Insight Brief
Immunotherapy and PD-L1: The Future of Precision Medicine Advances in precision medicine lead to new trends in immunotherapy
Radha Krishnan, M.D., Chief Pathologist and Senior Medical Director Patrice Hugo, Ph.D., Chief Scientific Officer
Advances in precision medicine have led to a paradigm shift for Q2 Solutions has helped develop a oncology research, from targeted therapies that rely largely on number of biomarkers commonly used tyrosine kinase inhibitors (TKIs) to personalized therapy that can today including BCR-Abl, ALK, BRAF, C-KIT, deliver demonstrable improvement in patient response along EGFR, KRAS, HER2, MET, and PD-L1. with considerably lower side effects. At the center of this shift is immunotherapy, in which researchers are developing drugs that How immunotherapy works harness the patient’s immune system to fight the cancer on its own. Cancer cells are known to create an immunosuppressive This research area has seen the introduction of new drugs, such environment by different mechanisms that allow cancer cells to as immune checkpoint inhibitors that target various pathways like thrive. There are three main immune checkpoints targeted by Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4), Programmed Cell approved drugs; namely anti-CTLA-4, anti-PD-1 and anti-PD-L1 Death Protein 1 (PD-1) or Programmed Death-Ligand 1 (PD-L1) antibodies. Therapeutic antibodies blocking those pathways deliver Such immuno-therapeutics are now representing a significant inhibitor signals at different levels of T cell function. The PD-1 proportion of all oncology drugs recently approved (Figure 1). pathway includes three proteins: PD-1 expressed mostly at the surface of T-lymphocytes, PD-L1 expressed on activated immune Q2 Solutions helped develop cells and antigen presenting cells, and importantly on many cancer 93% of the top 30 best-selling cells, Programmed Cell Death Ligand-2 (PD-L2) expressed on antigen presenting cells. When PD-1 binds to any one of its ligands oncology drugs of 2016 (PD-L1 or PD-L2), a negative signal is delivered to activated Figure 1: Cancer treatment has been transformed since 2011 by new medicines targeting 22 different cancer types New active substance launches 2011–2017 by indication
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T-lymphocytes. Therefore, expression of PD-L1 on tumor cells The role of PD-L1 assays forms a protective shield, which prevents cancer cells from being As we look to the future of immunotherapy, PD-L1 testing will detected and attacked by the body’s immune mechanism. The become even more important, as not all solid tumors express PD-L1 PD-1/PD-L1 checkpoint inhibitor drugs block either the PD-L1 and hence are appropriate for PD-1/PD-L1 immune checkpoint protein on cancer cells, or the corresponding PD-1 protein on inhibitor therapy. The PD-L1 immunohistochemistry (IHC) assay is immune cells (T-lymphocytes), preventing the inhibitory signal. the standard tool to assess PD-L1 increased expression in tumor Such therapeutic approaches enable the immune system to cells as well as in the tumor microenvironment. The PD-L1 IHC is recognize the cancer cells and attack them. Larger studies have currently developed as a companion diagnostic assay and predictive shown these drugs to be helpful in treating melanoma of the skin, biomarker to identify patients, which are more likely to benefit (i.e. non-small cell lung cancer, while smaller studies have shown responders) to PD-1/PD-L1 drugs. promising early results against other cancers, including bladder, Continued investigations into tumor biomarkers, tumor micro- kidney and colorectal cancer. environment 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.
www.Q2LabSolutions.com | 2 Q2 Solutions helped develop 67% of PD-L1 immune checkpoint inhibitors are certainly a good choice. Remarkable response rates have been seen in multiple cancer types all FDA-approved Oncology Precision particularly in patients whose tumor cells are expressing PD-L1. Medicine drugs of 2016 Increased awareness in the patient population allows patients to potentially benefit from immunotherapy. Next steps At Q2 Solutions, we have been contributing to this research by Just as many immunotherapies are still under development, so too supporting development of scoring algorithms, standardization and are the biomarker assays and companion diagnostics necessary validation of the PD-L1 IHC assay, and by supporting identification to ensure that such treatments are provided to the right patient of PD-L1 IHC assay pitfalls, including the pre-analytic variables, population. Development of the PD-L1 IHC as a companion analytic and post-analytic variables. Furthermore, we have been diagnostic requires rigorous precision, objectivity and reproducible involved, and continue to be involved, in several clinical trials to measurement by the pathologist. Although human tissue is one evaluate the efficacy of novel immune checkpoint inhibitors. We of the best matrices for development of tissue biomarkers, it are also bringing to the forefront of clinical trial research cutting- comes with the inherent challenges of obtaining adequate tissue edge biomarker technologies and assays such as high-content flow samples, including pre-analytic variables, analytic and post- cytometry to measure Tumor-Infiltrating Lymphocytes (TILs), analytic variables. Going forward we need to continue to validate Tumor Mutation Burden (TMB), T Cell Receptor Immune and standardize the development and use of these diagnostic Sequencing, Immune Gene Signature, and DNA-Mismatch Repair tools, standardize digital algorithms to validate quantification, and Deficiency (dMMR)/Microsatellite instability (MSI) in hope to continue to explore accurate measurement of specific biomarkers of identify biomarkers that can better predict patients that can respond the tumor and its microenvironment with multiplex immunoassays to innovative drugs. We are excited to continue to be a part of this or fluorescent-based assays to effectively distinguish tumor cells groundbreaking research. 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 For more information, see our white paper: an increasingly important role in oncology care going forward. Planning and implementing biomarker testing for The goal of all cancer research is to provide the best and ideally immuno-oncology trials. most cost-effective therapy to all cancer patients, and PD-1/
www.Q2LabSolutions.com | 3 About the authors
Radha Krishnan, M.D. Chief Pathologist and Senior Medical Director Radha Krishnan, M.D., is chief pathologist at Q2 Solutions, a Quintiles Quest Joint Venture. In this role, and in collaboration with the company’s chief scientific officer and chief operating officer, Dr. Krishnan defines the plan for global Anatomic Pathology (AP) service offerings, including instrumentation, technician and pathologists. Additionally, she serves as the scientific advisor for AP services, such as immunohistochemistry (IHC), In-Situ Hybridization (ISH) hematopathology and cytology. This includes the supervision of all assay validation, Pathologist and staff training, proficiency testing, the review and approval of related SOPs, and validations to ensure global harmonization of AP laboratory testing in accordance with applicable regulations governing clinical laboratories.
Dr. Krishnan has more than 22 years of post-specialization experience, with the last seven years in senior leadership roles within Quintiles and Q2 Solutions, including the senior medical director and head of AP for Europe and Asia. Prior to Quintiles, Dr. Krishnan worked as a consultant Pathologist in tertiary referral hospitals and cancer centers and specialized in tumor pathology. Dr. Krishnan has also been in the academia as an Associate professor in Pathology in the Faculty of Medicine at the University Technology MARA in Malaysia, and a lecturer in Pathology at the International Medical University in Kuala Lumpur.
Dr. Krishnan obtained her Bachelor of Medicine, Bachelor of Surgery (M.B.B.S) and her Doctorate in Medicine (M.D., Pathology) from the University of Madras in India. She is also a Member of the International Academy of Cytology (MIAC).
Patrice Hugo, Ph.D. Chief Scientific Officer Patrice Hugo, Ph.D., currently leads global scientific strategy and is responsible for the medical affairs and scientific activities in 2Q Solutions’ central laboratories, and genomic and BioAnalytical/ADME facilities worldwide. Dr. Hugo has more than 25 years of senior scientific leadership experience, with extensive management expertise in laboratory operations, biomarker discovery and validation applied to diagnostics, therapeutic targets and clinical trials. He obtained his Ph.D. at McGill University and completed five years of post-doctoral fellowship at the Walter Elisa Hall Institute in Australia, and Howard Hughes Medical Institute in Denver, Colorado.
Dr. Hugo was Associate Vice President and Chief Scientist, Scientific Affairs, at Laboratory Corporation of America (LabCorp)/Covance, and has held several other senior leadership positions at Clearstone Central Laboratories, Caprion and PROCREA BioSciences. A noted industry expert, Dr. Hugo has more than 75 scientific publications in internationally renowned journals. He also played an active role in a number of industry organizations, including being a member of the Board of Directors for the non-for-profit Personalized Medicine Partnership for Cancer in Quebec, and the Steering Committee for the Biomarker Factory.
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