PracticeUpdate: Dermatology - Winter 2018

EDITOR’S PICKS 12

Microbiome AssociatedWith Anti-PD-1 Efficacy in Metastatic Melanoma Patients Science Take-home message

Abstract Anti-PD-1-based immunotherapy has had a major impact on cancer treatment but has only benefited a subset of patients. Among the variables that could contribute to interpatient heterogeneity is differential composition of the patients' microbiome, which has been shown to affect antitumor immunity and immunother- apy efficacy in preclinical mouse models. We analyzed baseline stool samples from meta- static melanoma patients before immunotherapy treatment, through an integration of 16S ribo- somal RNA gene sequencing, metagenomic shotgun sequencing, and quantitative poly- merase chain reaction for selected bacteria. A significant association was observed between commensal microbial composition and clinical response. Bacterial species more abundant in responders included Bifidobacterium longum, Collinsella aerofaciens, and Enterococcus fae- cium. Reconstitution of germ-free mice with fecal material from responding patients could lead to improved tumor control, augmented T cell responses, and greater efficacy of anti-PD-L1 therapy. Our results suggest that the commen- sal microbiome may have a mechanistic impact on antitumor immunity in human cancer patients. The Commensal Microbiome Is Associated With Anti-PD-1 Efficacy in Metastatic Melanoma Patients. Science 2018 Jan 05;359(6371)104- 108, V Matson, J Fessler, R Bao, et al. www.practiceupdate.com/c/69998

• In this study, the authors investigated whether microbiome heterogeneity in met- astatic melanoma patients was associated with their response to anti-PD-1–based immunotherapy. The microbiome composition in baseline stool samples of patients before immunotherapy was significantly associated with clinical responses. Patients who responded to immunotherapy had increased abundance of Bifidobacterium longum , Collinsella aerofaciens , and Enterococcus faecium . Moreover, microbial reconstitution of germ-free mice with fecal material from responding patients improved tumor control and augmented T-cell responses in mice. • The results indicate that the composition of the commensal microbiome was sig- nificantly associated with a response to anti-PD-1 therapy in metastatic melanoma patients. The microbiome might affect antitumor immunity in cancer patients. InYoung Kim MD, PhD

COMMENT By Robert L. Modlin MD A major breakthrough in the treat- ment of melanoma and other cancers is based on the finding that expression of the programmed death-1 (PD-1) receptor on tumor cells prevents the activation of T cells that recognize the tumor and have the capacity to attack it. Administration of antibodies that block PD-1 (so-called checkpoint inhibitors) to patients with metastatic melanoma has resulted in unprecedented clinical responses, yet therapeutic efficacy varies among individuals. We now know that the composition of microbes in our intestine has a global influence on our immune sys- tem and could therefore be one variable that affects the response to immuno- therapy. The Gajewski lab measured the

that fecal matter from melanoma patients who responded to checkpoint blockade enhanced both the clinical and immune responses to anti-PD-1 therapy in mice as compared with that from non-responders. Therefore, it may be possible to awaken the unresponsive T cell to attack tumor cells with a little poop from your friends.

gut microbiota in patients undergoing anti-PD-1 therapy, finding 10 bacterial spe- cies that were differentially expressed in responders vs non-responders – 8 were greater in responders and 2 were greater in non-responders. These findings raise the possibility of fecal transplant to alter the gut micro- biome, given that this intervention is already being performed clinically to treat Clostridium difficile infection that causes pseudomembranous enterocol- itis. To evaluate the potential efficacy of fecal transplantation as an adjuvant to immunotherapy in melanoma, the Gajew- ski lab transplanted human fecal matter from melanoma patients into a mouse melanoma model. They demonstrated

Dr. Modlin is Klein Professor of Dermatology, Distinguished Professor of Medicine and Microbiology of Immunology and Molecular Genetics, Chief of the Division of

Dermatology, and Vice Chair for Cutaneous Medicine and Dermatological Research at the David Geffen School of Medicine in Los Angeles, California.

PRACTICEUPDATE DERMATOLOGY