Autologous CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy has transformed the management of chemorefractory large B-cell lymphoma. Despite the enthusiasm surrounding CAR-T therapy, it fails to provide durable remissions in 60 percent of patients, and the acute toxicities can result in a heavy burden on the health care system.1–3 Data on which patients are likely to benefit from the therapy are desirable to improve the appropriate delivery and subsequent outcomes of these complex therapies. Tumor burden, performance status, and inflammatory markers have been associated with less favorable outcomes. However, these characteristics are often attributed to disease burden, and in the absence of effective alternative options, CAR-T therapy may still be pursued.4,5 Additionally, these factors are generally not considered modifiable in the absence of disease control; therefore, awareness may not inform management decisions.
Across several cancer types, the gut microbiome has been shown to regulate T-cell immunity and modulate the antitumor response to immune therapy such as checkpoint blockade, allogeneic transplantation, and adoptive cellular therapy.6–8 Changes to the microbiome via fecal transplant or antibiotics has been associated with outcomes. Dr. Melody Smith and colleagues at Memorial Sloan Kettering Cancer Center and the University of Pennsylvania set out to explore whether antibiotic exposure or fecal microbiome composition was associated with efficacy and toxicity following anti-CD19 CAR-T therapy in 228 adult patients with B-cell malignancies. This work could identify modifiable risk factors to enhance outcomes with CAR-T therapy.
First, Dr. Smith and colleagues retrospectively explored whether exposure to antibiotics known to change the intestinal microbiota during a four-week period prior to CAR-T infusion was associated with outcomes. Antibiotic exposure was associated with worse overall survival. Specific anaerobe-targeting antibiotics including piperacillin/tazobactam, imipenem/cilastatin, and meropenem exposure correlated with decreased overall survival and increased neurotoxicity independent of known prognostic factors and CAR-T construct. A prospective cohort of 48 CAR-T recipients revealed that the fecal microbiome was altered at baseline compared to healthy controls, and clinical outcomes were associated with differences in specific bacterial taxa and metabolites.
In Brief
Further causal mechanistic work is needed to characterize the affect of specific bacterial taxa and metabolic pathways on immune cell subsets and the impact following immune therapy. A larger validation cohort would also be of value. The implications of this work now suggest that improved antibiotic stewardship particularly with broad-spectrum anaerobe-targeting therapy should be employed in the four weeks preceding CAR-T therapy. Additionally, interventional studies aimed at altering the gut microbiome are warranted. Trust the gut to help identify modifiable risk factors that may improve outcomes for patients undergoing CAR-T therapy.
Competing Interests
Dr. Nastoupil indicated no relevant conflicts of interest.
