Antibiotic use, certain gut bacteria affect CAR-T efficacy, toxicity
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The use of broad-spectrum antibiotics in the month leading up to chimeric antigen receptor T-cell therapy led to poorer outcomes and increased treatment-related toxicities, study results showed.
Certain types of gut bacteria had an impact on treatment efficacy and related toxicities among patients who received CAR-T for non-Hodgkin lymphoma or acute lymphoblastic leukemia, researchers reported.
Background
CAR T-cell therapies have produced “significant benefit for patients” in terms of overall response rates and survival, according to Melody Smith, MD, assistant professor of medicine in the division of blood and marrow transplantation and cellular therapy at Stanford University School of Medicine.
Despite these successes, a large proportion of patients either don’t respond to CAR-T or initially respond and then relapse.
Prior research has explored the effect of the gut microbiome on patients who undergo hematopoietic stem cell transplantation, as well as the effects of antibiotics on outcomes with the use of immune checkpoint inhibitors.
Smith — who participated in the study while serving as a postdoctoral researcher at Memorial Sloan Kettering Cancer Center — said her team sought to determine what effect the gut microbiome had on CAR-T outcomes and treatment-related toxicity.
Scientists have begun looking at humans as a “super organism” comprising a symbiosis of an individual’s cell microbiome, according to Marcel R.M. van den Brink, MD, PhD, head of the division of hematologic malignancies at Memorial Sloan Kettering.
“The gut microbiome can impact human health and disease in many ways,” van den Brink told Healio. “We saw hints from previous studies in allogeneic stem cell transplant that the gut microbiome can be a modulator of immunity, and we wanted to see if this held up and was relevant for CAR T cells.”
Methodology
Smith and colleagues’ study examined two cohorts of patients who received CD19-directed CAR T cells for non-Hodgkin lymphoma or B-cell acute lymphoblastic leukemia at Memorial Sloan Kettering or University of Pennsylvania.
The researchers used the first cohort (n = 228; median age, 56 years; 69.7% male) to retrospectively examine the impact of prior antibiotic use on CAR-T clinical outcomes. The second cohort (n = 48; median age, 64 years; 70.8% male) had prospective baseline fecal samples collected before CAR T-cell infusion for subsequent evaluation of the fecal microbiome.
Key findings
Researchers determined use of certain antibiotics — including piperacillin/tazobactam, meropenem and imipenem/cilastatin (P-I-M) — negatively affected OS (HR = 1.71; 95% CI, 1.12-2.59).
More granular analysis showed shorter OS (HR = 2.54; 95% CI, 1.41-4.56) among patients with non-Hodgkin lymphoma who received P-I-M prior to CAR-T, but results showed no significant effect on PFS in this group (HR = 1.29; 95% CI, 0.82-2.01).
Investigators also noted significantly increased risk for immune effector cell-associated neurotoxicity syndrome (ICANS) among the entire cohort evaluated for pre-CAR-T antibiotic use (P = .023). When broken into disease groups, patients with non-Hodgkin lymphoma showed significantly increased incidence of ICANS associated with prior P-I-M use (P = .013), whereas those with B-cell ALL did not.
Stool samples from the prospective cohort demonstrated an altered fecal microbiome — including lower alpha diversity, increased frequency of bacterial dominance and altered bacterial composition — compared with healthy controls.
Samples analyzed using 16S ribosomal RNA and metagenomic shotgun sequencing showed species in the class Clostridia demonstrated an association with complete responses to CAR T-cell therapy at day 100 after infusion.
Investigators noted a higher prevalence of the order Veillonellales and the family Veillonellaceae as the only taxa associated with decreased complete response at day 100.
Researchers did not identify any taxa associated with treatment-related toxicities, including cytokine release syndrome or ICANS.
Clinical implications
The results from this study suggest that gut microbiome composition has an effect on CAR-T outcomes, but both van den Brink and Smith cautioned that further prospective studies in larger patient populations are needed to confirm associations.
“Patients who were exposed to an antibiotic in the 4 weeks prior to CAR T cells did have worse overall survival compared with those patients who were not exposed to any antibiotics,” Smith told Healio. “Data on specific antibiotics that are more disruptive to the gut commensals — specifically the obligate anaerobes that reside in the gut — suggests that those antibiotics do more to disturb the intestinal microbiome and are likely to produce worse outcomes.”
Until researchers determine why antibiotics affect CAR T-cell activity, the results provide some initial insights “in terms of antibiotic stewardship” for individuals receiving CAR T-cell therapies, Smith said.
The results “suggest that there may be certain antibiotics that we want to avoid in the period prior to CAR T-cell therapy because of this association,” she added.
The results showing inferior survival with pre-infusion antibiotic use mirror associations observed in prior research of patients who underwent HSCT or received immune checkpoint inhibitors, van den Brink said.
“Antibiotics can have negative impacts on outcomes of immune therapies,” he said. “We've all learned that you should be careful with use of antibiotics because it might lead to multi-drug-resistant bacteria, but now we have another thing to consider: The use of antibiotics, specifically [by] those patients who are receiving immune therapies could negatively impact patient outcomes.”
For more information:
Melody Smith, MD, MS, can be reached at melodysm@stanford.edu.
Marcel R.M. van den Brink, MD, PhD, can be reached at vandenbm@mskcc.org.
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