1. Some interesting science…
Chris Parrish
St James’s Institute of Oncology

2. Checkpoint inhibitors
Proven efficacy, e.g. 20% of melanoma patients treated with ipilimumab live longer.
What separates them from the remaining 80%?
Ansell SM et al., NEJM 372;  

3. Checkpoint inhibition pathways are too straightforward
Christopher J. Nirschl and Charles G. Drake, Clin Cancer Res, DOI:  / CCR  Published September 2013

4. A clue from the side effect profile?
Rastogi, P et al., World J Gastroenterol. Apr 14, 2015; 21(14):

5. CTLA-4 blockade in germ-free mice
Differential response to CTLA4 blockade in specific pathogen-free (SPF) mice vs Germ-free mice.
Vétizou M et al., Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota Science. 27 Nov DOI: /science.aad1329

6. Gavage with B. fragilis confers tumoricidal effect
Vétizou M et al., Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota Science. 27 Nov DOI: /science.aad1329

7. ‘Identical’ C57BL/6 mice from different facilities
After co-habitation
Sivan A et al., Commensal Bifidobacterium promotes antitumor immunity and facilitates anti–PD-L1 efficacy. Science. 27 Nov DOI:  /science.aac4255

8. Cohabitation abolishes the difference
Sivan A et al., Commensal Bifidobacterium promotes antitumor immunity and facilitates anti–PD-L1 efficacy. Science. 27 Nov DOI:  /science.aac4255

9. Bifidobacterium augments anti-PD-L1 effect
Sivan A et al., Commensal Bifidobacterium promotes antitumor immunity and facilitates anti–PD-L1 efficacy. Science. 27 Nov DOI:  /science.aac4255

10. Mice are not humans. Routy et al, 2017: 249 NSCLC, RCC, UC patients
69 of whom had taken antibiotics for routine reasons prior to anti-PD-1 or anti-PD-L1 therapy
Routy B et al., Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors. Science  02 Nov 2017: DOI: /science.aan3706

11. Akkermansia muciniphilia
Routy B et al., Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors. Science  02 Nov 2017: DOI: /science.aan3706

12. A more diverse microbiome
Gopalakrishnan, V et al. Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients. Science  02 Nov 2017: DOI: /science.aan4236

13. A more diverse microbiome, improves response
Gopalakrishnan, V et al. Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients. Science  02 Nov 2017: DOI: /science.aan4236

14. Summary
The diversity of the gut microbiome, and the presence of specific species can dramatically affect the response to cancer immunotherapy treatment.
Mediated by anti-tumour T cell responses
Microbiomes likely vary by geography and diet
Implications:
Can avoiding antibiotics whilst on immunotherapy boost response rates?
Probiotics?
Microbiome transplants?
Checkpoint inhibition is even more complicated than you already thought.