Today and tomorrow will feature five different Scientific Symposia, offering an intellectual deep dive into the subdisciplines of hematology. For the cellular therapy enthusiasts at #ASH24, there are two standout sessions. This morning, Interrogating the Impact of the Intestinal Microbiome on Transplant and Cellular Therapies (9:30 a.m. - 10:45 a.m., Marriott Marquis, Grand Ballroom 11-13) will take attendees on a journey into the host-microbiome axis.
Treating hematological malignancies with intensive therapies — particularly allogeneic hematopoietic stem cell transplantation (alloHSCT) — leads hematologists to wield the double-edged sword of broad-spectrum antibiotics. Necessary for tackling neutropenic sepsis, they wreak havoc on the gut microbiota, diminishing diversity and promoting antibiotic-resistant bacteria to thrive. In 2020, a seminal study analyzing more than 8,700 stool samples from 1,362 patients revealed a direct link between microbiota injury and poor survival outcomes, driven by higher rates of graft-versus-host disease (GVHD)-related deaths.1 The findings underscore the urgent need — and potential therapeutic opportunity — for rational intervention to restore integrity to intestinal microbiota.
Enter fecal microbiota transplantation (FMT)! To the aesthetes amongst us, the concept of FMT may sound unappealing, but its potential to rejuvenate microbiota diversity is undeniable. Florent Malard, MD, PhD, from Sorbonne University, will present compelling new data showcasing how FMT can restore gut health after transplantation. “[FMT] is a promising immunomodulatory strategy, not only for the treatment of acute GVHD, but also as a preemptive approach to restore microbiome diversity after alloHSCT,” Dr. Malard said. And it’s not just a GVHD treatment. FMT could also improve outcomes for patients undergoing chimeric antigen receptor T cell (CAR-T) therapies, where prolonged cytopenias similarly drive antibiotic-induced injury to the microbiome.
We are what we eat, but what does an alloHSCT patient actually consume? Reliable data on oral intake has hampered investigation of the modifiers of an individual’s microbiome. “I’ll be sharing our lab’s work on developing FoodSeq, a DNA sequencing-based tool to track what patients eat,” said Lawrence A. David, PhD, from Duke University, the mastermind behind the technology. “FoodSeq allows us to monitor and study the diets of patients who might otherwise be too sick to share their eating habits with dietitians.” This, Dr. David noted, paves the way for nutrition strategies that promote microbiome reconstitution and potentially improve patient outcomes.
It is an uncomfortable truth that the most common source of gut injury is physician-prescribed antimicrobials. Tessa Andermann, MD, MPH, from the University of North Carolina at Chapel Hill, will explore how antibiotics shift gut bacteria composition, how this affects cellular therapy outcomes, and the role of prebiotics and probiotics in preventing microbiota dysbiosis. The goal? Smarter, more informed prescribing practices that balance fighting infections with protecting gut health.
Later today, another symposium will turn the spotlight on Cellular Heterogeneity and Relationship to Clinical Outcomes (4:30 p.m. - 5:45 p.m., Convention Center, Room 33), with an emphasis on optimizing CAR-T products. The U.S. Food and Drug Administration’s approval of two CAR-T treatments in 2017 was a historic moment in cellular therapies, and real-world experience since has borne out the potential for dramatic clinical responses. Yet there is plentiful scope for improvement, with one pinch-point being the manufacture of these “living agents,” where variability in CAR T cell potency, purity, and functionality impact therapeutic effectiveness.
Zinaida Good, PhD, from Stanford University, will discuss clinical implications of CAR T cell diversity. Her presentation will highlight how particular CAR T regulatory cells (Tregs) affect treatment efficacy and neurotoxicity. “Understanding specific infusion CAR T cell populations poised for homing to the tumor or expansion post-infusion is key,” Dr. Good said. Her focus on mapping these populations and defining how they correlate with patient response and toxicity is primed to advance the field.
Setting her sights on engineering a more perfect CAR-T, Julia Carnevale, MD, from the University of California San Francisco, will discuss genome-wide screening tools to identify genetic targets to optimize CAR T cells. She will showcase how custom-editing T cells by genetic engineering to tailor them for maximum therapeutic impact could become a reality.
Rounding out the symposium, Megan Levings, PhD, from the University of British Columbia, will shine a spotlight on Tregs and their potential as therapeutic agents. “The first engineered Treg products are now in clinical testing in the context of solid organ transplantation, and many groups are poised to begin testing them in autoimmunity,” Dr. Levings said. “I plan to talk about different approaches to harnessing the immunoregulatory properties of Tregs to control [GVHD].” Innovative approaches include isolating therapeutic Tregs from discarded human thymuses and engineering “super Tregs” using CRISPR editing, paving the way to a new era of Treg-based therapies for hematological disease.
The Scientific Symposia at #ASH24 promise something for everyone. Should harnessing the diversity of the gut microbiome or fine-tuning the precision of CAR-T therapies not do it for you, other options include exploring geroscience in hematology and newly discovered functions of megakaryocytes and platelets. If interdisciplinary translational science gets your heart racing, get yourself a front-row seat!
REFERENCE
- Peled JU, Gomes ALC, Devlin SM, et al. Microbiota as predictor of mortality in allogeneic hematopoietic-cell transplantation. N Engl J Med. 2020;382(9):822-834.
