An integrated liquid biopsy framework for surveillance of residual disease and host immune status of T-cell lymphomas
Takeshi Sugio
MD, PhDStanford University
Project Term: July 1, 2023 - June 30, 2025
I aim to develop an accurate disease monitoring system and identify immunologic determinants of development and progression in T-cell lymphoma (TCL). I will integrate noninvasive liquid biopsy methods by high-throughput sequencing. I will study blood samples at various milestones, including pre-diagnostic, diagnostic/baseline, and post-treatment specimens during the natural history of TCL. Using these novel tools and unique specimens, my goal is the development of effective therapies for TCL.
Most patients with T-cell lymphomas (TCL) are not cured after standard therapies, with a dismal prognosis upon relapse. Therapeutic intervention is often delayed due to the lack of a standardized method to monitor residual disease, which is a huge unmet need. TCLs are tumors arising from mature T cells, which normally play key roles in anti-tumor immunity across cancers. Immune dysfunction is likely critical for TCL development and progression for several reasons. First, infection with endemic pathogens including HTLV-1 and EBV causes the development of TCLs. Second, recurrent somatic mutations are identified in genes critical for anti-tumor immunity. Finally, immunotherapy is effective in some relapsed refractory cases. Yet the relationship between evolving deficits in anti-tumor immunity and the onset/progression of TCL remains unclear, which is another unmet need. Addressing these unmet needs is significant, not only because of the global prevalence of TCL and its dismal outcomes but also the limitations of current methods to assess the host immune status and residual disease in TCLs as might inform therapy. These limitations arise from (1) difficulty of distinguishing normal from malignant T cells, (2) challenges of repeated invasive biopsies considering anatomical and temporal sampling, (3) barrier to adequate specimens because of the rarity of TCL Our lab has developed methods for noninvasive detection and monitoring of diverse tumors using DNA and RNA dissolved in liquid biopsy samples (cfDNA/RNA). Preliminary experiments indicate that integrative analysis of cfDNA/RNA may be useful to assess immune status, including non-circulating immune cells in tumor tissues, and to distinguish normal from malignant T cells. Therefore, we hypothesized that we can simultaneously monitor residual disease and immune status of TCL using cfDNA/RNA. To address this hypothesis, we obtained access to key biobanks of plasma samples of pre/post-onset, on-treatment, and tumor tissues.
The goal of my proposal is to address the unmet needs by (1) establishing noninvasive framework to detect residual disease and (2) identifying the key immunological features associated with the development and progression of TCLs.
The indicator for success of this study is to develop systems applicable to various types of TCLs. The next step is to identify the optimal therapeutic targets. This study will benefit future patients by leading to the development of effective therapy for TCLs.