Gut Microbiome May Impact CAR T-Cell Therapy Response in Patients With Lymphoma

A recent study published in Nature Medicine found that the gut microbiome influenced chimeric antigen receptor (CAR) T-cell therapy responses in patients with non-Hodgkin lymphoma.

Increasing research has found that the gut microbiome, which comprises microorganisms including bacteria, viruses, fungi, and yeast, could affect patient responses to cancer treatments such as immunotherapy or transplantation. The prospective clinical study, conducted by researchers at Moffitt Cancer Center in tandem with 5 German cancer centers, aimed to determine the role of the microbiome and potential confounders in the context of CD19-targeted CAR T-cell therapy outcomes.

Recent reports have implicated gut microbiome disruption due to broad-spectrum antibiotics as a potential factor in reduced immunotherapy effectiveness, the authors noted.

“Understanding the causal nature of possible microbiome contributions to CAR-T therapy effectiveness and adverse effects may enable better understanding of differential CAR-T cell activation, persistence and clinical efficacy, and ultimately the prediction of response to CAR-T cell immunotherapy even prior to treatment,” the authors wrote.

A total of 172 patients with non-Hodgkin lymphoma that was relapsed or refractory to previous therapies were included in the study. Of those patients, 122 were treated with axicabtagene ciloleucel, 49 received tisagenlecleucel, and 1 received lisocabtagene maraleucel. Patients received a median of 3 prior therapy lines before receiving CAR T-cell therapy.

First, researchers looked for connections between broad-spectrum, which the study authors deemed high-risk, antibiotic treatment prior to CAR T-cell therapy and outcomes. They found that receiving broad-spectrum antibiotics before CAR T-cell therapy was associated with lower microbial diversity and worse treatment outcomes. However, this finding may be due to a higher tumor burden before treatment and systemic inflammation in patients who received high-risk antibiotics ahead of treatment.

To determine the effect of those confounding factors, the authors analyzed the patient population not exposed to high-risk antibiotics. In these patients, higher pre-treatment Bifidobacterium longum was linked to better survival outcomes after CAR T-cell therapy.

A microbiome-based machine learning algorithm was developed using the German not exposed to high-risk antibiotics and tested in the American cohort. The algorithm was able to differentiate patients who had a long-term response with those who did not respond to therapy. The findings showed Bacteroides, Ruminococcus, Eubacterium, and Akkermansia to be most relevant in determining CAR-T responsiveness. Akkermansia was also linked to peripheral T cell levels prior to infusion.

Overall, the findings suggest that microbiome features may impact outcomes for patients with lymphoma treated with CAR T-cell therapy. Further, these features may be useful in determining which patients will have favorable outcomes after CAR T-cell therapy.

The study was limited by small cohort sizes and its observational nature, the authors noted. Therefore, further studies are needed to determine potential causative effects.

“Our clinical and analytical design enabled the identification of a novel set of microbiome-based biomarkers that enable data-driven stratification in non-antibiotics-pretreated patients,” the authors concluded. “These may be potentially clinically linked to the individual and used to optimize patient selection or for tailored management and follow-up of CAR-T cell-treated patients.”

Reference

Thoeringer CK, Saini NY, Zamir E, et al. A non-antibiotic-disrupted gut microbiome is associated with clinical responses to CD19-CAR-T cell cancer immunotherapy. Nat Med. Published online March 13, 2023. doi:10.1038/s41591-023-02234-6