28Microbial metabolic pathways to abrogate immunotherapy toxicity and promote anti-tumor response in metastatic renal cell cancer

Abstract Background Metastatic RCC has a poor prognosis. Despite improvement in treatment outcomes with ICB and targeted therapy, many patients fail to respond to first line therapy and immune mediated adverse events(irAE) remains a major challenge, often leading to treatment discontinuation. Therefore, mitigating irAE without compromising antitumor immunity is a critical unmet need. Tryptophan microbial metabolic pathway is known to play a major role in immune homeostasis through its action on Aryl hydrocarbon receptor (AhR) balancing immune suppresser with immune effector responses. We hypothesize that microbial metabolism of tryptophan to indole metabolites may play a role in ICB resistance as well in irAE, identification of which may help us predict patients most likely to respond, without life threatening toxicity. Methods We prospectively collected paired stool and blood samples of treatment naïve metastatic RCC patients, treated with ICB +/- Tyrosine kinase inhibitors (TKI) at treatment initiation and at time of first response assessment (12+/-3 weeks). We evaluated stool metagenomics and untargeted stool and plasma metabolomics among responders (R) and non-responders (NR). We focused on kynurenine/tryptophan and indoles/tryptophan ratio to evaluate differential host and microbial metabolism of tryptophan. A responder was classified as progression free survival (PFS) greater than 6 months while patients with grade 3 or higher irAE was classified as serious IrAE. Results Among 120 patients accrued, 49 were treated with combination ICB, while 71 patients were treated with ICB + TKI. Median follow up was 27 months. 28 patients (23%) had a Grade 3 or higher irAE. 3 patients died from complications attributable to irAE. The median duration to development of any irAE was 3.5 months. Using negative binomial regression model evaluating baseline relative abundance of microbial tryptophan metabolites that were associated both with response as well as serious irAE, we noted significant higher abundance of Indole acetic acid (IAA), indole acetonitrile(ACN), indole acetyl phenylalanine (IAAP)and IAA/kynurenine (Kyn) and lower abundance of tryptophol, indole 3 pyruvic (IPA), (coefficient of 6.4, 1.8, 7.15, 4.6, 0.04, 0.46, with adj p value < 0.05) with serious irAE as well as ICB resistance (Coefficient-5.42, 1.83, 6.15, 4.05, 0.03, 0.4, P < .05). Conclusions This is one of the first studies evaluating microbial metabolic pathways that may play a role in predicting patients who are more likely to respond with lower likelihood of serious irAE in RCC, thus helping to identify strategies to decouple tumor immunity from autoimmunity to improve ICB outcomes. Further the results can be extrapolated to many other solid tumor treated with immunotherapy, as tryptophan metabolism plays a immune homeostatic role across cancers.