rat tumor cell lines produce PD-L1.
Immunotherapies Targeting PD-L1-positive Tumors
In the U.S., investigational monoclonal antibody therapies that target either PD-1 or PD-L1, sometimes called PD-1 checkpoint inhibitors, include Roche’s MPDL3280A, Merck’s KEYTRUDA® (pembrolizumab), Bristol-Myers Squibb Company’s Opdivo (nivolumab), and AstraZeneca’s MEDI4736.
Roche reported that MPDL3280A (an anti-PD-L1 monoclonal antibody) shrank tumors (overall response rate) in 43 percent (13/30) of people previously treated for metastatic urothelial bladder cancer. That is an almost astonishingly good response rate.
The U. S. Food and Drug Administration (FDA) has granted first Breakthrough Therapy Designation in bladder cancer for Roche’s MPDL3280A. The company’s Phase 1 open-label study included patients whose biopsied tumors tested positive for PD-L1.
“Bladder cancer is the ninth most common cancer worldwide, for which there have been no new treatment advances in nearly 30 years,” said Sandra Horning, M.D., chief medical officer and head of Global Product Development. "We are evaluating MPDL3280A in a broad range of tumors, and have begun pivotal studies that include a companion diagnostic test in lung and bladder cancers.”
Bristol-Myers Squibb Company announced “encouraging” Phase 2 findings on Oct. 30, 2014, of a single-arm, open-label study of Opdivo (nivolumab), an investigational anti-PD-1 monoclonal antibody, administered as a single agent in patients with advanced squamous cell non-small cell lung cancer (NSCLC) who had progressed after at least two prior systemic treatments.
AstraZeneca in May 2014 initiated a Phase 3 clinical trial of MEDI4736, a monoclonal antibody targeting PD-L1, for the treatment of non-small cell lung cancer (NSCLC) and other cancers. The goal of the PACIFIC trial, the first study in the Phase III NSCLC program, is to evaluate progression free survival and overall survival of MEDI4736 compared to placebo in patients with locally advanced, unresectable NSCLC (Stage III) following completion of treatment with chemo-radiotherapy and no evidence of tumor progression. The PACIFIC trial is the first pivotal study of an immunotherapy in this patient population.
In November and December, Merck will present data for the first time on the investigational use the use of KEYTRUDA® (pembrolizumab), the company’s anti-PD-1 monoclonal antibody therapy. The immunotherapy was tested in patients with advanced melanoma in comparison to chemotherapy, and in relapsed/refractory classical Hodgkin Lymphoma as well as advanced triple negative breast cancer.
To read more about Epic's PD-L1 assay, click here.