Recent years have seen remarkable advances in chimeric antigen receptor T (CAR-T) cell therapy in the treatment of hematological malignancies. However, unexpected severe toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome still hamper therapeutic application. Moreover, the role of the gut microbiome in the treatment of malignancies has received great attention and there is evidence that the gut microbiome affects the efficacy of immunotherapy, such as PD-1 and CTLA-4. Thus, how to improve the therapeutic efficacy of CAR-T therapy by targeting the gut microbiome is of great interest.
On September 10, 2022, Professor HUANG He and Professor LI Mingding from First Affiliated Hospital, Zhejiang University School of Medicine co-published a paper titled CAR-T cell therapy-related cytokine release syndrome and therapy response is modulated by the gut microbiome in hematological malignancies in the journal Nature Communications. This study uncovers the link between the gut microbiome and CAR-T therapy-related responses, which may help improve the therapeutic efficacy of CAR-T therapy.
Researchers investigated the relationship between the gut microbiome and CRS related to CAR-T cell therapy and therapeutic responses in patients with relapsed and refractory multiple myeloma. By applying 16S rRNA sequencing technology and metabolic liquid chromatography-mass spectrometry, researchers found that patients significantly decreased alpha diversity after CAR-T infusion, especially patients in partial remission. Additionally, bacteria, such as Bifidobacterium, Faecalibacterium, Sutterella, and Ruminococcus, were enriched in patients in complete remission after CAR-T infusion, indicating the correlation between bacterial abundance composition and therapeutic response. Additionally, associations between CRS grade and microbial composition have been identified, with patients with severe CRS showing greater abundance of Bifidobacterium, Leuconostoc, and Lactococcus.
Figure 1 Association of differences in gut microbiome composition with responses to CAR-T treatment in patients with multiple myeloma
Additionally, through time-dependent differential analysis, the study revealed a correlation of gut microbial functions with CAR-T therapy and identified differential pathways related to RNA polymerase function, amino acid metabolism , fatty acid metabolism and glutathione metabolism between patients in complete remission and those in partial remission. Moreover, the pathways, such as antibiotic synthesis, lipoic acid metabolism, amino acid metabolism, and nucleic sugar metabolism, differed in patients with different grades of CRS. In addition, the study further analyzed samples from the validation group by applying metabolic liquid chromatography-mass spectrometry. The results showed that metabolites, such as deoxycortone, L-phenylalanine, L-cystine and choline, were significantly enriched in patients in complete remission, while phosphocreatine annotated the metabolism of arginine and proline was found to be significantly enriched in patients with severe CRS. .
Figure 2 Compositional differences between subjects with different CRS scores
in patients with multiple myeloma.
This is the first study in the world to reveal the relationship and mechanisms between the gut microbiome and the effects associated with CAR-T cell therapy in patients with relapsed or refractory multiple myeloma. It details how the gut microbiome influences the efficacy of immunotherapy and CAR-T-related CRS. The study may guide therapeutic intervention to increase efficacy and decrease toxicity in patients receiving CAR-T therapy.