Probiotics Cancer Interaction, Prevention, and Therapy

Historically, tumor burden has been considered an impediment to efficacy of immunotherapeutic agents, including vaccines, stem cell transplant, cytokine therapy, and intravesical bacillus Calmette-Guérin. This effect has been attributed to hypoxic zones in the tumor core contributing to poor T-cell infiltration, formation of immunosuppressive stromal cells, and development of therapy-resistant cell populations. However, the association between tumor burden and efficacy of immune checkpoint inhibitors is unknown. We sought to determine the association between radiographic tumor burden parameters and efficacy of immune checkpoint inhibitors in advanced lung cancer. We performed a retrospective analysis of patients with advanced lung cancer treated with immune checkpoint inhibitors. Demographic, disease, and treatment data were collected. Serial tumor dimensions were recorded according to RECIST version 1.1. Associations between radiographic tumor burden (baseline sum of longest diameters, longest single diameter) and clinical outcomes (radiographic response, progression-free survival, and overall survival) were determined using log-rank tests, Cox proportional-hazard regression, and logistic regression. Among 105 patients, the median baseline sum of longest diameters (BSLD) was 6.4 cm; median longest single diameter was 3.6 cm. BSLD was not associated with best radiographic, progression-free survival, or overall survival. In univariate and multivariate analyses, no significant associations were observed for the other radiographic parameters and outcomes when considered as categorical or continuous variables. Although tumor burden has been considered a mediator of efficacy of earlier immunotherapies, in advanced lung cancer it does not appear to affect outcomes from immune checkpoint inhibitors. Historically, tumor burden has been considered an impediment to the efficacy of various immunotherapies, including vaccines, cytokines, allogeneic stem cell transplant, and intravesical bacillus Calmette-Guérin. However, in the present study, no association was found between tumor burden and efficacy (response rate, progression-free survival, overall survival) of immune checkpoint inhibitors in advanced lung cancer. These findings suggest that immune checkpoint inhibitors may provide benefit across a range of disease burden, including bulky tumors considered resistant to other categories of immunotherapy.

Immune checkpoint inhibitors (ICIs) have transformed oncological treatment by modulating immune responses against tumors. However, their efficacy is subject to inter-patient variability and is associated with immune-related adverse events (irAEs). The human gut microbiota, a complex microbial ecosystem, is increasingly implicated in modulating responses to ICIs. This bibliometric analysis examines the 100 most-cited articles to elucidate trends and advancements in research concerning the gut microbiota's impact on ICI efficacy. A systematic literature retrieval was conducted within the Web of Science Core Collection (WoSCC), focusing on the 100 most-cited articles. VOSviewer and CiteSpace were utilized for bibliometric analysis, examining collaborative patterns and keyword co-occurrences. The relationship between citing and cited entities was analyzed, and burst ranking identified research hotspots based on citation frequency. The 100 most-cited publications encompassed a range of disciplines, with a predominance of oncological research. The United States and China were leading in publication volume, with France and Canada also contributing significantly. French institutions, particularly INSERM and Université Paris Cite, were prolific. Routy, Bertrand and Zitvogel, Laurence were prominent among high-impact authors. Dominant keywords included "gut microbiota," "immunotherapy," "efficacy," and "cancer." The article by Routy etal. (2018) was the most frequently cited. This study highlights the significant role of the gut microbiota in ICI development and efficacy, emphasizing the necessity for international and interdisciplinary collaboration. The research is progressively focusing on managing immunotherapy side effects and optimizing treatment strategies. Challenges, including individual variability in gut microbiota composition, persist. Further research is imperative to exploit the potential of the gut microbiota in cancer therapy, advocating for personalized approaches and a more profound comprehension of the underlying mechanisms.

Meeting Proceedings of the 2nd Annual Immuno-Oncology Society of India Conference (I-OSICON-2020), Mumbai, India.

The rapid increase in the number of elderly patients with cancer necessitates treatment strategies based on the effects of aging because of drastic side effects of cytotoxic anticancer agents. Immune checkpoint inhibitors (ICIs) are relatively less toxic and can be easily administered to vulnerable and aged patients suffering from cancer. The diversity of gut microbiota and specific bacteria affects the efficacy and safety of ICIs. Therefore, this study aimed to assess the effect of aging on gut microbiota that play crucial roles in determining antitumor efficacy of drugs. Stool samples were collected from 36 aged patients pathologically diagnosed with solid tumors before the start of drug therapy, and gut microbial composition was analyzed using next generation sequencing. The association between gut microbiota and efficacy and safety of ICIs was analyzed. The abundance of Veillonella species significantly decreased in patients aged ≥75 years. Additionally, the gut microbiota in the responder group was significantly higher than that in the non-responder group regardless of age. The abundance of Streptococcus species was significantly higher in the responder group than that in the non-responder group. These gut microbiota changes with aging, and its characteristics are important parameters that also affect the efficacy of ICIs.

Immune checkpoint inhibitors (ICIs) are one of the most significant oncological treatment modalities as a result of the rapid advancement of immunotherapy. Programmed Cell Death-Ligand 1 (PD-L1) and tumor mutational burden (TMB) have emerged as key markers for predicting the efficacy and prognosis of ICIs in non-small cell lung cancer (NSCLC), and the predictive role of tumor-infiltrating lymphocytes (TILs) has also received significant attention. However, the prognosis of some individuals cannot be determined by these indicators; for instance, some patients with low PD-L1 expression also benefit from longer survival. Therefore, the purpose of this research was to investigate the connection between new haematological and pathological markers and clinical outcomes in NSCLC patients receiving ICIs. Seventy-six patients with stage III-IV NSCLC treated with ICIs were included in this study. We used the Mann-Whitney test, COX regression and Kaplan-Meier analysis to retrospectively analyze peripheral blood indicators and survival prognostic data of 76 patients in order to investigate the relationship between baseline neutrophil-to-lymphocyte ratio (NLR) and the efficacy of ICIs. To investigate the correlation between CXCL13, CXCR5, CD8 and the efficacy of ICIs, we assessed the expression levels of aforementioned indicators in biopsied tissues of 10 non-small cell lung tumors by immunohistochemistry (IHC) and immunofluorescence (IF) and performed statistical analysis. Disease control rate (DCR) was higher in patients with baseline NLR <3.4 (p=0.016) and neutrophil percentage <71% (P=0.015). Baseline NLR (HR=2.364, P=0.003) and neutrophil percentage (HR=2.824, P=0.013) had the greatest influence on patients' survival prognosis, with baseline NLR exhibiting a stronger predictive value (AUC=0.717), according to univariate and multifactorial COX regression analyses of progression-free survival (PFS) and overall survival (OS). In NSCLC tissues, higher expression of CXCL13 was associated with better clinical outcomes (P=0.032) and higher expression of CD8 was associated with prolonged survival (P=0.022). Low baseline NLR in peripheral blood and high expression of CD8 in tissues are associated with longer PFS and may have a potential predictive value for patients with stage III-IV NSCLC using ICIs.

Background: It has been established that women usually mount a stronger immune response than men of the same age. Data for the efficacy of immune checkpoint inhibitors (ICIs) based on the patient’s’ sex are scarce. Objectives: We aimed to evaluate the impact of the patients’ sex on the efficacy and toxicity of ICIs. Materials and Methods: Aretrospective audit of a prospectively collected database of patients receiving ICIs for advanced solid tumors between August 2015 and November 2018 was performed at the Tata Memorial Hospital in Mumbai, India. The categorical and continuous variables were evaluated using descriptive statistics. The Kaplan–Meier estimator was used to analyze the progression-free survival (PFS) and overall survival (OS). Results: Atotal of 155 patients were included in the study, of which 36 (23.2%) were female and 119 (76.8%) were male. The median PFS was 2.8 months (95% confidence interval [CI], 1.4–4.2) for the male patients and 1.9 months (95% CI, 1.0–2.8) for the female patients (hazard ratio [HR], 1.06; 95% CI, 0.69–1.66; P = 0.764). The median OS was 5.9 months (95% CI, 1.5–10.2) for the male patients and 4.2 months (95% CI, 1.1–7.3) for the female patients (HR, 1.27; 95% CI, 0.77–2.12; P = 0.342). The rates of all toxicities, except for pneumonitis, were similar between the male and female patients. All-grade pneumonitis occurred in a total of 7 (5.8%) male patients, while it was not reported in any female patients. All-grade immune-related adverse effects occurred in 24 (20.2%) male and 4 (18.1%) female patients (P = 0.216). Conclusions: This study shows that the efficacy and toxicity of ICIs are similar in the male and female patients. However, future trials with a balanced number of male and female patients are required to ensure an unbiased estimation of the efficacy and safety of ICIs.

EP08.01-105 Efficacy of First-Line Immune Checkpoint Inhibitors in Patients with Advanced NSCLC harboring KRAS, MET, FGFR, RET, BRAF, and HER2 Alterations

Background: Biliary tract cancer, typically diagnosed at advanced stages with a poor prognosis, has witnessed a glimmer of hope in the progress of immune checkpoint inhibitors (ICIs). Yet, their limited response rates necessitate the search for effective biomarkers to refine patient selection. Methods: A total of 125 patients with a confirmed histological diagnosis of unresectable advanced or metastatic biliary tract cancers (BTC) who received first-line ICIs in combination with chemotherapy (chemoimmunotherapy) were prospectively enrolled. All baseline samples from 125 patients underwent targeted DNA sequencing, with an additional 62 patients undergoing RNA sequencing, and 85 patients had accessible mIHC data. The associations between molecular characteristics and the response to chemoimmunotherapy, progression-free survival (PFS) and overall survival (OS) were evaluated. Results: The cohort had a median age of 63 years (range from 34 to 82) and 52.8% (66/125) were male, including 54 with gallbladder cancer, 57 with intrahepatic cholangiocarcinoma, and 14 with extrahepatic cholangiocarcinoma. The median duration of follow-up was 14.8 months for the entire cohort, with the median PFS and OS of 6.9 months (95%CI: 6.2-7.9) and 11.8 months (95%CI: 10.3-14.8), respectively. The most mutated genes were TP53 (64/125, 51.2%), KRAS (34/125, 27.2%), ERBB2 (18/125, 14.4%), and ARID1A (17/125, 13.6%). Mutations of TP53 (51.2%, p = 0.042), BRCA2 (4.8%, p = 0.002), cytokine genes (6.4%, p = 0.004), and high tumor mutation burden (p = 0.072) demonstrated significant correlation with chemoimmunotherapy response. KRAS G12D mutations (PFS: P &amp;lt; 0.001; OS: P = 0.034) and ARID1A loss-of-function mutations (PFS: P = 0.009; OS: P = 0.012) were adverse survival factors, while high CXCL9 or CTLA4 expression was associated with response (CXCL9, P = 0.014; CTLA4, P = 0.067), improved PFS (CXCL9, P = 0.018; CTLA4, P = 0.008), and longer OS (CXCL9, P = 0.010; CTLA4, P = 0.008) under chemoimmunotherapy. Patients were classified into three subtypes using the identified survival biomarkers. Among them, Type I patients, characterized by the absence of KRAS G12D or ARID1A mutations but expressing high levels of CTLA4 or CXCL9, demonstrated the best outcomes under chemoimmunotherapy. Interestingly, further RNA analysis suggested that elevated CXCL9 expression correlated with heightened immune checkpoint expressions, including CTLA4, PD-L1, and PD-1 (all P &amp;lt; 0.001), as well as increased tumor microenvironment immune activity, findings validated in two additional independent patient cohorts both internal and external. Conclusions: Our study revealed predictive biomarkers relevant to the response and efficacy of immune checkpoint inhibitors in combination with chemotherapy in advanced biliary tract cancer. Citation Format: Jieer Ying, Qi Xu, Jiaojiao Ni, Hanlin Chen, Chaoqun Li, Yanru Xie, Qinhong Zheng, Jianying Jin, Junrong Yan, Xiaoying Wu, Qiuxiang Ou, Li Yuan, Wei Zhuo, Haimeng Tang. Multi-omics analysis uncovers predictive biomarkers for the efficacy and outcomes of immune checkpoint inhibitor in combination with chemotherapy in advanced unresectable biliary tract cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5132.

BackgroundWhile the efficacy of immune checkpoint inhibitors (ICIs) is increasingly recognized in advanced gastric cancer (aGC), overall survival (OS) has not been consistently improved across the different randomized controlled trials (RCTs). This meta-analysis aimed to quantify the efficacy and safety of ICI and explore potential predictive tumor tissue biomarkers in aGC.MethodsA random-effect pairwise meta-analysis was used to evaluate the primary outcome of OS. Sensitivity analysis was performed to investigate the effects of ICIs on PD-L1 status, TMB, MSI-H, and the Asian patient population. We extracted the OS Kaplan–Meier curves from the included trials to compare the effect of PD-L1 status on response to ICIs using DigitizeIt 2.5 and Guyot’s algorithm.ResultsA pairwise meta-analysis of seven RCTs included in this study showed that ICIs were more effective than the comparator in improving OS (pooled HR: 0.84). We demonstrated that PD-1 ICIs were additive when combined with the comparator arm (pooled HR: 0.79). A sensitivity analysis showed that PD-1 ICIs were associated with better OS outcomes in the Asian patient population as monotherapy (pooled HR: 0.66) or in combination with chemotherapy (pooled HR: 0.83). We demonstrated that tumors with PD-L1 ≥1 (P = 0.02) and PD-L1 ≥10 (P = 0.006) derived OS benefit from ICI monotherapy. Equally, MSI-H (P <0.00001) and TMB-high (P <0.0001) tumors derived favorable survival benefits from ICIs.Conclusions and relevanceThe results of this meta-analysis suggest that ICIs result in improved OS outcomes in aGC. The benefits varied with different ethnicities, class of ICI, PD-L1 expression, MSI status, and TMBSystematic Review Registrationhttps://www.crd.york.ac.uk/prospero, identifier (CRD42019137829).

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6617 Background: In cancer patients, gut microbiota influences the antitumor immune response, efficacy, and safety of immune checkpoint inhibitors (ICIs). Antibiotics (ATBs), proton pump inhibitors (PPIs), and corticosteroids can alter the distribution of gut microbiota, resulting in dysbiosis, which can potentially reduce the efficacy of ICIs and may contribute to increased incidence of immune-related adverse effects (irAEs). Methods: We conducted a retrospective observational study to investigate the influence of concurrent medicines on patients receiving ICIs at the University of Vermont Cancer Center. We examined the medical records of people who received ICIs alone or in combination with chemotherapy or targeted therapy as a first-line therapy between January 2017 and June 2022. Patients who got ATBs, PPIs, and corticosteroids (&gt;10 mg prednisone) one month before commencing ICIs and during the first six months of treatment were compared to those who did not. We looked at the relative risk for overall survival and the occurrence of irAEs in both cohorts. Results: We identified 266 patients, of which 99 (37%) have died. The mean age was 64 years, 55% were male, and 97% of the patients were White. Lung cancer was the most commonly identified malignancy at 36%, and 55% of the cancers were stage IV. The median ECOG was 1, and the median Charlson morbidity index was 6. Of the total cohort, 62% received antibiotics, 67% received steroids, 45% received PPIs, 31% received two of the three, and 27% received all three. The relative risk (RR) of death in the cohort which received antibiotics was 1.53 (p = 0.02), the cohort which received steroids was 1.73 (p = 0.006), and the cohort that received PPIs was 1.61 (p = 0.006). For the group that received two or all three medications, the RR was 2.18 (p = 0.003). Regarding irAEs, the group that received steroids had a RR of 2.13 (p = 0.07); however, most of these patients likely received steroids for an irAE. Antibiotics and PPIs were not associated with a higher risk of irAEs. One of the significant limitations of our study is the small sample size and the retrospective data collection. Data is also confounded because it includes patients who have received ICIs in combination with chemotherapy or other agents. Conclusions: Our study suggests that patients who received any of the gut microbiome-modifying medications before starting and within the early phase of ICIs treatments are at higher risk of mortality, likely owing to the poor efficacy of ICIs or possibly because these patients are sicker at baseline. However, we must be judicious with using such medications when patients undergo treatment with ICIs. Large prospective studies looking at this association are needed to understand the risk and potential outcomes. [Table: see text]

1168P Effect of antibiotic treatment on immune checkpoint inhibitor efficacy in patients with advanced non-small cell lung cancer

&lt;div&gt;Abstract&lt;p&gt;Although the gut microbiome is associated with cancer development and progression, little is known about the effects of the gut microbiome landscape and the efficacy of immune checkpoint inhibitors (ICI) across cancer types. We investigated the association between the microbiome, clinical features, and ICI efficacy across cancer types in a large nationwide screening project for solid tumors. Among 2,180 patients with advanced solid tumors enrolled in the SCRUM-Japan MONSTAR-SCREEN between October 2019 and September 2021, in the chemotherapy-naïve cohort (&lt;i&gt;n&lt;/i&gt; = 817), a high prevalence of oral bacteria was observed in patients using proton pump inhibitors (PPI) and those with upper gastrointestinal cancers, particularly postoperative patients with gastric or pancreatic cancer. Among patients treated with ICIs (&lt;i&gt;n&lt;/i&gt; = 333), a high abundance of sequence variants in the gut microbiome was not significantly associated with ICI efficacy across cancer types (HR = 0.94; 95% confidence interval, 0.73–1.21). However, high oral bacteria in feces significantly correlated with a shorter progression-free survival compared with low oral bacteria (median, 4.34 vs. 6.97 months; HR = 1.38; 95% confidence interval, 1.07–1.78). Notably, in patients using PPIs, a higher proportion of oral bacteria influenced progression-free survival outcomes of ICI treatment (median, 3.15 vs. 2.04 months; &lt;i&gt;P&lt;/i&gt; = 0.08), unlike in PPI nonusers (median, 7.13 vs. 5.55 months; &lt;i&gt;P&lt;/i&gt; = 0.74). This study of the gut microbiome has unveiled significant insights into its landscape and potential impact on ICI efficacy. It highlights that the abundance of oral bacteria in feces may play a critical role in diminishing ICI efficacy among patients using PPIs.&lt;/p&gt;Significance:&lt;p&gt;As part of the MONSTAR-SCREEN, a prospective nationwide project for patients with solid tumors, we found that although gut microbiome diversity does not consistently predict ICI efficacy across cancer types, a high level of oral bacteria in the gut is linked to reduced ICI effectiveness, especially in patients using PPIs. These findings highlight the potential clinical impact of microbiome variations on cancer treatment outcomes.&lt;/p&gt;&lt;/div&gt;

The influence of antacids use on immune checkpoint inhibitor (ICI) efficacy remains unclear. A systematic review and meta-analysis was performed to evaluate the effect of proton pump inhibitors (PPIs) and histamine-2-receptor antagonists (H2RAs) on ICI efficacy in advanced solid cancer patients. A systematic literature search in PubMed, EMBASE, and Web of Science was performed to retrieve studies investigating the effect of antacid use on ICI efficacy. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and immune-related adverse events were measured using hazard ratios (HRs) or odds ratios (ORs). Thirty studies enrolling 16,147 advanced cancer patients receiving ICI treatment were included. The pooled analysis indicated that PPI use was associated with shorter OS (HR=1.40, 95% CI, 1.25-1.57) and PFS (HR=1.34, 95% CI, 1.19-1.52) in advanced cancer patients treated with ICIs. PPI use did not show effect on ORR or immune-related adverse event of advanced cancer patients receiving ICI treatment. OS, PFS, and ORR did not differ between H2RA users and non-H2RA users. In subgroup analyses, PPI use was associated with shorter OS and PFS in NSCLC and urothelial carcinoma patients and in patients treated with anti-programmed cell death 1 or anti-programmed cell death ligand 1 monotherapy. In addition, ICI efficacy was different in the antacid exposure time frame subgroups. In conclusion, PPI use has a negative effect on OS and PFS among advanced cancer patients receiving ICI treatment. PPIs should be cautiously administered among advanced cancer patients treated with ICI. The safety of H2RAs and the influence of H2RAs on ICI efficacy need further investigation.

Limited data exist on safety and efficacy of immune checkpoint inhibitors (ICIs) among organ transplant recipients. The objective of this study was to report a case series of two patients with renal transplant who received treatment with an ICI and to conduct a pooled analysis of published cases to describe the safety and efficacy of ICIs in organ transplant patients. A systematic search in the Google Scholar and PubMed databases was carried out to include all the published cases of organ transplant patients who received treatment with ICIs including programmed cell death protein 1 (PD-1), programmed death-ligand 1, or cytotoxic lymphocyte antigen-4 inhibitors since their inscription to January 31, 2019. In the present series of two cases with renal allografts who received pembrolizumab, one patient with squamous cell carcinoma of the skin experienced complete response (CR), whereas another patient with melanoma had a mixed response. Both patients experienced allograft rejection, but graft was salvaged. The pooled analysis of 64 patients published in literature showed that overall allograft rejection rate is 41% in organ transplant recipients following ICI therapy. The graft rejection rate was 44% (17/39) for renal, 39% (7/19) for liver, and 20% (1/5) for cardiac allografts. The highest risk was seen among patients who were treated with PD-1 inhibitors, 20/42 (48%)-13/24 (54%) on nivolumab and 7/18 (39%) on pembrolizumab. The risk was lowest with ipilimumab, 23% (3/13). The overall response rate (CR + partial response [PR]) was 20% with ipilimumab, 26% with nivolumab, and 53% with pembrolizumab, whereas disease control rate (CR + PR + stable disease) was 35% with ipilimumab, 37% with nivolumab, and 53% with pembrolizumab. None of the variables including age, gender, type of cancer, type of allograft, type of immunosuppression, time since transplantation to initiation of ICI, and prior history of rejection were significantly associated with the transplant rejection on univariate analysis. The efficacy of ICI among patients with organ transplant appears promising, warranting testing in prospective clinical trials. The risk of rejection and allograft loss is considerable; therefore, the risk and alternative form of therapies should be thoroughly discussed with the transplant patients prior to initiating ICI therapy. IMPLICATIONS FOR PRACTICE: Transplant recipients are at higher risk of developing cancers. Although immune checkpoint inhibitors have been shown to improve the outcome in more than one cancer type, transplant recipients were excluded from these trials. Most of the data on the safety and efficacy of immune checkpoint inhibitors in transplant patients are based upon case series and case reports. The pooled data from these reports suggest that anti-programmed death-ligand 1 inhibitors have reasonable safety and efficacy among organ transplant patients, which warrants testing in clinical trials.