Scientists from the Weizmann Institute of Science and the German Cancer Research Center (DKFZ), together with colleagues from Israel, Germany and the United States, have discovered that the intestinal microbiome can modulate the effectiveness of CAR-T cell immunotherapy in patients with lymphomas. B cells. Individualized microbiological information obtained from patients' gut microbiomes before the initiation of CAR-T therapy could accurately predict their subsequent responsiveness to therapy, but only on the condition that these patients were not pretreated with broad-spectrum antibiotics. .
There is increasing evidence from human studies and preclinical experiments that the gut microbiome can modulate the effectiveness of T cell-based cancer immunotherapies, such as immune checkpoint blockade. Immunotherapy with CD19 chimeric antigen receptor (CAR) T cells has opened new treatment options for patients with certain forms of refractory and relapsed B-cell leukemias or lymphomas. But therapy is hampered by considerable heterogeneity in responses. Complete, 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 Division of Microbiome and Cancer at DKFZ-Weizmann Institute of Science, have discovered that the gut microbiome can modulate the effectiveness of immunotherapy with CD19 CAR-T cells. in patients with B-cell leukemias and lymphomas.
In this larger prospective study, 172 patients with lymphoma who had previously failed multiple rounds of chemotherapy were followed from before the start of CAR-T immunotherapy until two years later. Interestingly, 20% of patients who received a subset of broad-spectrum ("high-risk") antibiotics, such as meropenem, piperacillin-tazobactam, or cefepime, had an impaired clinical response to subsequent CAR-T therapy, compared to those patients who received other antibiotics and patients who were not treated with antibiotics before therapy.
However, this lower response to antibiotic-associated CAR-T therapy was not due to the effects of the antibiotics themselves, but rather to the fact that patients treated with "high-risk" antibiotics before the start of therapy CAR-T tended to have higher pre-therapy tumor burden and higher systemic inflammation compared to patients not treated with antibiotics. These adverse pretreatment conditions made subsequent CAR-T therapy less effective.
Importantly, excluding these antibiotic-treated “high-risk” patients from the analysis allowed the researchers to identify robust and previously masked associations between the pre-CAR-T gut microbiome and subsequent clinical response to immunotherapy (including patient survival). To further strengthen the connections between the baseline microbiome and the effectiveness of CAR-T therapy beyond geography, diet, and other “local” confounding factors, the researchers next used machine learning models trained on the patients. Germans and then applied as validation in the respective American patients.
Importantly, the models were able to powerfully predict therapy outcomes, but only after excluding 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 in all populations, unless their microbiome is altered by broad-spectrum antibiotics. spectrum.
The researchers identified several key microbiome characteristics that predict CAR-T efficacy, including Bacteroides, Ruminococcus, Eubacterium, and Akkermansia species. Of these species, Akkermansia was also associated with higher levels of peripheral T cells in these patients.
Taken together, the study reveals strong associations between microbiomes and CAR-T outcomes, which first author Christoph Stein-Thoeringer (now professor at the University Medical Center Tübingen, Germany) believes may contribute to the development of predictions based on microbiomes of CAR-T cell immunotherapy outcomes. Furthermore, the findings of this study may provide a better understanding of the differential activation of CAR-T cells, their persistence, and their clinical efficacy in different patients. The study also highlights the need to further investigate the causal nature of the relationship between the gut microbiome and cancer immunotherapy outcomes.
“These exciting findings,” said Prof. Elinav, “exemplify the potential for the unique signatures of our microbiome to be harnessed as potential markers of disease and treatment response in multiple human disorders, including cancer. “With new research, we hope that microbiome-based diagnostics and therapies will enter the field of precision oncology.”