Gut microbiome composition affects CAR T-cell therapy outcomes in lymphoma
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An international research collaboration has contributed new insights into how the gut microbiome contributes to the effectiveness of immunotherapy for cancer.
Investigators from five academic centers in the United States and Germany published an analysis in Nature Medicine showing that wide-spectrum antibiotics used before CD19-directed chimeric antigen receptor T-cell therapy led to poorer outcomes among adults with relapsed or refractory large B-cell lymphoma.
The findings are similar to those of a previous retrospective study published last year, according to Michael D. Jain, MD, PhD, associate member and ICE-T medical director in the department of blood and marrow transplant and cellular immunotherapy at Moffitt Cancer Center. However, Jain’s group found the negative effect of antibiotics on treatment outcomes likely is confounded by factors that include increased tumor burden and systemic inflammation among patients pretreated with high-risk antibiotics.
“Patients who get antibiotics are very different than the patients who don’t,” Jain told Healio. “Patients who have these large tumors also have very low T-cell counts, and the types of T cells that they have in their body are really deranged.”
Given the potential confounders, Jain and colleagues decided to also examine gut microbiome composition among patients who received CAR-T but did not receive antibiotics prior to infusion.
“We found the predictive capacity of the microbiome to associate with treatment outcomes using machine learning analysis was much stronger,” he said. “Including patients who received prior antibiotics negated the predictive capacity of the microbiome to associate with treatment outcomes because it was confounded by other reasons why these patients might not do as well.”
Jain spoke with Healio about the research findings, the strengths of these results compared with those of prior studies, and how he and his fellow investigators hope to leverage what they have learned into meaningful interventions that can improve treatment outcomes with CAR T-cell therapy.
Healio: What motivated your team to conduct this study?
Jain: Previous research has suggested that gut microbiome composition affects patient outcomes after receiving immune checkpoint inhibitors. These investigations yielded evidence that the use of antibiotics and immune checkpoint inhibitors has been associated with worse outcomes. The hypothesis is that the gut microbiome is important. Although CAR T-cell therapy is quite different than immune checkpoint inhibitor therapy, there are some similarities that make exploring a potential relationship with gut microbiome composition a worthwhile effort.
After CAR T cells are reinfused into a patient, they grow until they hit a peak in the patient's blood. This takes about a week, at which point the number of CAR T cells typically drops off. As the cell numbers grow, they eliminate tumor cells by releasing cytokines. One of the major things that our immune system is doing all the time is encountering and interacting with bacteria, and one of the largest sources of bacteria — whether they're pathogenic or not — is within the human gut, so it is easy to imagine that the way a person’s immune system interacts with gut microbes may affect how these highly engineered immune cells interact with the rest of the immune system and their ability to eradicate a person’s cancer. So, the overall aim of our work examines whether the types of bacteria that live in the human gut influence characteristics of the immune system to impact treatment outcomes after engineered CAR T-cell therapy.
Healio: This study contained two separate analyses. Can you explain what you found?
Jain: First, we demonstrated that patients who received prior antibiotic treatment had worse CAR-T outcomes and that the antibiotics had a negative effect on the patient's gut microbiome diversity. However, this association was confounded by tumor burden and poor T-cell quality.
In a separate analysis of patients not treated with antibiotics, we partnered with the lab of Eran Elinav, MD, PhD, and Christoph K. Stein-Thoeringer, MD, at the German Cancer Research Center (DKFZ). Both are experts in analyzing microbial complexity and the gut microbiome. They performed a series of machine learning methods that showed gut microbiome composition does affect patient outcomes after CAR T-cell therapy among those not treated with antibiotics. For example, patients who had higher levels of Bifidobacterium longum had longer overall survival after CAR T. The analysis also identified specific types of bacteria — mainly, those associated with dysbiosis — linked with worse outcomes after CAR-T.
Healio: What are the clinical implications of your study results?
Jain: The microbiome is a hot area in drug development. There are a lot of startup companies involved and working on drugs that can reregulate the microbiome. Simultaneously, there is a developing body of research literature on the utility of fecal transplant. Additionally, there are capsules of defined microbial mixtures that people can take that can restore their microbiome. There are likely many drugs other than antibiotics with an ability to affect humans' gut microbiome. Finding the associations between druggable targets that affect the microbiome and using that information to provide a simple intervention to improve people's cancer outcomes is the goal.
Healio: Are there plans to apply knowledge from these results into an intervention that may improve CAR-T efficacy?
Jain: Our collaborators at The University of Texas MD Anderson Cancer Center can create these defined mixtures of bacteria to help restore a healthy gut microbiome. They are hoping to test this in a clinical trial of patients who received antibiotics or had dysbiosis to see if such an intervention can reregulate their gut to improve CAR T-cell therapy directly. At Moffitt, we are looking for ways to do the same thing, but there is always a bit of a risk because the patients we treat with CAR-T are immunosuppressed. Somehow giving bacteria directly to immunocompromised individuals — even if they are good bacteria — may cause infections. So, we are trying to see if there are more elegant ways that we can modulate the microbiome without giving live bacteria unnecessarily.
Healio: Is there anything else you feel is important to emphasize?
Jain: The microbiome is quite complex and is heavily influenced by factors that include diet and location of residence. One of the strengths of our study is the international patient cohort. Including individuals from Germany and Texas — plus those in Florida treated at Moffitt Cancer Center — ensures a study population with different genetic backgrounds, lifestyles and diets. This type of diversity is needed for these studies to ensure results are not confounded by human cultural factors that really influence human microbiomes.
References:
- Smith M, et al. Nat Med. 2022;doi:10.1038/s41591-022-01702-9.
- Stein-Thoeringer CK, et al. Nat Med. 2023;doi:10.1038/s41591-023-02234-6.
For more information:
Michael D. Jain, MD, PhD, can be reached at michael.jain@moffitt.org.
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