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The Impact of the Microbiota on Immunotherapy of Hematological Malignancies

PhD Trainee
Program: Scientific Symposia
Sunday, December 10, 2023: 9:30 AM-10:45 AM
Room 25 (San Diego Convention Center)
Marco Ruella, MD, University of Pennsylvania
Ruella: NanoString: Consultancy, Research Funding; viTToria biotherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Scientific Founder, Research Funding; AbClon: Consultancy, Research Funding; Beckman Coulter: Research Funding; Bayer: Consultancy; Bristol Myers Squibb: Consultancy; GlaxoSmithKline: Consultancy.
This session focuses on the rapidly growing role of the human microbiota – i.e., the microorganisms that colonize the human body – in Hematological Malignancies and their therapies. We will focus, in particular, on the role of the microbiome in affecting outcomes and toxicities of immunotherapies such as CAR T cells and allogeneic stem cell transplant. We will also discuss how the microbiota affects hematopoiesis and functional immune recovery after transplantation.

Dr. Melody Smith will discuss the role of the intestinal microbiome on outcomes following treatment with chimeric antigen receptor (CAR) T cell therapy. She will highlight how exposure to antibiotics prior to CAR T cell therapy impacts clinical outcomes – both efficacy and CAR-mediated toxicity. Dr. Smith will also discuss how profiling of the fecal microbiome by 16S and metagenomic shotgun sequencing links clinical outcomes with differences in the composition of specific bacterial taxa and metabolic pathways in the intestinal microbiome.

Dr. Marcel Van Den Brink will discuss the intestinal microbiome can modulate immune responses in the context of cancer immunotherapy, such as allogeneic hematopoietic cell transplantation (allo-HCT). In allo-HCT patients and mouse models, dysbiosis characterized by loss of commensal anaerobes like Blautia and expansion of pathobionts like Enterococcus results in worse outcomes, including survival and lethal GVHD. Many drugs (apart from antibiotics) can alter the intestinal microbiome. GVHD in mouse models and allo-HCT patients with GVHD is associated with a loss of secondary bile acids, which are dependent on transformation of primary bile acids by enzymes provided by a (healthy) intestinal microbiome. Secondary bile acids have immunomodulatory properties, including decreased levels of Th17 and increased levels of Tregs. The bile acid receptor Farnesoid X Receptor (FXR) expression is increased on activated T cells, and FXR activation increases T cell proliferation and inflammation while FXR inhibition has opposite effects. In allo-HCT mouse models, FXR disruption in donor T cells reduces lethal GVHD.

In allo-HCT patients, ursodeoxycholic acid (a secondary bile acid) administration is associated with reduced Enterococcus abundance and decreased GVHD. Rational probiotic consortia may improve dysbiosis early after allo-HCT and improve outcomes.

Dr Kate Markey will describe our current understanding of how the intestinal microbiome influences hematopoiesis and functional immune recovery after transplantation. In her presentation, she will share data from human studies and mouse preclinical models and highlight the promise of manipulating the intestinal microbiome for patient benefit.

Melody Smith, MD, MS

Division of Blood and Marrow Transplantation & Cellular Therapy, Stanford University, Stanford, CA

Marcel R.M. van den Brink

City of Hope, Los Angeles, CA

Kate A. Markey, MBBS, PhD, FRACP, MPH

Fred Hutchinson Cancer Center, Seattle, WA

See more of: Scientific Symposia