Abstract 3523: A Black Raspberry dietary intervention to modify the gut microbiome and improve the response to immune checkpoint inhibitors
Authors: Bibi Amna , Pallerla Aaditya , Williams Nyelia , Wheeler Caroline , Hoyd Rebecca , Suman Shankar , Amann Joseph , Goruganthu Mounika , Okimoto Tamio , Liu Yangyang , Bittoni Marisa , Shi Ni , Zhang Shiqi , Anand Alvin , Heitman Kristen , Mendelson Maxine , Grainger Elizabeth M. , Grogan Madison , Presley Carolyn J. , Tabung Fred K. , Li Lang , Vodovotz Yael , Zhu Jiangjiang , Carbone David P. , Chen Tong , Clinton Steven K. , Spakowicz Daniel 
Published: June 2022

Abstract
Lung cancer kills more people annually worldwide than any other cancer. Outcomes have improved with the use of immune checkpoint inhibitor (ICI) treatment, however, only about 20% of tumors respond. Emerging data demonstrate that responses to ICI may depend on the host microbiome. The challenge is to identify strategies to manipulate the gut microbiome to improve response to ICIs. Here we explore a targeted dietary intervention to modify the microbiome and determine the response to ICIs. Studies in a preclinical murine model showed that freeze-dried black raspberry powder (AIN-76A synthetic diet containing 5% lyophilized black raspberry powder) increased the abundance of Akkermansia muciniphila, which has been associated with improved response to ICIs in melanoma. Next, we conducted a human intervention trial called the BEWELL Study (Black raspberry nEctar Working to prEvent Lung cancer NCT04267874). This placebo-controlled, randomized, cross-over trial examined the impact of 2x 80 mL black raspberry (BRB) nectar drink boxes per day for 4 weeks. There were 96 participants recruited and classified as being at high risk of developing lung cancer (eligibility criteria: &gt;30 pack-year smoking history and 55-77 years old) in an attempt to match the phenotype of typical lung cancer patients but allowing us to clearly assess the impact of the intervention on the microbiome. Pre- and post-dietary intervention gut microbiome, blood, and urine samples were collected. Black raspberry dietary supplementation was not associated with a significant change in A. muciniphila (logistic regression with negative binomial Wald test p-value 0.056), however, changes in other taxa were observed. Finally, stool from participants in the BEWELL study was gavaged into C57BL/6J mice to create human microbiome avatar models. Mouse colon cancer cells (mc38) were injected subcutaneously and treated with anti-PD1 Ab (5mg/kg mouse; clone RMP1-14) or isotype control (clone 2A3). Preliminary experiments using avatar mice with post-BRB human microbiomes showed smaller tumors relative to mice receiving stool from that same individual pre-BRB dietary intervention, relative to isotype control (t-test, p-value 0.05). These results suggest that black raspberry nectar may modify the human gut microbiome in a way that promotes an improved response to immunotherapy.
Citation Format: Amna Bibi, Aaditya Pallerla, Nyelia Williams, Caroline Wheeler, Rebecca Hoyd, Shankar Suman, Joseph Amann, Mounika Goruganthu, Tamio Okimoto, Yangyang Liu, Marisa Bittoni, Ni Shi, Shiqi Zhang, Alvin Anand, Kristen Heitman, Maxine Mendelson, Elizabeth M. Grainger, Madison Grogan, Carolyn J. Presley, Fred K. Tabung, Lang Li, Yael Vodovotz, Jiangjiang Zhu, David P. Carbone, Tong Chen, Steven K. Clinton, Daniel Spakowicz. A Black Raspberry dietary intervention to modify the gut microbiome and improve the response to immune checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3523.