title: Validation of biomarkers to predict response to immunotherapy in cancer: Volume I - pre-analytical and analytical validation.
abstract: Immunotherapies have emerged as one of the most promising approaches to treat patients with cancer. Recently, there have been many clinical successes using checkpoint receptor blockade, including T cell inhibitory receptors such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death-1 (PD-1). Despite demonstrated successes in a variety of malignancies, responses only typically occur in a minority of patients in any given histology. Additionally, treatment is associated with inflammatory toxicity and high cost. Therefore, determining which patients would derive clinical benefit from immunotherapy is a compelling clinical question. Although numerous candidate biomarkers have been described, there are currently three FDA-approved assays based on PD-1 ligand expression (PD-L1) that have been clinically validated to identify patients who are more likely to benefit from a single-agent anti-PD-1/PD-L1 therapy. Because of the complexity of the immune response and tumor biology, it is unlikely that a single biomarker will be sufficient to predict clinical outcomes in response to immune-targeted therapy. Rather, the integration of multiple tumor and immune response parameters, such as protein expression, genomics, and transcriptomics, may be necessary for accurate prediction of clinical benefit. Before a candidate biomarker and/or new technology can be used in a clinical setting, several steps are necessary to demonstrate its clinical validity. Although regulatory guidelines provide general roadmaps for the validation process, their applicability to biomarkers in the cancer immunotherapy field is somewhat limited. Thus, Working Group 1 (WG1) of the Society for Immunotherapy of Cancer (SITC) Immune Biomarkers Task Force convened to address this need. In this two volume series, we discuss pre-analytical and analytical (Volume I) as well as clinical and regulatory (Volume II) aspects of the validation process as applied to predictive biomarkers for cancer immunotherapy. To illustrate the requirements for validation, we discuss examples of biomarker assays that have shown preliminary evidence of an association with clinical benefit from immunotherapeutic interventions. The scope includes only those assays and technologies that have established a certain level of validation for clinical use (fit-for-purpose). Recommendations to meet challenges and strategies to guide the choice of analytical and clinical validation design for specific assays are also provided.
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, 171 76 Stockholm, Sweden.
authors.forename: Giuseppe V
authors.initials: GV
authors.lastname: Masucci
authors.affiliation: NanoString, Inc, 500 Fairview Avenue North, Seattle, WA 98109 USA.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Cesano
authors.affiliation: Nodality, Inc, 170 Harbor Way, South San Francisco, 94080 CA USA.
authors.forename: Rachael
authors.initials: R
authors.lastname: Hawtin
authors.affiliation: ZellNet Consulting, Inc, 555 North Avenue, Fort Lee, 07024 NJ USA.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Janetzki
authors.affiliation: Covaris Inc, 14 Gill St, Woburn, MA 01801 USA.
authors.forename: Jenny
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Adaptive Biotechnologies, Inc, 1551 Eastlake Ave. E, Seattle, WA 98102 USA.
authors.forename: Ilan
authors.initials: I
authors.lastname: Kirsch
authors.affiliation: Department of Epidemiology and Biostatistics, College of Public Health, The University of Georgia, 101 Buck Road, Athens, 30602 GA USA.
authors.forename: Kevin K
authors.initials: KK
authors.lastname: Dobbin
authors.affiliation: Janssen Research & Development, LLC, Spring House, PA 19477 USA.
authors.forename: John
authors.initials: J
authors.lastname: Alvarez
authors.affiliation: Pfizer, San Diego, CA USA.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Robbins
authors.affiliation: Omni Array Biotechnology, 15601 Crabbs Branch Way, Rockville, 20855 MD USA.
authors.forename: Senthamil R
authors.initials: SR
authors.lastname: Selvan
authors.affiliation: National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Bethesda, 20892 MD USA.
authors.forename: Howard Z
authors.initials: HZ
authors.lastname: Streicher
authors.affiliation: Department of Medicine, Surgery and Immunology, University of Pittsburgh Cancer Institute, 5117 Centre Avenue, Pittsburgh, PA 15213 USA.
authors.forename: Lisa H
authors.initials: LH
authors.lastname: Butterfield
authors.affiliation: National Cancer Institute, Cancer Diagnosis Program, DCTD, National Institutes of Health, 9609 Medical Center Drive, Bethesda, 20892 MD USA ; Adaptive Biotechnologies, Inc, 1551 Eastlake Ave. E, Seattle, WA 98102 USA.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Thurin
mesh_terms: D000074322:Antineoplastic Agents, Immunological / Q000494:pharmacology / Q000627:therapeutic use; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors; D001681:Biological Assay / Q000379:methods / Q000592:standards; D014408:Biomarkers, Tumor; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors; D002986:Clinical Trials as Topic; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000175:diagnosis* / Q000401:mortality / Q000628:therapy*; D011379:Prognosis; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors; D015203:Reproducibility of Results; D016896:Treatment Outcome
chemical_list: D000074322:Antineoplastic Agents, Immunological; D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; D060908:CTLA-4 Antigen; D061026:Programmed Cell Death 1 Receptor
keywords: Assay; Biomarker; Cancer; Immunotherapy; Standardization; Validation