CAR-T cell therapy-related cytokine release syndrome and therapeutic response is modulated by the gut microbiome in hematologic malignancies

Abstract

Immunotherapy utilizing chimeric antigen receptor T cell (CAR-T) therapy holds promise for hematologic malignancies, however, response rates and associated immune-related adverse effects widely vary among patients. Here we show, by comparing diversity and composition of the gut microbiome during different CAR-T therapeutic phases in the clinical trial ChiCTR1800017404, that the gut flora characteristically differs among patients and according to treatment stages, and might also reflect patient response to therapy in relapsed/refractory multiple myeloma (MM; n = 43), acute lympholastic leukemia (ALL; n = 23) and non-Hodgkin lymphoma (NHL; n = 12). We observe significant temporal differences in diversity and abundance of Bifidobacterium, Prevotella, Sutterella, and Collinsella between MM patients in complete remission (n = 24) and those in partial remission (n = 11). Furthermore, we find that patients with severe cytokine release syndrome present with higher abundance of Bifidobacterium, Leuconostoc, Stenotrophomonas, and Staphylococcus, which is reproducible in an independent cohort of 38 MM patients. This study has important implications for understanding the biological role of the microbiome in CAR-T treatment responsiveness of hematologic malignancy patients, and may guide therapeutic intervention to increase efficacy. The success rate of CAR-T cell therapy is high in blood cancers, yet individual patient characteristics might reduce therapeutic benefit. Here we show that therapeutic response in MM, ALL and NHL, and occurrence of severe cytokine release syndrome in multiple myeloma are associated with specific gut microbiome alterations.

Recent advances in 2D material-based phototherapy

“…Immunotherapies, including chimeric antigen receptor T cell (CAR-T) therapies, immunological checkpoint blockade (ICB) therapies, and tumor vaccines, have shown promising results in identifying and killing cancer cells with durable anticancer responses by stimulating the body's immune system (Han C et al, 2018;Helmink et al, 2018;Lecoq et al, 2022). Despite its potential, immunotherapy is limited in its use because of patient-to-patient variance, poor antitumor efficacy, and coexisting adverse effects (Wei et al, 2019;Fisher et al, 2020;Hu et al, 2022). PTT has been used in conjunction with immunotherapy to improve cancer therapies in recent years.…”

Gut microbiome in multiple myeloma: Mechanisms of progression and clinical applications

“…The gut microbial composition exhibits great individual specificity (110), which may be an important environmental factor contributing to individual differences in response to treatment. Intriguingly, recent studies have revealed a potential role for the gut microbiota in the efficacy and toxicity of CAR-T cell therapy for B-cell-derived hematologic malignancies, including relapsed/ refractory (r/r) MM, acute lymphoblastic leukemia (B-ALL), and non-Hodgkin lymphoma (B-NHL) (111,112). Hu et al have reported that B-cell maturation antigen (BCMA) CAR-T cell therapy-related cytokine release syndrome (CRS) and treatment response is regulated by the intestinal microbiome in MM (111).…”

“…Intriguingly, recent studies have revealed a potential role for the gut microbiota in the efficacy and toxicity of CAR-T cell therapy for B-cell-derived hematologic malignancies, including relapsed/ refractory (r/r) MM, acute lymphoblastic leukemia (B-ALL), and non-Hodgkin lymphoma (B-NHL) (111,112). Hu et al have reported that B-cell maturation antigen (BCMA) CAR-T cell therapy-related cytokine release syndrome (CRS) and treatment response is regulated by the intestinal microbiome in MM (111). Taxonomic analysis by bacterial 16S rRNA gene sequencing of the fecal microbiota showed that high abundance of genus Sutterella was related to both complete remission (CR) and prolonged survival after CAR-T treatment, in addition, Bifidobacterium and Leuconostoc were found to be abundant in MM patients with severe CRS while Butyricicoccus were abundant in patients with mild CRS (111).…”

“…have reported that B-cell maturation antigen (BCMA) CAR-T cell therapy-related cytokine release syndrome (CRS) and treatment response is regulated by the intestinal microbiome in MM ( 111 ). Taxonomic analysis by bacterial 16S rRNA gene sequencing of the fecal microbiota showed that high abundance of genus Sutterella was related to both complete remission (CR) and prolonged survival after CAR-T treatment, in addition, Bifidobacterium and Leuconostoc were found to be abundant in MM patients with severe CRS while Butyricicoccus were abundant in patients with mild CRS ( 111 ). Bifidobacterium is a probiotic commonly used to boost host immunity, and its species composition can influence cytokine production ( 113 ).…”

“…Microbial derived SCFAs pentanoate and butyrate have been reported to enhance the antitumor activity of CAR-T cells through metabolic and epigenetic reprogramming ( 115 ). In addition, researchers found that pathways associated with amino acid metabolism, including phenylalanine, glutamate, tyrosine and arginine metabolism pathway, were differentially abundant across treatment outcomes and CRS grades in MM patients treated with CAR-T ( 111 ). These amino acids play an important role in the regulation of immune response by stimulating T lymphocytes, B lymphocytes and natural killer cells, regulating gene expression and lymphocyte proliferation, and promoting the production of antibodies, cytokines and other cytotoxic substances ( 116 ).…”