Abstract 2822: Low intestinal microbial diversity is associated with severe immune-related adverse events and lack of response to neoadjuvant combination antiPD1, anti-CTLA4 immunotherapy
Authors: Batten Marcel , Shanahan Erin R. , Silva Ines P. , Adhikari Chandra , Conway Jordan , Tasker Annie , Menzies Alexander M. , Wilmott James S. , Saw Robyn P. , Spillane Andrew J. , Shannon Kerwin F. , Blank Christian U. , Holmes Andrew J. , Scolyer Richard A. , Long Georgina V. 
Published: August 2019

Abstract
Background: Immunotherapies targeting PD-1/PD-L1 and CTLA4 have revolutionized the treatment of advanced melanoma. Combining the two therapeutics increases the response rates compared to either treatment alone. However, this increased efficacy is accompanied by a higher incidence of severe immune-related adverse events (irAEs). Metrics of the intestinal microbiome are associated with cancer patients’ responses to immunotherapy but the value of microbiome metrics as predictors for irAEs, are unknown. In an effort to reduce irAEs during combination neoadjuvant therapy, the OpACIN-neo trial (Rozeman et al. ESMO 2018) was initiated wherein Stage III melanoma patients were treated with 2 doses each of ipilimumab and nivolumab in the neoadjuvant setting, according to three dosing regimen. Involved lymph nodes were resected after 6 weeks.
Aims: (1) To determine whether intestinal microbial components are associated with response to antiPD1/anti-CTLA4 immunotherapy in the neoadjuvant setting or with the development of severe irAEs. (2) To determine the effects of antiPD1/anti-CTLA4 immunotherapy on the microbiome over the 6 week course of treatment.
Methods: Of Melanoma Institute Australia patients enrolled in the OpACIN-neo trial (n=38), 68% of patients experienced complete, or near complete pathological responses and 61% experienced at least one irAE of grade 3 or more. Faecal microbiomes at baseline, and at resection (6 weeks immunotherapy), were analyzed using 16S ribosomal gene and metagenomic sequencing and the results compared with patient response and development of G3-G5 irAEs. Results: In baseline samples, Inverse Simpson’s diversity index indicated significantly lower overall microbial diversity in non-responders (p=.014), as well as those who went on to experience severe irAEs (p=.002). Importantly, the group of patients who were both non-responders and experienced severe irAEs had the lowest microbial diversity of all patients (p=.0033). Specific taxa associated with irAEs are distinct from those described for response. The 6 week course of immunotherapy led to a slight increase in microbial diversity but few specific taxa were observed to be significantly altered between the timepoints.
Conclusions: The findings suggest that not only are patients with extremely low microbial diversity predisposed to develop severe irAEs but they are also unlikely to respond to combination immunotherapy. Thus, microbial diversity may delineate patients who are likely to have poor outcomes and would benefit from microbial modulation.
Citation Format: Marcel Batten, Erin R. Shanahan, Ines P. Silva, Chandra Adhikari, Jordan Conway, Annie Tasker, Alexander M. Menzies, James S. Wilmott, Robyn P. Saw, Andrew J. Spillane, Kerwin F. Shannon, Christian U. Blank, Andrew J. Holmes, Richard A. Scolyer, Georgina V. Long. Low intestinal microbial diversity is associated with severe immune-related adverse events and lack of response to neoadjuvant combination antiPD1, anti-CTLA4 immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2822.