Intestinal Microbiome May Play a Role in CAR T-Cell Therapy Outcomes

Pharmacy Times^® interviewed Melody Smith, MD, MS, a medical oncologist and hematologist at Stanford Medicine, on her presentation titled “Interrogating the impact of the intestinal microbiome on CAR T cell therapy” at the American Association for Cancer Research Immunotherapy Conference, held February 23-26, 2025, in Los Angeles, California.

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In the interview, Smith discussed her research into how the intestinal microbiome influences the efficacy and durability of CAR T-cell therapy in patients with hematologic malignancies. Conducted at Memorial Sloan Kettering and the University of Pennsylvania, Smith and her colleagues found that prior exposure to certain antibiotics (piperacillin, tazobactam, imipenem, and meropenem [PIM]) can negatively impact outcomes for certain CAR T-cell therapies.

Smith explained that these findings suggest that microbiome composition plays a critical role in CAR T-cell responses. While studies on modifying the microbiome before therapy are still ongoing, she highlights the potential of dietary interventions, such as high-fiber and fermented food diets, to promote a healthier microbiome. Additionally, Smith noted that chemotherapy and conditioning regimens likely alter the microbiome, but more research is needed to understand their precise impact on CAR T-cell functionality.

Pharmacy Times: How does the composition of the intestinal microbiome influence CAR T-cell efficacy and durability in patients with hematologic malignancies?

Melody Smith, MD, MS: We and others have investigated how the intestinal microbiome modulates car T cell response. I was the lead and first author on the first paper that really characterized this phenotype. We used a cohort of patients from 2 academic institutions, both Memorial Sloan Kettering Cancer Center and the University of Pennsylvania.

In our studies, we were really curious about this question as to how the microbiome impacts responses following CAR T-cell therapy, and we specifically focused on a cohort of patients who had received CD19 CAR T-cell therapy. We first evaluated medications because we know medications can induce alterations to the microbiome, known as dysbiosis. We, in fact, did find that those patients who received antibiotics in the 4 weeks prior to CAR T-cell therapy, but more specifically antibiotics that target obligate anaerobes such as piperacillin, tazobactam, imipenem, and meropenem [PIM]—these patients had decreased overall survival as well as progression free survival. That gave a hint that the microbiome was playing a role, and we did various multivariate analysis to evaluate for confounders, to ensure that this exposure to antibiotics wasn't a confounder for a sicker patient, but really that it was suggestive of a microbiome impact.

Also in that study, we analyzed specific bacterial taxa by prospective banking of patients who were receiving CD19 CAR T-cell therapy, and we identified specific bacterial taxa and metabolic pathways that were associated with CAR T-cell outcomes.

I'll just mention too that our initial publication was insightful, but it's been quite encouraging to see subsequent papers now, to date, about 3 papers that have evaluated patient cohorts of recipients of C19 CAR T-cell therapies analyzing the microbiome and have substantiated many of our initial findings.

Pharmacy Times: How can microbiome dysbiosis resulting from prior antibiotic use impact CAR T-cell therapy outcomes?

Smith: So just to highlight the antibiotic phenotype, specifically, we found that the antibiotic exposure prior to CAR T-cell therapy, specifically these anaerobe targeting antibiotics, which we denoted as PIM—piperacillin, tazobactam, imipenem, and meropenem—they were associated with decreased overall survival and decreased progression free survival in CD19 CAR T-cell recipients, even when we stratified by disease, looking at non-Hodgkin lymphoma and B-cell acute lymphoblastic leukemia.

We also found that those patients who were exposed to PIM in the 4 weeks prior to CAR T-cell therapy had an association of increased immune effector cell-associated neurotoxicity syndrome [ICANS], which is the toxicity that can occur in patients after CAR T-cell therapy. We didn't see any association of antibiotic exposure with cytokine release syndrome. Just to note again, that this ICANS association, as well as decreased overall survival, has been seen in other independent cohorts that have been published in the literature.

Pharmacy Times: What are the implications of modifying the microbiome prior to CAR T-cell therapy?

Smith: I think that these studies are really exciting. This is a new space compared to other studies of the intestinal microbiome in cancer immunotherapies, such as the data in allogeneic hematopoietic cell transplantation or immune checkpoint blockade, which have much more longitudinal data, much more depth of data. For the allotransplant space, over a decade, and for immune checkpoint blockade also nearing around that timeframe now. But the CAR T cell studies are quite recent. So when thinking about interventional implications of modifying the microbiome, those studies still need to be done. These microbiome insights from the bacterial taxa that have already been identified are hypothesis generating, but additional studies need to be done for mechanism. So that is an ongoing question, I would say.

But certainly, the things that we know that modulate the microbiome or have the greatest impact in addition to antibiotics and other medications, are the diet. So, I always tell patients that there may be insights we can glean from other diet studies as to what diet is going to promote a healthy microbiome, whether high fiber or a diet rich in fermented foods, other studies outside of the CAR T cell space have shown that these promote a diverse microbiome. So, these are some of the things I talk to patients about when this question is asked, but we don't have any data concretely in the field of CAR T cell therapy just yet.

Pharmacy Times: How do microbiome changes during chemotherapy or conditioning regimens affect CAR T-cell functionality?

Smith: That is a really important question, because we know from, again, other studies of the microbiome, that chemotherapy does impact the microbiome; it alters the microbiome. In our initial publication, we characterized the baseline microbiome phenotype, and we defined baseline as the sample prior to CAR T-cell infusion, so that could have been before or after patients received chemotherapy, and so specifically looking at the impact of the chemotherapy on the microbiome. That data is not yet out there, but I know that we and others are looking at that in our ongoing studies.