Immune checkpoint blockade (ICB) has revolutionized cancer treatment, yet quality of life and continuation of therapy can be constrained by immune-related adverse events (irAEs). Limited understanding of irAE mechanisms hampers development of approaches to mitigate their damage. To address this, we examined whether mice gained sensitivity to anti-CTLA-4 (αCTLA-4)–mediated toxicity upon disruption of gut homeostatic immunity. We found αCTLA-4 drove increased inflammation and colonic tissue damage in mice with genetic predisposition to intestinal inflammation, acute gastrointestinal infection, transplantation with a dysbiotic fecal microbiome, or dextran sodium sulfate administration. We identified an immune signature of αCTLA-4–mediated irAEs, including colonic neutrophil accumulation and systemic interleukin-6 (IL-6) release. IL-6 blockade combined with antibiotic treatment reduced intestinal damage and improved αCTLA-4 therapeutic efficacy in inflammation-prone mice. Intestinal immune signatures were validated in biopsies from patients with ICB colitis. Our work provides new preclinical models of αCTLA-4 intestinal irAEs, mechanistic insights into irAE development, and potential approaches to enhance ICB efficacy while mitigating irAEs.

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The microbiome (bacteria, viruses, and fungi) that exist within a patient's gastrointestinal tract and throughout their body have been increasingly understood to play a critical role in a variety of disease, including a number of cancer histologies. These microbial colonies are reflective of a patient's overall health state, their exposome, and germline genetics. In the case of colorectal adenocarcinoma, significant progress has been made in understanding the mechanism the microbiome plays beyond mere associations in both disease initiation and progression. Importantly, this improved understanding holds the potential to further identify the role these microbes play in colorectal cancer. We hope this improved understanding will be able to be leveraged in the future through either biomarkers or next-generation therapeutics to augment contemporary treatment algorithms through the manipulation of a patient's microbiome—whether through diet, antibiotics, prebiotics, or novel therapeutics. Here we review the role of the microbiome in the setting of patients with stage IV colorectal adenocarcinoma in both the development and progression or disease as well as response to therapeutics.

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e19511 Background: CLL is the most prevalent adult leukemia and is associated with an increased risk of melanoma. CLL alters systemic immunity and can induce T-cell exhaustion, which may limit the efficacy of ICI in patients with CLL. Immune checkpoint inhibitors (ICI) have revolutionized management of AM, but data on ICI effectiveness have largely been restricted to clinical trials, thereby excluding patients with co-existing malignancies. We, therefore, sought to examine the efficacy of ICI for melanoma in patients with concomitant CLL and AM. Methods: In this international and multicentre retrospective study, review of clinical databases identified patients with concomitant CLL and AM treated with ICI from two US tertiary cancer centers (n = 39) and an Australian multi-institutional experience (AUS, n = 19). Objective response rates (ORR), defined as complete or partial response by RECIST v1.1, and survival outcomes (overall survival, OS, and progression-free survival, PFS) among patients with CLL and AM were assessed. Clinical factors associated with improved ORR and survival were explored. Results: Between 1997 and 2020, 58 patients with CLL were treated with ICI for concomitant AM. Among all patients with CLL and AM, ORR to ICI was 41% and median duration of response was 18 months. A majority were untreated for CLL (64%) at the time of ICI. Patients with prior history of treatment for CLL had significantly reduced ORRs (21% vs 51%, p = 0.04), PFS (3.6 vs. 14.6 months, p = 0.005), and OS (7.4 vs. 52.2 months, p = 0.002), compared to patients on observation for their CLL. Prior treatment with T-lymphocyte depleting chemoimmunotherapy (fludarabine, bendamustine, and alemtuzumab) was particularly associated with poor outcomes (median OS of 7.0 months, median PFS of 3.4 months). On univariate analysis, prior treatment for CLL, high risk CLL 17p deletion, and higher CLL Rai stage were associated with shorter PFS from ICI, though CLL treatment was the only factor independently associated with shorter PFS in the multivariate model (HR 6.5, [CI 2.1-20.3], p = 0.001]. Overall, 3 patients developed CLL progression while on ICI, though in two of these patients, the AM had an objective, durable clinical response to ICI. Overall, immune-related adverse events (irAE) occurred following 38% of ICI and rates of irAE were similar by CLL treatment status. Conclusions: Our case series of patients with concomitant CLL and melanoma demonstrate frequent, durable clinical responses to ICI However, those with prior chemoimmunotherapy treatment for CLL had significantly worse outcomes. We found that CLL disease course is largely unchanged by treatment with ICI.

e16247 Background: Patients with small bowel neuroendocrine tumors (SBNETs) frequently present with metastatic disease, and unfortunately, the range and efficacy of available therapies is limited. Immunotherapeutic checkpoint inhibitors have demonstrated benefit in other malignancies and may also play a role in SBNETs, although relatively little is known about the immune infiltrate in these tumors. Toward a goal of developing novel immunomodulatory strategies, we sought to evaluate the tumor immune microenvironment of SBNETs utilizing Nanostring transcriptional profiling. Methods: Patients with SBNETs who underwent surgical resection at MD Anderson Cancer Center from 2003 to 2016 were retrospectively analyzed. Clinicopathologic data was collected, and patients were stratified by survival. Overall survival (OS) from date of resection was assessed using the Kaplan-Meier method, and p-values were calculated using the log-rank test. Multivariate (MV) analysis was performed using the Cox proportional hazards model. Transcription expression from bulk RNA was analyzed using the Nanostring PanCancer Immune Profiling Panel. Results: Resected SBNETs from 45 patients were selected for transcriptional analysis. Unsupervised clustering of RNA expression data revealed separation into high and low expression groups in two distinct transcription panels: cancer testis antigens (CTA) and interleukins (IL). All patients in the IL-high group also were in the CTA-high group. CTA-high patients (n=13) had significantly improved overall survival compared to CTA-low patients (n=32; median OS not reached vs 1975 days, p=0.0032). MV analysis controlling for age, gender, metastatic disease and history of carcinoid syndrome confirmed CTA-high status as an independent predictor of improved OS (hazard ratio 6.6, 95% confidence interval 1.7-26.4, p=0.008). CTA-high patients had significantly elevated expression of CTAs (such as PRAME and GAGE1) and cytokines (such as IL2 and CXCR1). High normalized expression levels of these single genes were independent predictors of improved OS in MV analysis (PRAME p=0.008, GAGE1 p=0.006, IL2 p=0.008, CXCR1 p<0.0001). Conclusions: High expression of CTA and IL signatures in resected SBNETs identified patients with improved survival agnostic of stage. While CTA expression across multiple tumor subtypes have been implicated in their immunogenicity and potential for therapeutic targeting, this is the first work to identify a clinically relevant signal in SBNET. The concurrent increase of key cytokines (which are known to mediate anti-tumor activity) among CTA-high patients suggests an immune-mediated component to their improved survival. Further work is underway to elucidate the epigenetic mechanisms of CTA expression and silencing, with the goal of validating key CTAs such as PRAME and GAGE1 as predictive and therapeutic targets for immunologic intervention.

Active surveillance (AS) is a safe management strategy for men with low-risk prostate cancer; however, nearly 35% of men on AS will undergo definitive treatment within 4 years, most commonly due to disease progression. Determining a non-invasive means of limiting disease progression would allow men to avoid quality of life issues associated with radical prostate treatment. Some modifiable factors, such as obesity and lipid levels, are associated with prostate cancer risk, though no behavioral intervention has been shown to affect prostate cancer outcomes. Using a prospective study of men on active surveillance, our group recently demonstrated that higher quality diets were associated with a significantly lower risk of disease progression. The Mediterranean diet (MD) specifically may be beneficial for men with localized prostate cancer (PCa) on active surveillance (AS) because of its anti-inflammatory, antilipidemic, and chemopreventive properties. Furthermore, recent evidence supports that dietary interventions can induce modulation of the gut microbiome, and consequently, immune function and inflammatory pathways, which warrants further investigation of the microbiome’s role in the context of prostate cancer. Here, we describe a novel dietary intervention among a group of men with localized prostate cancer who are electing to undergo prostatectomy for prostate cancer treatment. The intervention is a feeding study involving the provision of an isocaloric, high quality diet based on the lipid-lowering and anti-inflammatory parameters of the Mediterranean diet, including a strong focus on fiber-rich plant foods and healthy sources of mono and poly-unsaturated fatty acids. The primary outcome in this pilot study is the feasibility of a neoadjuvant dietary intervention. Secondary outcomes include studying the effects of the diet on metabolic parameters, the fecal microbiome, and changes in circulating metabolites shown to be associated with progression on active surveillance. Furthermore, by focusing on African-American and non-Hispanic White males, this study may provide insights into the key differences in inflammatory, immune and microbiome signatures, which may underly the prominent cancer-racial disparity seen in African-American men. Therefore, this study will gain preliminary data needed to inform further dietary interventions that may impact risk of progression in select men with prostate cancer enrolled on active surveillance. Citation Format: Samuel Cass, Jennifer Wargo, Curtis Pettaway, Louis Pisters, John Davis, Brian Chapin, John Ward, Carrie Daniel, Justin Gregg. A novel Mediterranean dietary intervention for prostate cancer [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 3495.

TPS9602 Background: Preoperative antibiotic prophylaxis is commonly used to reduce surgical site infections (SSIs). However, the rate of SSIs following surgical procedures classified as clean is only 2-3%. Overuse of antibiotics is associated with several potential adverse effects, including dysregulation of the gut microbiome. Disruption of the composition and function of the native gut microbiota, referred to as dysbiosis, has been implicated in a number of inflammatory and autoimmune disorders, as well as gastrointestinal (GI) and non-GI cancers. Recent studies have demonstrated that antibiotics have a profound and persistent effect on the gut microbiota, as evidenced by diminished overall abundance and diversity, as well as alteration of community composition that includes a decreased relative abundance of bacteria in the Ruminococcaceae family. In melanoma, diversity of gut microbiota and relative abundance of Ruminococaceae have been linked to improved survival and enhanced response following immune checkpoint blockade. In this study, we seek to determine the impact of preoperative prophylactic antibiotic use on the gut microbiome in patients following surgery for stage I or II melanoma. Methods: In this non-comparative randomized pilot trial, the impact of prophylactic antibiotic use at the time of surgical intervention on gut microbiome diversity and composition will be studied. Patients diagnosed with clinical stage I or II melanoma undergoing wide excision with or without lymphatic mapping and sentinel lymph node biopsy are randomized 1:1 to either receive preoperative cefazolin or no preoperative antibiotics. Stool samples and peripheral blood are collected before surgery, the day of surgery (optional), on post-operative day 3 (optional), and 2 weeks and 3 months following surgery. The primary endpoint for the study is change in microbiome alpha diversity at 2 weeks following surgery. Secondary endpoints are change in relative abundance of microbes at 2 weeks and 3 months after surgery and SSI rates according to whether or not prophylactic antibiotics were administered at time of surgery. Exclusion criteria include recent antibiotic use (within 3 months), allergy to beta-lactam or cephalosporin antibiotics, increased risk of infection due to medical comorbidity or use of immunosuppressive medication. Enrollment began in October 2021. As of January 2022, 22 of 30 patients have been accrued to ensure complete sample collection for 20 patients. Study findings may inform a larger trial evaluating interventions to mitigate antibiotic impact. Clinical trial information: NCT04875728.