Large-Scale Post-Transplant TCR Deep Sequencing Reveals a Major T Cell Diversity Bottleneck with Post-Transplant Cyclophosphamide with Implications for Both Efficacy and Toxicity: Results of the BMT CTN 1801 Study

作者：Leslie S. Kean, Steven J. Siegel, Joseph Schmalz, Stephanie A. Bien, Danielle Scheffey, Catherine Miller Sanders, Harlan S. Robins, Kristy Applegate, Merav Bar, Saurabh Chhabra, Sung Won Choi, William Clark, Suman R. Das, Robert R. Jenq, Richard John Jones, John E. Levine, Brent R. Logan, Hemant S. Murthy, Armin Rashidi, Marcie Riches, Wael Saber, Karamjeet Sandhu, Anthony Derek Sung, Karilyn T. M. Larkin, Monzr M. Al Malki, Mahasweta Gooptu, Hany Elmariah, Amin Majid Alousi, Lyndsey Runaas, Brian C. Shaffer, Andrew R. Rezvani, Najla El Jurdi, Alison Wakoff Loren, Mary M. Horowitz, Javier Bolaños‐Meade, Shernan G. Holtan, Ami Siddharth Bhatt, Miguel‐Angel Perales, Susan DeWolf · 发表于：Blood · 年份：2023 · DOI：10.1182/blood-2023-188032 · 被引用次数：12 · 研究领域：Renal Transplantation Outcomes and Treatments、Hematopoietic Stem Cell Transplantation、CAR-T cell therapy research

Background: BMT CTN 1703 was a Phase 3 trial comparing Tac/MTX (n = 217) to post-transplant cyclophosphamide (PT-Cy)/Tac/MMF (n = 214) GVHD prophylaxis after reduced intensity conditioning unrelated donor hematopoietic cell transplant (HCT). PT-Cy significantly improved GVHD-free Relapse-Free Survival (Bolanos-Meade et al NEJM 2023). However overall survival was not significantly different and the # of Grade 2 infections was higher with PT-Cy. To investigate its biologic underpinnings 1703 was linked to a mechanistic study, BMT CTN 1801, which co-enrolled 324 pts (159 CNI/MTX 165 PT-Cy). The resulting dataset enabled an analysis of post-HCT T cell reconstitution at an unprecedented level of detail. Methods: Samples were collected from the HCT infusion and on D+7, 14, 28, 63, 98, 180, 270, 1- and 2-yr. We extracted DNA (2,225 samples) and performed Adaptive Biotech β-strand T Cell Receptor (TCR) Immunosequencing (TCR-Seq). We profiled 44,077 (median) TCRs/sample resulting in 215,155,719 T cells analyzed. We evaluated multiple TCR diversity measures longitudinally and before/after cGVHD and infections. Each measure evaluates a specific aspect of TCR diversity, including Simpsons Clonality (focuses on the most expanded clones) Diversity Slope (mid-range clones) Richness (both mid-range and less-expanded clones) and Singletons (the TCR-Seq equivalent of naïve T cells). This analysis was robust to the full range (1000-50,000) of down-sampled TCRs sequenced. Results: We identified ...