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Anti-CD19 chimeric antigen receptor (CAR) T cell therapy has led to unprecedented responses in patients with high-risk hematologic malignancies. However, up to 60% of patients still experience disease relapse and up to 80% of patients experience CAR-mediated toxicities, such as cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. We investigated the role of the intestinal microbiome on these outcomes in a multicenter study of patients with B cell lymphoma and leukemia. We found in a retrospective cohort ( n  = 228) that exposure to antibiotics, in particular piperacillin/tazobactam, meropenem and imipenem/cilastatin (P-I-M), in the 4 weeks before therapy was associated with worse survival and increased neurotoxicity. In stool samples from a prospective cohort of CAR T cell recipients ( n  = 48), the fecal microbiome was altered at baseline compared to healthy controls. Stool sample profiling by 16S ribosomal RNA and metagenomic shotgun sequencing revealed that clinical outcomes were associated with differences in specific bacterial taxa and metabolic pathways. Through both untargeted and hypothesis-driven analysis of 16S sequencing data, we identified species within the class Clostridia that were associated with day 100 complete response. We concluded that changes in the intestinal microbiome are associated with clinical outcomes after anti-CD19 CAR T cell therapy in patients with B cell malignancies. In an analysis of adult patients with hematologic malignancies who received anti-CD19 chimeric antigen receptor T cell therapy, baseline gut microbiome composition was correlated with clinical response and treatment with broad-spectrum antibiotics in the four weeks prior to infusion was associated with worse survival and increased neurotoxicity.

In this study, the gastrointestinal microbiome was serially monitored in patients undergoing allogeneic hematopoietic-cell transplantation at four centers. Lower microbial diversity was associated with poorer outcomes after HCT.

The opportunities genetic engineering has created in the field of adoptive cellular therapy for cancer are accelerating the development of novel treatment strategies using chimeric antigen receptor (CAR) and T cell receptor (TCR) T cells. The great success in the context of hematologic malignancies has made especially CAR T cell therapy a promising approach capable of achieving long-lasting remission. However, the causalities involved in mediating resistance to treatment or relapse are still barely investigated. Research on T cell exhaustion and dysfunction has drawn attention to host-derived factors that define both the immune and tumor microenvironment (TME) crucially influencing efficacy and toxicity of cellular immunotherapy. The microbiome, as one of the most complex host factors, has become a central topic of investigations due to its ability to impact on health and disease. Recent findings support the hypothesis that commensal bacteria and particularly microbiota-derived metabolites educate and modulate host immunity and TME, thereby contributing to the response to cancer immunotherapy. Hence, the composition of microbial strains as well as their soluble messengers are considered to have predictive value regarding CAR T cell efficacy and toxicity. The diversity of mechanisms underlying both beneficial and detrimental effects of microbiota comprise various epigenetic, metabolic and signaling-related pathways that have the potential to be exploited for the improvement of CAR T cell function. In this review, we will discuss the recent findings in the field of microbiome-cancer interaction, especially with respect to new trajectories that commensal factors can offer to advance cellular immunotherapy.

Disease progression is a substantial challenge in patients with non-Hodgkin lymphoma (NHL) undergoing chimeric antigen receptor T cell (CAR-T) therapy. Here we present InflaMix (INFLAmmation MIXture Model), an unsupervised quantitative model integrating 14 pre-CAR-T infusion laboratory and cytokine measures capturing inflammation and end-organ function. Developed using a cohort of 149 patients with NHL, InflaMix revealed an inflammatory signature associated with a high risk of CAR-T treatment failure, including increased hazard of death or relapse (hazard ratio, 2.98; 95% confidence interval, 1.60–4.91; P  < 0.001). Three independent cohorts comprising 688 patients with NHL from diverse treatment centers were used to validate our approach. InflaMix consistently and reproducibly identified patients with a higher likelihood of disease relapse and mortality, and it provided supplementary predictive value beyond established prognostic markers, including tumor burden. Moreover, InflaMix exhibited robust performance in cases with missing data, maintaining accuracy when considering only six readily available laboratory measures. These findings show that InflaMix is a valuable tool for point-of-care clinical decision-making in patients with NHL undergoing CAR-T therapy. A preinfusion circulatory inflammation biomarker-based signature predicts the likelihood of treatment failure in patients with non-Hodgkin lymphoma who were treated with CAR-T cell therapy, with an inflammatory cluster assignment being prognostic of clinical response and survival outcomes.

Microbial transformation of bile acids affects intestinal immune homoeostasis but its impact on inflammatory pathologies remains largely unknown. Using a mouse model of graft-versus-host disease (GVHD), we found that T cell-driven inflammation decreased the abundance of microbiome-encoded bile salt hydrolase (BSH) genes and reduced the levels of unconjugated and microbe-derived bile acids. Several microbe-derived bile acids attenuated farnesoid X receptor (FXR) activation, suggesting that loss of these metabolites during inflammation may increase FXR activity and exacerbate the course of disease. Indeed, mortality increased with pharmacological activation of FXR and decreased with its genetic ablation in donor T cells during mouse GVHD. Furthermore, patients with GVHD after allogeneic hematopoietic cell transplantation showed similar loss of BSH and the associated reduction in unconjugated and microbe-derived bile acids. In addition, the FXR antagonist ursodeoxycholic acid reduced the proliferation of human T cells and was associated with a lower risk of GVHD-related mortality in patients. We propose that dysbiosis and loss of microbe-derived bile acids during inflammation may be an important mechanism to amplify T cell-mediated diseases. Graft-versus-host disease, a T cell-driven inflammatory condition, is associated with altered microbial bile acid metabolism in both mice and humans and this is linked to outcomes.

Intestinal microbiota composition is implicated in several diseases; understanding the factors that influence it are key to elucidating host-commensal interactions and to designing microbiome-targeted therapies. We quantified how diet influences microbiome dynamics in hospitalized patients. We recorded 9,419 meals consumed by 173 patients undergoing hematopoietic cell transplantation and profiled the microbiome in 1,009 longitudinally collected stool samples from 158 of them. Caloric intake was correlated with fecal microbiota diversity. Bayesian inference revealed associations between intake of sweets or sugars during antibiotic exposure with microbiome disruption, as assessed by low diversity or expansion of the pathobiont Enterococcus. We validated this observation experimentally, finding that sucrose exacerbated antibiotic-induced Enterococcus expansion in mice. Taken together, our results suggest that avoiding sugar-rich foods during antibiotic treatment may reduce microbiome injury.

Emerging data have highlighted a correlation between microbiome composition and cancer immunotherapy outcome. While commensal bacteria and their metabolites are known to modulate the host environment, contradictory effects and a lack of mechanistic understanding impede the translation of microbiome-based therapies into the clinic. In this study, we demonstrate that abundance of the commensal metabolite pentanoate is predictive for survival of chimeric antigen receptor (CAR) T cell patients in two independent cohorts. Its implementation in the CAR T cell manufacturing workflow overcomes solid tumor microenvironments in immunocompetent cancer models by hijacking the epigenetic-metabolic crosstalk, reducing exhaustion and promoting naive-like differentiation. While synergy of clinically relevant drugs mimicked the phenotype of pentanoate-engineered CAR T cells in vitro, in vivo challenge showed inferior tumor control. Metabolic tracing of 13C-pentanoate revealed citrate generation in the TCA cycle via the acetyl- and succinyl-CoA entry points as a unique feature of the C5 aliphatic chain. Inhibition of the ATP-citrate lyase, which links metabolic output and histone acetylation, led to accumulation of pentanoate-derived citrate from the succinyl-CoA route and decreased functionality of SCFA-engineered CAR T cells. Our data demonstrate that microbial metabolites are incorporated as epigenetic imprints and implementation into CAR T cell production might serve as embodiment of the microbiome-host axis benefits for clinical applications.

The microbiome is a complex host factor and key determinant of the outcome of antibody-based and cellular immunotherapy. Its postbiotics are a blend of soluble commensal byproducts that are released into the host environment and have been associated with the regulation of immune homeostasis, particularly through impacts on epigenetics and cell signaling. In this study, we show that the postbiotic pentanoate is metabolized to citrate within the TCA cycle via both the acetyl- and succinyl-CoA entry points, a feature uniquely enabled by the chemical structure of the C5 aliphatic chain. We identified ATP-citrate lyase as the crucial factor that redirects pentanoate-derived citrate from the succinyl-CoA route to the nucleus, thereby linking metabolic output and histone acetylation. This epigenetic-metabolic crosstalk mitigated T cell exhaustion and promoted naive-like differentiation in pentanoate-programmed chimeric antigen receptor (CAR) T cells. The predictive and therapeutic potential of pentanoate was corroborated in two independent patient cohorts and three syngeneic models of CAR T adoptive therapy. Our data demonstrate that postbiotics are integrated into mitochondrial metabolism and subsequently incorporated as epigenetic imprints. This bridge between microbial and mammalian interspecies communication can ultimately impact T cell differentiation and efficacy.

This research addresses the problem of constructing a week-long labor schedule for the nonsalaried workers in a fast food restaurant. The primary objective is to minimize, for each operating hour of the week and each task in the operation, the number of on-duty workers in excess of the minimum number required (the latter is based on the hour's forecasted sales dollars). The secondary objective is to minimize the difference between each worker's number of hours scheduled and the number targeted (the latter is based on the needs of the management and the expectations of the workers). Three factors in particular contribute to the complexity of the problem. The number of workers required varies significantly over the course of a day and the within-day pattern of variability differs from day to day. Also, there are numerous restrictions placed on the design of work tours, including allowed minimum and maximum shift lengths. Finally, the workers differ in both the hours they are available to work and the tasks they are qualified to perform. This problem theoretically can be modeled by means of a set of linear equations which are simultaneously solved. Existing methodologies however are not capable of efficiently solving the model which, in a mathematical sense, is very large and ill-structured. Consequently, a two-phased heuristic solution procedure was developed and is presented in step-by-step detail. In the first phase a labor schedule which satisfies the minimum staffing requirements is constructed, and in the second phase the schedule is improved in terms of the formal objectives. The heuristic procedure was tested on both real and synthetic problems. The method used to generate synthetic problems is described. The degrees of achievement of the formal objectives are reported for each of the test problems and the results indicate the procedure is an efficacious scheduling tool.