The Microbiome in Advanced Melanoma: Where Are We Now?

PURPOSE OF REVIEW: This review summarizes recent data linking gut microbiota composition to ICI outcomes and gut microbiota-specific interventional clinical trials in melanoma. RECENT FINDINGS: Preclinical and clinical studies have demonstrated the effects of the gut microbiome modulation upon ICI response in advanced melanoma, with growing evidence supporting the ability of the gut microbiome to restore or improve ICI response in advanced melanoma through dietary fiber, probiotics, and FMT. Immune checkpoint inhibitors (ICI) targeting the PD-1, CTLA-4, and LAG-3 negative regulatory checkpoints have transformed the management of melanoma. ICIs are FDA-approved in advanced metastatic disease, stage III resected melanoma, and high-risk stage II melanoma and are being investigated more recently in the management of high-risk resectable melanoma in the peri-operative setting. The gut microbiome has emerged as an important tumor-extrinsic modulator of both response and immune-related adverse event (irAE) development in ICI-treated cancer in general, and melanoma in particular.

Screening costs associated with donor selection for fecal microbiota transplantation for treatment of PD-1 refractory melanoma patients.

The gut microbiome acts as a tumor-extrinsic regulator of responses to immune-checkpoint inhibitors (ICIs) targeting PD-1 and CTLA-4 receptors. Primary resistance to anti-PD-1 ICI can be reversed via responder-derived fecal microbiota transplant (FMT) in patients with refractory melanoma. Efforts to create stool banks for FMT have proved difficult. Therefore, we aimed to establish a novel donor-screening program to generate responder-derived FMT for use in PD-1 refractory melanoma. Candidate PD-1 responder donors and PD-1 refractory recipients were recruited via clinic-based encounters at the University of Pittsburgh Medical Center hospitals. Eligible donors and recipients underwent physician assessment and screening of serum, stool and nasopharynx for transmissible agents, which included SARS-CoV-2 modification. The cost of donor and recipient screening was calculated. Initially, 29 donors were screened with 14 eligible donors identified after exclusion; of the 14 donors, eight were utilized in clinical trials. The overall efficiency of screening was 48%. Seroprevalence rates for cytomegalovirus, Epstein-Barr virus, HSV-2, HHV-6, HTLV-1, HTLV-2, and syphilis were similar to published statistics from healthy blood donors in the USA. Donor stool studies indicated a 3.6% incidence of E. histolytica and norovirus, 3.7% incidence of giardia and 7.1% incidence of C. difficile. A single donor tested positive for SARS-CoV-2 in stool only. The cost for finding a single eligible donor was $2260.24 (pre-COVID) and $2,460.24 (post-COVID). The observed screening efficiency suggests that a well-resourced screening program can generate sufficient responder-derived donor material for clinical trial purposes. Eliminating testing for low-prevalence organisms may improve cost-effectiveness.