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.Electronic supplementary materialThe online version of this article (doi:10.1186/s40425-016-0178-1) contains supplementary material, which is available to authorized users.

Role of tumor-infiltrating lymphocytes in patients with solid tumors: Can a drop dig a stone?

“…Also, the response to immunotherapy [63,64] in advanced NSCLC patients can be predicted through the study of the tumor microenvironment . Also, a tumoral context dense of CD8+ [65] and FOXP3+ Treg TILs can be considered as predictive marker of response to platinum-based neoadjuvant chemotherapy in advanced NSCLC patients , as well as high levels of the transforming [66,67] growth factor (TGF-) in TILs are predictive of poor post-operative β β survival . Furthermore, there is still much to be studied to evaluate [59] possible epigenetic modi cations that can drive a more conscious fi therapeutic choice for lung cancer patients.…”

Assessing Tumor-infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method From the International Immunooncology Biomarkers Working Group: Part 1: Assessing the Host Immune Response, TILs in Invasive Breast Carcinoma and Ductal Carcinoma In Situ, Metastatic Tumor Deposits and Areas for Further Research

“…Development of prognostic and predictive biomarkers in oncology requires robust assessment of the test’s analytical validity, clinical validity and clinical utility [6,7]. Evidence is accumulating to support the use of TILs scoring as a prognostic biomarker in various solid tumors and evidence for the predictive benefit of TILs is being investigated at present.…”

Gene Expression Signatures Can Aid Diagnosis of Sexually Transmitted Infection-Induced Endometritis in Women

“…The nCounter Dx Analysis system (NanoString) used to confirm the mRNA results in this study, provides rapid, reliable, inexpensive, and reproducible molecular sub-grouping of clinical samples (Northcott et al, 2012; Veldman-Jones et al, 2015; Masucci et al, 2016). Results of the assay can easily be available within 24–48 h of obtaining blood from the patient.…”