Introduction of FDA BCR-SEQC initiative

With the rapid emergence and adaptation of next generation sequencing (NGS) technologies, we have the unprecedented opportunity to interrogate many fundamental and transformative questions surrounding the adaptive immune system and human disease. The convergence of high-depth sequencing, novel analysis methods and tools, and advancements in immunotherapy and drug development has set the stage for standardizing the quantitative study of human immune cell receptor repertoire composition and diversity. With this prodigious opportunity comes many technical challenges. The overarching study objectives of this research proposal are to elucidate current limitations, address fundamental technical needs, provide reference samples and data sets, and establish best practices for reconstructing B cell receptor repertoires from NGS data. Specifically, with simulated reads and contrived samples using short and long-read sequencing technologies, we will critically evaluate and compare sequencing platforms and technologies, BCR gene mapping/alignment, clonotype classification, diversity, and convergence methods and tools to provide best-practice standards and a state-of-the-art analysis framework for B cell profiling. We will accurately measure clonotype detection sensitivity by spiking-in linear mixtures of simulated reads and B cells from banked samples. In doing so, we will establish the technical standards (reference samples and data sets) and protocols for reliable, accurate, and cost-effective B cell receptor profiling. This work is necessary to advance our technical understanding of B cell receptor profiling and thus immune cell function and adaptive immunity. In accordance with the FDA regulatory mission, this work will advance our ability to provide orthogonal, functional cellular and genetic evidence for the efficacy of cancer drugs and immunotherapies. Finally, our analytical framework will allow for the comprehensive examination and evaluation of immunological disorders, cancer treatments, pathogenic response, germline-targeted vaccine design, immunotherapies, and drug efficacy.