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Radha Krishnan, MD | February 25, 2016

Immunotherapy and PD-L1: A primer

Advances in precision medicine have led to a shift in paradigm for oncology research, from targeted therapies that rely largely on tyrosine kinase inhibitors (TKIs) to personalized therapy that can deliver demonstrable improvement in patient response along with considerably lower side effects. At the center of this trend is immunotherapy, in which researchers are developing drugs that harness the patient’s immune system to fight the cancer on its own. This research area has seen the introduction of new drugs, known as immune checkpoint inhibitors that target various pathways such as Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) or Programmed cell Death Protein 1 (PD-1).

How immunotherapy works
Cancer cells are known to create an immunosuppressive environment by different mechanisms that allow cancer cells to thrive. There are two main immune checkpoints targeted by approved drugs, namely CTLA-4 and PD-1. Therapeutic antibodies blocking those pathways deliver inhibitor signals at different levels of T-cell function. The PD-1 pathway includes three proteins: PD-1 expressed mostly at the surface of T-lymphocytes, Programmed cell Death Ligand-1 (PD-L1) expressed on activated immune cells and antigen presenting cells, and importantly on many cancer cells, Programmed Ccell Death Ligand-2 (PD-L2) expressed on antigen presenting cells. When PD-1 binds to any one of its ligands (PD-L1 or PD-L2), a negative signal is delivered to activated T-lymphocytes. Therefore, expression of PD-L1 on tumor cells forms a protective shield, which prevents cancer cells from being detected and attacked by the body’s immune mechanism. The PD-1/PD-L1 checkpoint inhibitor drugs block either the PD-L1 protein on cancer cells, or the corresponding PD-1 protein on immune cells (T-lymphocytes), preventing the inhibitory signal. Such therapeutic approaches enables the immune system to recognize the cancer cells and attack them. Larger studies have shown these drugs to be helpful in treating melanoma of the skin, non-small cell lung cancer, while smaller studies have shown promising early results against other cancers, including kidney and colorectal cancer.

The role of PD-L1 assays
As we look to the future of immunotherapy, PD-L1 testing will become even more important, as not all solid tumors express PD-L1 and hence are appropriate for PD-1/PD-L1 immune checkpoint inhibitor therapy.  The PD-L1 immunohistochemistry (IHC) assay is the standard tool to assess PD-L1 increased expression in tumor cells as well as in the tumor microenvironment. The PD-L1 IHC is currently developed as a companion diagnostic assay and predictive biomarker to identify patients, which are more likely to benefit (i.e.  responders) to PD-1/PD-L1 drugs.  

Continued investigations into tumor biomarkers, tumor microenvironment and pharmacodynamics expect to provide insights into the mechanism of action of PD-L1, and guide future development of synergistic combination therapy with combination of cancer vaccine and immune checkpoint inhibitors, and/or chemotherapy.
Next steps
Just as many immunotherapies are still under development, so too are the biomarker assays and companion diagnostics necessary to ensure that such treatment are provided to the right patient population. Development of the PD-L1 IHC as a companion diagnostic requires rigorous precision, objectivity and reproducible measurement by the pathologist.  Although human tissue is one of the best matrix for development of tissue biomarkers, it comes along with the inherent challenges of obtaining adequate tissue samples, including pre-analytic variables, analytic and post-analytic variables. Going forward we need to continue to validate and standardize the development and use of these diagnostic tools, standardize digital algorithms to validate quantification, and continue to explore accurate measurement of specific biomarkers of the tumor and its microenvironment with multiplex immunoassays or fluorescent-based assays to effectively distinguish tumor cells versus non-tumor cells. 

Physicians and patients need to pay close attention to the development of these diagnostic tools and immune checkpoint inhibitory drugs, as such therapeutic approaches will certainly play an increasingly important role in oncology care going forward. The goal of all cancer research is to provide the best and ideally most cost-effective therapy to all cancer patients, and PD-1/PD-L1 immune checkpoint inhibitors are certainly a good choice. Remarkable response rate have been seen in multiple cancer types particularly in patients whose tumor cells are expressing PD-L1. Increased awareness in the patient population allows patients to potentially benefit from immunotherapy.

At Q2 Solutions, we have been contributing to this research by supporting development of scoring algorithms, standardization and validation of the PD-L1 IHC assay, and by supporting identification of PD-L1 IHC assay pitfalls, including the pre-analytic variables, analytic and post-analytic variables. Furthermore, we have been involved, and continue to be involved, in several clinical trials to evaluate the efficacy of novel immune checkpoint inhibitors. We are excited to be a part of this groundbreaking research.