1. Gallagher, Amy

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While the medical literature has reported on the impact of the intestinal microbiome on human health and disease, a study conducted by researchers from Memorial Sloan Kettering Cancer Center and the University of Pennsylvania showed that the gut microbiota influences the response to cancer immunotherapy with chimeric antigen receptor (CAR) T cells. In an ongoing effort to improve patients' response to CAR T cells, the researchers investigated how microorganisms in the gut impact clinical outcomes in patients with leukemia and lymphoma who receive CAR-T therapy.

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"With CAR-T therapy, a patient's own immune cells are engineered to recognize and destroy cancer," said physician-scientist Marcel R.M. van den Brink, MD, PhD, Head of the Division of Hematologic Malignancies and member of the Sloan Kettering Institute Immunology Program. "Certain changes in the microbiota-the ecosystem of bacteria and other microorganisms that live on and in the body-have been linked to many aspects of human health, including in patients who receive CAR-T therapy."


For over a decade, Memorial Sloan Kettering Cancer Center has been at the forefront of studying how the gut microbiota influences outcomes in patients receiving bone marrow transplant.


"The purpose of this study was to examine how changes in the gut microbiota may influence the clinical outcome of patients receiving CAR T-cell therapy," said van den Brink. "If we can identify the factors that are associated with more toxicity and lower efficacy, we might be able to modify them so that we can improve care."


Exposure of Broad-Spectrum Antibiotics

Anti-CD19 CAR T-cell therapy has led to unprecedented responses in patients with high-risk hematologic malignancies. However, up to 60 percent of patients still experience disease relapse and up to 80 percent of patients experience CAR-mediated toxicities, such as cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. Researchers found that exposure to certain antibiotics in the 4 weeks before CAR-T therapy, those known as broad-spectrum antibiotics, were associated with worse survival and higher rates of toxicity.


"We investigated the role of the intestinal microbiome on clinical outcomes in a multicenter study of patients with B-cell lymphoma and leukemia in a retrospective cohort of 228 patients," said van den Brink. "We found that exposure to antibiotics, specifically piperacillin/tazobactam, meropenem and imipenem/cilastatin, in the 4 weeks before therapy was associated with worse survival and increased neurotoxicity."


Response & Toxicity

In the other aspect of the study, fecal samples from CAR T-cell recipients were profiled by 16S ribosomal RNA and metagenomic shotgun sequencing. This data was assessed to identify correlates between clinical outcomes with abundances in specific bacterial taxa and metabolic pathways.


According to the study's first author Melody Smith, MD, MS, a hematologic oncologist (and former member of The Marcel van den Brink Lab who is a physician-scientist with her own lab at Stanford University School of Medicine), a study was conducted with stool samples from 48 patients collected before the patients received their CAR-T therapy.


"Metrics were used to study the alpha diversity to assess the evenness of the microbiome," she explained. "Prior to the infusion, we observed that the alpha diversity was lower-there was a loss of evenness-in the CAR T-cell recipients in comparison to healthy volunteers. Assessment of the alpha diversity as well as other studies showed that the fecal microbiome was altered at baseline in CAR T-cell recipients compared to healthy controls."


Through both untargeted and hypothesis-driven analysis of 16S sequencing data, we identified species within the class Clostridia that were associated with Day 100 complete response, explained van den Brink.


"We concluded that changes in the intestinal microbiome are associated with clinical outcomes after anti-CD19 CAR T-cell therapy in patients with B-cell malignancies," he noted. "The take-home message of our work demonstrates that bacteria in our gut may modulate the responses in recipients of CD19 CAR-T cells."


Future Studies

"The gut microbiota is a modulator of the immune system," said van den Brink, who also studies strategies to enhance thymic immune reconstitution. "Therefore, it makes sense that having a healthy gut is important for the efficacy of immunotherapies like CAR-T cells."


In future studies, the researchers plan to evaluate the impact of the intestinal microbiome on outcomes in CAR T-cell patients in a larger multicenter cohort. They also plan to investigate the impact of bacterial metabolites on clinical outcomes.


In his efforts to study the relationship between the microbiota and the response to CAR-T therapy in mouse models in his lab, van den Brink noted, "We have done a number of studies with mice, looking at the connection between the microbiota and CAR T-cell outcomes and believe these animal models will help us learn more about the underlying mechanism of this relationship. Our research could ultimately lead to ways to manage the microbiota and improve the efficacy of CAR-T therapy."


Simultaneously, the team seeks to evaluate the relationship of diet and the effect of diet on the microbiome.


"While many drugs can affect changes in the gut, we plan to gain more knowledge about how changes in the diet affect the microbiome and how the diet effects normal physiology," van den Brink concluded.


Amy Gallagher is a contributing writer.