Increasing evidence from human studies and preclinical experiments suggests that the gut microbiome may modulate the efficacy of T cell-driven cancer immunotherapies, such as immune checkpoint blockade. Immunotherapy with CD19 chimeric antigen receptor (CAR) T cell has opened up new treatment options for patients with certain forms of refractory and relapsing B-cell leukemias or lymphomas. But the therapy is hampered by considerable heterogeneity in responses. Complete and long-term remission is only achieved in up to 40% of patients.
Researchers from multiple centers in Germany and the United States, led by Eran Elinav, director of the DKFZ-Weizmann Institute of Science Microbiome & Cancer Bridging division, have found that the gut microbiome may modulate the efficacy of CD19 CAR T cell immunotherapy in patients with B cell leukemias and lymphomas.
This largest prospective study of its kind has followed 172 lymphoma patients previously failing multiple rounds of chemotherapy, from before CAR T immunotherapy initiation until two years later. Interestingly, 20% of patients receiving a subset of broad-spectrum (“high-risk”) antibiotics, such as meropenem, piperacillin–tazobactam or cefepime, featured an altered clinical response to subsequent CAR-T therapy, compared to patients who received other antibiotics and patients who were not treated with antibiotics prior to therapy.
However, this antibiotics-associated reduced CAR T therapy response was not driven by the effects of the antibiotics themselves, but rather by the fact that patients treated with “high-risk” antibiotics before initiation of CAR T therapy tended to have higher pre-therapy tumor burden and systemic inflammation as compared to non-antibiotics-treated patients. These adverse pre-treatment conditions rendered subsequent CAR T therapy less effective.
Importantly, exclusion of these confounding “high-risk” antibiotics-treated patients from the analysis enabled the researchers to identify strong and previously masked associations between the pre-CAR T therapy gut microbiome and subsequent clinical response to immunotherapy (including patients’ survival). To further strenghen the connections between the starting microbiome and CAR-T efficacy across geography, diet, and and other confounders, the researchers next used machine learning models trained on the German cohort and then applied as a validation on the respective American patients. Importantly, the models were able to potently predict therapy outcomes, but only upon exclusion of patients exposed to “high-risk” antibiotics. In other words, the study showed that the pre-therapy gut microbiome in lymphoma patients can help predict their response to subsequent CD19 CAR T therapy across populations, unless their microbiome is disrupted by wide-spectrum antibiotics.
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