Microbiome as Predictor of Benefit and Toxicity in Cancer Immunotherapy
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1 Microbiome as Predictor of Benefit and Toxicity in Cancer Immunotherapy Giuliana Magri, Ph.D Optimizing Immunotherapy New Approaches, Biomarkers, Sequences and Combinations PRBB Auditorium, Barcelona October 20th 2017
2 Cancer Immunotherapy Cancer Immunotherapy is defined as the approach to treat the tumor by either inducing de novo or reac5va5ng tumor specific immune responses Treatment of cancer with bacterial products ( Coley s toxin ) Treatment of bladder cancer with BCG Adoptive cell therapy Adoptive T cell therapy Immune checkpoint blockers FDA approval of sipuleucel-t (DC vaccine) in prostate cancer FDA approval of anti-pd1 for melanoma , Description of immune infiltrates in tumors by Virchow Cancer immunosurveillance hypothesis (Burnet, Thomas) IL-2 therapy for cancer Discovery of human tumor antigens (Boon, others) HPV vaccination in VIN FDA approval of anti-ctla4 (ipilumimab) for melanoma
3 Immune Checkpoint Blockers (ICB) Atezolixumab e.g. ipilimumab 3 e.g. nivolumab, pembrolizumab Ribas A. N Engl J Med 2012;366:
4 Despite the Clinical Success in a Variety of Cancers only a Subset of patients Exhibits Durable Responses Broad Ac5vity but only a subset of pa5ents exhibits durable responses: %
5 Factors Contributing to Anti Cancer Immunity: The Role of The Microbiota
6 The Human Microbiota Ø The human microbiota is the ensemble of bacteria and other microorganisms (such as archaea, fungi, protozoa and virus) that inhabit the epithelial surface of our body Ø Most of these microorganisms reside in the gastrointestinal tract ( trillions bacteria in the human intestine) These microorganisms are not just passenger but actively participate in many physiological processes
7 Human Microbiome Complexity Ø Our microbiome is dominated by 4 large groups of bacteria phyla: Firmicutes, Bacteroidetes, Actinobacteria and Proteobacteria Ø In the human body each site is different in terms of its predominant microbial types Ø There is considerable variation in microbial composition among healthy individuals Ø Several factors can affect microbiota composition (environmental factors, age,life s style, disease, disease treatment) Ø Loss of microbial complexity and stability can have detrimental effect to human health
8 Role of Gut Microbiota Metabolism Provide complement digestive pathway Synthesize essential metabolites (vitamins and SCFA) Host Protection Colonization resistance Innate and adaptive immunity activation Structural Function Maintenance of Mucosal Barrier Adaptive and Innate Immune System development
9 Microbiota and Cancer Immunotherapy Ø The gut microbiota represents a significant source of human genetic and metabolic diversity Ø Distinct bacteria, or bacterial products can promote alteration in both innate and adaptive immune responses The microbiota can determine the immune fitness of an individuals and this has consequence in the outcome of therapies that are involving the immune system (toxicity and benefit)
10 Microbiota and ICB Therapy
11 Microbiota Influences Anti-PDL1 Immunotherapy MB B16 MELANOMA CELL LINE TAC MB JAX CO- HOUSING: hybrid Microbiota ANTI-PDL1 JAX MB Oral Gavage TAC Sivan et Al. Science 2015
12 Bifidobacterium facilitates anti PD-L1 efficacy ANTI-PDL1 TAC BIFIDOBACTERIUM Induces augmented DC function and enhanced CD8 + T cell priming Sivan et Al. Science 2015
13 Microbiota is Required for the Immunomodulatory Effect of Anti CTLA-4 Vetizou et Al. Science 2015
14 Anti CTLA-4 favours the Overgrowth of Bacteroides Fragilis that Boosts anti Cancer Immunity Colonization of germ free mice with B. Fragilis improved the anti tumoral response of anti CTLA-4 therapy Vetizou et Al. Science 2015
15 Human Studies Analysis of 113 fecal samples of patients with MM treated with anti PD-1 q The gut microbiota of responders had a greater diversity q Responders had increased abundance of Clostridiales (specifically the Ruminoccocaceae family) q No association between oral microbiome and response to therapy
16 Future Directions: Microbiota as Biomarkers Ig-SEQ MICROBIOME CULTUROMICS TRANSCRIPTOMICS 16S RNA SEQUENCING SHOTGUN METAGENOMICS FUNCTION
17 Future Directions: Probiotics MICROBIOTA FROM RESPONDERS TEST EFFICACY IN MODULATING CANCER IMMUNOTHERAPY IN MOUSE MODELS
18 Thank you for Your Attention
19 MICE GERM FREE OR ANTIBIOTIC TREATED MICE BEARING SUBCUTANEUS SYNGENIC TUMOURS DO NOT RESPOND TO CHEMOTHERAPIES (OXALIPLATIN AND CYCLOPHOSPHAMIDE) AS WELL AS THEIR MICROBIOTA SUFFICIENT COUNTERPARTS. CTX- >TRASLOCATION OF DISTINCT GRAM+ BACTERIA (ENTEROCCOCCUS HIRAE LACTOBACILLUS JOHNSONII) FROM THE GUT TO SECONDARY LYMPHOID ORGANSà INDUCTION OF TH17 TH1 EFFECTOR T CELLS THAT CONTRIBUTE TO THE ANTI- TUMOUR EFFICACY OF CTX OXALIPLATIN- HEALTHY MICROBIOTA IS NECESSARY FOR THE TUMOR INFILTRATION OF MIELOID CELLS WHICH PROMOTE TUMOR REGRESSION BY PRODUCTION OF OXIGEN REACTIVE SPECIES.
20 Influence of the Microbiota on T cells
21 Future Directions Nature Reviews Cancer 16, (2016)
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