Understanding the relationship between gut microbiome and CAR T-cell therapy response

Microorganisms live in or on almost every part of the human body and play an important role in the regulation of normal human processes. As a result, changes in the number or type of microorganisms, also known as the microbiome, can contribute to disease and altered responses to therapy, including cancer treatment.

In a new study published in Nature Medicine, Moffitt Cancer Center physician-scientists, in collaboration with four cancer centers in the United States and Germany, reveal how microorganisms in the gut influence non-Hodgkin lymphoma patient outcomes to a type of cellular immunotherapy called chimeric antigen receptor T-cell therapy, or CAR T.

It is estimated that there are 10 microorganisms for every human cell in the human body. These microorganisms are primarily bacteria, but also include viruses, fungi and yeast. The microorganisms that inhabit humans, called the microbiome, live around and interact with every human cell and influence many human processes. Recent studies have suggested that the microbiome can impact cancer patient responses to treatments, such as immunotherapies and stem cell transplants.

Moffitt researchers teamed up with MD Anderson Cancer Center and three German institutions – University Hospital of the Ludwig Maximilian University, University Hospital Heidelberg and University Hospital Regensburg – to assess whether the gut microbiome impacts outcomes for patients receiving CAR T-cell therapies. CAR T is a personalized treatment approach where a patient's own T cells are harvested, genetically engineered in a laboratory to target a specific cancer marker, expanded in number, and then reinfused into the patient. CAR T cells are approved to treat several types of blood cancers, including lymphoma, leukemia and multiple myeloma.

For this study, the research team analyzed the microbiome from 172 non-Hodgkin lymphoma patients who relapsed or were refractory to prior treatment. They discovered that patients who had taken strong, broad-spectrum antibiotics before receiving CAR T cell therapy had less microbiome diversity and poorer outcomes to treatment. However, the researchers found that these poor outcomes could also have been due to a higher tumor burden among the patients who received antibiotics and a more suppressed immune system. Additional factors associated with microbiome diversity included country of residence, general health before treatment and tumor burden.

Because tumor burden could influence antibiotic use and outcomes, the researchers decided to focus on patients who received either no or lower-risk antibiotics. Among this population, the researchers discovered that patients who had higher levels of the bacterium Bifidobacterium longum had an improved overall survival rate after CAR T.

They used this data to create a machine learning algorithm to predict patient CAR T outcomes based on their microbiomes. The algorithm was tested with patient data from Germany and validated with patient data from the U.S. Their analysis identified bacterial groups associated with either improved or poorer CAR T outcomes. For example, the bacterium Bacteroides eggerthii was associated with a higher chance of developing a response to treatment, while the bacterium Bacteroides stercoris was associated with patients not achieving a response.

We hope these data will lead to an improved understanding of the relationship between the microbiome and patient responses to CAR T-cell therapy. Understanding the causal nature of possible microbiome contributions to CAR T 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 prior to treatment."

Michael Jain, Study Co-Senior Author and Associate Member, Department of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center

This study was supported by the National Cancer Institute (P30 CA076292).

Source:
Journal reference:

Stein-Thoeringer, C. K., et al. (2023). A non-antibiotic-disrupted gut microbiome is associated with clinical responses to CD19-CAR-T cell cancer immunotherapy. Nature Medicine. doi.org/10.1038/s41591-023-02234-6.

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