My research studies focus on understanding the biology of chronic lymphocytic leukemia (CLL), a disease of clonal CD19+CD5+CD23+ B cells, with the goal of developing effective and potentially personalized therapies to treat this currently incurable and common adult leukemia. We have been leveraging the recent availability of next-generation massively parallel sequencing technologies to perform comprehensive genomic dissection of CLL cells. Initially through genome sequencing of 91 CLL samples and integration of mutation data with clinical annotation, my group defined several key mutated genes and discrete pathways involved in CLL pathogenesis (N Engl J Med, 2011). As we have continued to expand our set of exome-sequenced CLL samples to over 500 patients and have refined our computational tools to analyze this genomic data, we have appreciated that the majority of CLL samples commonly harbor mutations occurring at subclonal frequencies. In recent analyses, we have investigated the composition and impact of subclonal mutations and alterations in methylation on CLL progression (Cell, 2013; Cancer Cell 2014), as well as the impact of CLL therapy on clonal evolution (Nature 2015, Nat Comm 2016). These studies have uncovered the dynamic changes in genetic alterations underlying CLL progression and introduce new approaches for earlier prognosis and therapeutic decision-making. We have further leveraged massively parallel sequencing technology to pioneer computational tools for the comprehensive discovery of potential personal tumor-specific neoantigens (Blood 2014; Nat Biotech 2015).
Neoantigens are a promising novel class of cancer vaccine targets created by the personal mutations found in each patient’s tumor. Because these mutations generate peptides that are distinct from “self”-peptides, the resulting epitopes are expected to escape the immune dampening effects of central tolerance. As these targets
are exquisitely tumor-specific, being completely absent in all normal tissues, we have initiated phase I clinical trials to test the concept of developing personalized cancer vaccines that target patient tumor-specific neoantigens (NCT 01970358). As a physician-scientist with deep insight into how to bridge important basic discoveries with questions of high clinical relevance, I am committed to focusing on examining the role of neoantigens in tumor-host co-evolution and am uniquely poised to effectively address the question of relating somatic mutation with functional changes in the microenvironment, and to understand how these features relate to clonal evolution in CLL.
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