Seres Therapeutics Presents Research from its Early-Stage Microbiome Therapeutic Oncology Programs at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting
- Decreased microbial gastrointestinal diversity in patients undergoing allogeneic HSCT procedures associated with higher mortality and increased incidence of intestinal GvHD -
- Data support a cancer-specific microbiome relationship, with correlation identified between microbiome composition and response to immune checkpoint inhibitor treatment in patients with certain cancers –
Seres is advancing development programs in oncology to evaluate the potential of microbiome therapeutics to modulate host immunity or inflammation to improve response and tolerability of cancer treatments. This includes SER-155, an investigational, oral, rationally-designed, cultivated microbiome therapeutic, which is advancing into a Phase 1b clinical trial to reduce the incidence of antibiotic-resistant bacterial infections and GvHD in patients following transplant procedures.
“Disruption of microbiome-modulated functions can impact clinical outcomes for patients being treated for cancer, including those who are undergoing allogeneic hematopoietic stem cell transplantation and those treated with cancer immunotherapy,” said
Clinical Evidence of Impact of Microbial Diversity on Mortality and GvHD in HSCT Patients
In collaboration with the
“Frequent complications associated with stem cell transplantation include antibiotic-resistant infection and GvHD. Current treatments for the prevention of GvHD rely on increased immunosuppression, leaving the patient susceptible to a host of bacterial infections – and offer limited efficacy. The findings from this prospective study demonstrate a need for continued investigation into the use of microbiome therapeutics to reduce morbidity and mortality among transplant recipients,” said
Twenty-eight patients (42%) developed intestinal GvHD and 16 (25%) died prior to study completion. Across all subjects, a decline in microbiome diversity was observed immediately following HSCT. Decreased diversity and intestinal domination by two bacterial groups – Enterococcus and Enterobacteriaceae - was significantly associated with mortality across the study time course (p<0.001). Further, patients who ultimately developed intestinal GvHD had a significantly lower diversity at the time of stem cell engraftment (p<0.05) and that lower diversity was maintained throughout the study period.
Evaluation of Microbiome Composition in Correlation to Cancer-Specific Immune Checkpoint Inhibitor (ICI) Response
A study conducted with Memorial Sloan Kettering explored the relationship between microbiome composition and ICI response in patients with metastatic melanoma, metastatic lung (NSCLC), urothelial, or renal cancer. Fecal microbiome samples were collected from 94 patients (metastatic melanoma, n=17, NSCLC, n=44, urothelial, n=23, renal cancer, n=10) immediately before ICI therapy. Bacterial genomic DNA was isolated and profiled by whole metagenomic sequencing to evaluate bacterial signatures associated with response (R) and nonresponse (NR).
Treatment included anti-PD(L)1 monotherapy (n=51), anti-PD1 + anti-CTLA4 combination therapy (n=17), or a combination of anti-PD1 and chemotherapy (n=26). Clinical response was observed in 58% of patients, including partial or complete response (45%) and on treatment for more than 6 months (55%, with 31% on treatment for more than 1 year). Ordination of microbiome data from all four cancers reveals a small cluster of patients that were NR regardless of cancer type. Although the variance in the composition of pretreatment microbiome samples did not explain response alone (R vs. NR, PERMANOVA, p=0.273), a significant portion of the variance in microbiome composition was explained by the interaction of cancer type and outcome (PERMANOVA, p=0.014), suggesting a cancer-specific microbiome relationship. Notably, there was some similarity in the signature of NR across three of the four cancer types. The relationship observed in this study was also identified and corroborated in pre-clinical models of ICI response. In these models, NR was characterized by active tumor growth in mice and a lack of induction of cytotoxic CD8+ T cells after ICI treatment.
SER-155, an investigational oral consortium of cultivated bacteria, is a microbiome therapeutic candidate intended to advance into clinical development. SER-155 is designed using microbiome biomarker data from human clinical data, human cell-based assays, and in vivo disease models, with the aim to decrease infection and translocation of antibiotic-resistant bacteria in the gastrointestinal tract and modulate host immune responses to decrease GvHD. The rationale for this program is based in part on published clinical evidence from Seres’ collaborators at
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