Efficacy Of Immune Checkpoint Inhibitors Research Articles

Isobutyric acid enhances the anti-tumour effect of anti-PD-1 antibody.

The low response rate of immune checkpoint inhibitors (ICIs) is a challenge. The efficacy of ICIs is influenced by the tumour microenvironment, which is controlled by the gut microbiota. In particular, intestinal bacteria and their metabolites, such as short chain fatty acids (SCFAs), are important regulators of cancer immunity; however, our knowledge on the effects of individual SCFAs remains limited. Here, we show that isobutyric acid has the strongest effect among SCFAs on both immune activity and tumour growth. In vitro, cancer cell numbers were suppressed by approximately 75% in humans and mice compared with those in controls. Oral administration of isobutyric acid to carcinoma-bearing mice enhanced the effect of anti-PD-1 immunotherapy, reducing tumour volume by approximately 80% and 60% compared with those in the control group and anti-PD-1 antibody alone group, respectively. Taken together, these findings may support the development of novel cancer therapies that can improve the response rate to ICIs.

The later-line efficacy and safety of immune checkpoint inhibitors plus anlotinib in EGFR-mutant patients with EGFR-TKI-resistant NSCLC: a single-center retrospective study.

Effective treatment after EGFR-TKI resistance is of great clinical concern. We aimed to investigate the efficacy and safety of anlotinib in combination with an anti-PD-1/PD-L1 antibody in later-line therapy for EGFR-mutant NSCLC patients after TKI treatment failure and to explore the independent predictive factors of therapeutic efficacy. A total of 71 patients with confirmed advanced EGFR-mutated NSCLC who progressed after previous standard EGFR-TKI therapy but still failed after multiline treatments were included retrospectively in this study. Most of the patients had previously received at least three lines of treatment. All were treated with anlotinib combined with anti-PD-1 or anti-PD-L1 therapy. The safety of this combined treatment was assessed by the incidence of adverse events. The efficacy of the regimens was evaluated by survival analysis (OS, PFS, ORR, DCR). The median follow-up period was 28.6months (range: 2.3-54.0months), and the median number of treatment lines was 4. The overall response rate (ORR) and disease control rate (DCR) were 19.7% and 77.5%, respectively. The median PFS was 5.8months (95% CI 4.2-7.4months), and the median OS was 17.1months (95% CI 12.0-22.3months). Patients who received immune checkpoint inhibitors plus anlotinib had an encouraging intracranial ORR of 38.5% and a DCR of 80.8%. ECOG performance status < 2 at baseline was independent protective factors of PFS. Metastatic organs and ECOG performance status were independent parameters in predicting OS. Treatment-related adverse events occurred in 66 (93.0%) patients; most of the adverse events were Grade 1-2, and no increase in adverse events was observed compared to monotherapy. Anlotinib combined with an anti-PD-1/PD-L1-based regimen exhibited promising efficacy and tolerance in NSCLC patients with EGFR mutations after previous TKI failure. The efficacy of this combined regimen in patients with EGFR mutations should be further evaluated.

The optimal threshold of PD-L1 combined positive score to predict the benefit of PD-1 antibody plus chemotherapy for patients with HER2-negative gastric adenocarcinoma: a meta-analysis.

Immune checkpoint inhibitors (ICIs) combined with chemotherapy have become the first-line treatment of metastatic gastric and gastroesophageal adenocarcinomas (GEACs). This study aims to figure out the optimal combined positive score (CPS) cutoff value. We searched for randomized phase III trials to investigate the efficacy of ICIs plus chemotherapy for metastatic GEACs compared with chemotherapy alone. Pooled analyses of hazard ratios (HRs) based on PD-L1 expression were performed. A total of six trials (KEYNOTE-062, KEYNOTE-590, KEYNOTE-859, ATTRACTION-04, CheckMate 649, and ORIENT-16) were included, comprising 5,242 patients. ICIs plus chemotherapy significantly improved OS (HR: 0.79, 95% CI 0.72-0.86 in global patients; HR: 0.75, 95% CI 0.57-0.98 in Asian patients) and PFS (HR: 0.74, 95% CI 0.68-0.82 in global patients; HR: 0.64, 95% CI 0.56-0.73 in Asian patients) compared with chemotherapy alone. The differences in OS (ratio of HR: 1.05, 95% CI 0.79-1.40; predictive value: - 5.1%) and PFS (ratio of HR: 1.16, 95% CI 0.98-1.36; predictive value: - 13.5%) were not statistically significant between the global and Asian patients. Subgroup analyses indicated that the optimal CPS threshold was at ≥ 5 for OS and ≥ 10 for PFS with the highest predictive values. The benefit derived from ICIs plus chemotherapy is similar between Asian and global GEAC patients. However, those with a PD-L1 CPS < 5 or CPS < 10 may not have significant benefits from ICIs therapy. Therefore, it is advisable to routinely assess PD-L1 expression in GEAC patients considered for ICIs treatment.

Development and interpretation of a pathomics-driven ensemble model for predicting the response to immunotherapy in gastric cancer

BackgroundOnly a subset of patients with gastric cancer experience long-term benefits from immune checkpoint inhibitors (ICIs). Currently, there is a deficiency in precise predictive biomarkers for ICI efficacy. The aim...

Immune checkpoint inhibitor score (IChIS) predicts survival benefit of immunotherapy in patients with non-small cell lung cancer.

The use of immune checkpoint inhibitors (ICIs) in patients with advanced lung cancer is increasing. Despite ongoing studies to predict the efficacy of ICIs, its use in clinical practice remains difficult. Thus, we aimed to discover a predictive marker by analyzing blood cell characteristics and developing a scoring system for patients treated with ICIs. This was a prospective multicenter study in patients with advanced non-small cell lung cancer (NSCLC) who received ICIs as second-line treatment from June 2021 to November 2022. Blood cell parameters in routine blood samples were evaluated using an automated hematology analyzer. Immune checkpoint inhibitor score (IChIS) was calculated as the sum of neutrophil count score and immature granulocyte score. A total of 143 patients from 4 institutions were included. The treatment response was as follows: partial response, 8.4%; stable disease, 37.1%; and progressive disease, 44.8%. Median progression-free survival and overall survival after ICI treatment was 3.0 and 8.3 months, respectively. Median progression-free survival in patients with an IChIS of 0 was 4.0 months, which was significantly longer than 1.9 months in patients with an IChIS of 1 and 1.0 month in those with an IChIS of 2 (p = 0.001). The median overall survival in patients with an IChIS of 0 was 10.2 months, which was significantly longer than 6.8 and 1.8 months in patients with an IChIS of 1 and 2, respectively (p < 0.001). Baseline IChIS could be a potential biomarker for predicting survival benefit of immunotherapy in NSCLC.

PCDH11X mutation as a potential biomarker for immune checkpoint therapies in lung adenocarcinoma.

Immune checkpoint inhibitors (ICIs) have achieved impressive success in lung adenocarcinoma (LUAD). However, the response to ICIs varies among patients, and predictive biomarkers are urgently needed. PCDH11X is frequently mutated in LUAD, while its role in ICI treatment is unclear. In this study, we curated genomic and clinical data of 151 LUAD patients receiving ICIs from three independent cohorts. Relations between PCDH11X and treatment outcomes of ICIs were examined. A melanoma cohort collected from five published studies, a pan-cancer cohort, and non-ICI-treated TCGA-LUAD cohort were also examined to investigate whether PCDH11X mutation is a specific predictive biomarker for LUAD ICI treatment. Among the three ICI-treated LUAD cohorts, PCDH11X mutation (PCDH11X-MUT) was associated with better clinical response compared to wild-type PCDH11X (PCDH11X-WT). While in ICI-treated melanoma cohort, the pan-cancer cohort excluding LUAD, and the non-ICI-treated TCGA-LUAD cohort, no significant differences in overall survival (OS) were observed between the PCDH11X-MUT and PCDH11X-WT groups. PCDH11X mutation was associated with increased PD-L1 expression, tumor mutation burden (TMB), neoantigen load, DNA damage repair (DDR) mutations, and hot tumor microenvironment in TCGA-LUAD cohort. Our findings suggested that the PCDH11X mutation might serve as a specific biomarker to predict the efficacy of ICIs for LUAD patients. Considering the relatively small sample size of ICI-treated cohorts, future research with larger cohorts and prospective clinical trials will be essential for validating and further exploring the role of PCDH11X mutation in the context of immunotherapy outcomes in LUAD. KEY MESSAGES: PCDH11X mutation is associated with better clinical response compared to wild type PCDH11X in three ICIs-treated LUAD cohorts. In ICIs-treated melanoma cohort, the pan-cancer cohort excluding LUAD, and non-ICIs-treated TCGA-LUAD cohortsPCDH11X mutation is not associated with better clinical response, suggesting PCDH11X mutation might be a specific biomarker to predict the efficacy of ICIs treatment for LUAD patients. PCDH11X mutation is associated with increased PD-L1 expression, tumor mutation burden, and neoantigen load in TCGA-LUAD cohort. PCDH11X mutation is associated with hot tumor microenvironment in TCGA-LUAD cohort.

Clinical evidence for the prognostic impact of metformin in cancer patients treated with immune checkpoint inhibitors

BackgroundPreclinical studies suggest that metformin might enhance the efficacy of immune checkpoint inhibitors (ICIs) and potentially influence the prognoses of cancer patients undergoing ICIs treatment. This study endeavors to assess the prognostic significance of metformin in cancer patients undergoing ICIs therapy, aiming to furnish evidence-based insights for clinical practice. MethodsA thorough literature search was conducted across electronic databases to encompass all potential records published before November 20th, 2023. A meta-analysis was executed utilizing Stata 17.0 to derive pooled hazard ratios (HRs) with 95% confidence intervals (CIs) for both overall survival (OS) and progression-free survival (PFS). ResultsA total of 22 studies encompassing 9,011 patients met the inclusion criteria. Meta-analyses revealed a significant correlation between metformin use and poorer OS (HR, 1.13; 95 %CI, 1.04–1.23; P = 0.004) rather than PFS (HR, 1.04; 95 %CI, 0.96–1.14; P = 0.345) among cancer patients undergoing ICIs treatment. Subgroup analysis delineated that the concurrent administration of metformin and ICIs significantly associated with adverse prognoses in the European population (OS: HR, 1.23; 95 %CI, 1.10–1.39; P = 0.001; PFS: HR, 1.14; 95 %CI, 1.02–1.28; P = 0.024). ConclusionBased on current clinical evidence, concomitant metformin use does not appear to improve the prognostic outcomes for cancer patients undergoing ICIs therapy and may potentially correlate with inferior prognoses. Further studies are imperative to comprehensively elucidate the impact of metformin within the realm of ICIs therapy.

Efficacy of Pembrolizumab vs. Nivolumab Plus Ipilimumab in Metastatic NSCLC in Relation to PD-L1 and TMB Status

The efficacy of immune checkpoint inhibitor (ICI) therapy concerning programmed death ligand 1 (PD-L1) status is well established in patients diagnosed with non-small cell lung cancer (NSCLC). However, there remains a paucity of evidence regarding the efficacy concerning tumor mutational burden (TMB) in both clinical trials and real-world data (RWD). In the current article, clinicopathological and molecular epidemiological data were meticulously collected, and treatment modalities were meticulously recorded. The final analysis included a study population of 194 patients. Median age was 67 years (range 37–86), with the majority being male (71.13%), and 85.71% of patients were either current or former smokers at diagnosis. Adenocarcinoma accounted for most diagnoses (71.65%), followed by squamous cell carcinoma (24.23%). In terms of PD-L1 status, 42.78% had an expression level below 1%, 28.35% had an expression between 1–49%, and 28.87% had an expression above 50%. The TMB ranged from 0 to 75, with a median of 10.31 (range 0–75) for PD-L1 expression below 1%, with a median of 9.73 (range 0.95–39.63) for PD-L1 expression between 1–49%, and a median of 9.72 (range 0.95–48) for PD-L1 expression above 50%. Corresponding to patients with low PDL-1 less than 1% and low TMB (0–5), the median overall survival (mOS) was 16 (p = 0.18), and 15 months (p = 0.22), patients with medium PDL-1 (1–49%) and medium TMB (5–10), the mOS was 15 (p = 0.18) and 16 months (p = 0.22), patients with high PDL-1 (&gt;50) and high TMB (&gt;10), the mOS was 24 (p = 0.18) and 21 (p = 0.22) months. This study represents the largest academic RWD dataset concerning PD-L1 and TMB status in patients with locally advanced and metastatic NSCLC.

Assessing the role of programmed cell death signatures and related gene TOP2A in progression and prognostic prediction of clear cell renal cell carcinoma

Kidney Clear Cell Carcinoma (KIRC), the predominant form of kidney cancer, exhibits a diverse therapeutic response to Immune Checkpoint Inhibitors (ICIs), highlighting the need for predictive models of ICI efficacy. Our study has constructed a prognostic model based on 13 types of Programmed Cell Death (PCD), which are intertwined with tumor progression and the immune microenvironment. Validated by analyses of comprehensive datasets, this model identifies seven key PCD genes that delineate two subtypes with distinct immune profiles and sensitivities to anti-PD-1 therapy. The high-PCD group demonstrates a more immune-suppressive environment, while the low-PCD group shows better responses to PD-1 treatment. In particular, TOP2A emerged as crucial, with its inhibition markedly reducing KIRC cell growth and mobility. These findings underscore the relevance of PCDs in predicting KIRC outcomes and immunotherapy response, with implications for enhancing clinical decision-making.

Impact of Nutritional Status on Neutrophil-to-Lymphocyte Ratio as a Predictor of Efficacy and Adverse Events of Immune Check-Point Inhibitors

The neutrophil -to-lymphocyte ratio (NLR) is useful for predicting the effectiveness of treatment with immune checkpoint inhibitors (ICIs) and immune-related adverse events (irAEs). Because a growing body of evidence has recently shown that the number of lymphocytes that comprise NLR fluctuates according to nutritional status, this study examined whether the usefulness of NLR varies in ICI treatment due to changes in nutritional status. A retrospective analysis was performed on 1234 patients who received ICI treatment for malignant tumors at our hospital. Progression-free survival (PFS) was significantly prolonged in patients with NLR &lt; 4. Multivariate analysis revealed that the factors associated with the occurrence of irAE were NLR &lt; 4 and the use of ipilimumab. However, when limited to cases with serum albumin levels &lt;3.8 g/dL, lymphocyte counts significantly decreased, and the associations between NLR and PFS and between NLR and irAE occurrence disappeared. In contrast, when limited to the cases with serum albumin levels ≥3.8 g/dL, the associations remained, with significantly prolonged PFS and significantly increased irAE occurrence at NLR &lt; 4. NLR may be a good predictive tool for PFS and irAE occurrence during ICI treatment when a good nutritional status is maintained.

Application of immune checkpoint inhibitors for resectable gastric/gastroesophageal cancer

Gastric/gastroesophageal junction (G/GEJ) cancer represents a significant global health challenge. Radical surgery remains the cornerstone of treatment for resectable G/GEJ cancer. Supported by robust evidence from multiple clinical studies, therapeutic approaches, including adjuvant chemotherapy or chemoradiation, and perioperative chemotherapy, are generally recommended to reduce the risk of recurrence and enhance long-term survival outcomes post-surgery. In recent years, immune checkpoint inhibitors (ICIs) have altered the landscape of systemic treatment for advanced or metastatic G/GEJ cancer, becoming the standard first-line therapy for specific patients. Consequently, exploring the efficacy of ICIs in the adjuvant or neoadjuvant setting for resectable G/GEJ cancer is worthwhile. This review summarizes the current advances in the application of ICIs for resectable G/GEJ cancer.

Stabilizing tumor resident mast cells restores T cell infiltration and sensitizes sarcomas to PD-L1 inhibition.

To explore the cellular crosstalk of tumor resident mast cells (MCs) in controlling the activity of cancer-associated fibroblasts (CAFs) to overcome TME abnormalities, enhancing the efficacy of immune checkpoint inhibitors (ICIs) in sarcoma. We used a coculture system followed by further validation in mouse models of fibrosarcoma and osteosarcoma with or without administration of the MC stabilizer and antihistamine ketotifen. To evaluate the contribution of ketotifen in sensitizing tumors to therapy, we performed combination studies with doxorubicin chemotherapy and anti-PD-L1 (B7-H1, clone 10F.9G2) treatment. We investigated the ability of ketotifen to modulate the TME in human sarcomas in the context of a repurpose phase II clinical trial. Inhibition of MC activation with ketotifen successfully suppressed CAF proliferation and stiffness of the extracellular matrix accompanied by an increase in vessel perfusion in fibrosarcoma and osteosarcoma as indicated by ultrasound shear wave elastography imaging. The improved tissue oxygenation increased the efficacy of chemo-immunotherapy, supported by enhanced T cell infiltration and acquisition of tumor antigen-specific memory. Importantly, the effect of ketotifen in reducing tumor stiffness was further validated in sarcoma patients highlighting its translational potential. Our study suggests the targeting of MCs with clinically administered drugs, such as antihistamines, as a promising approach to overcome resistance to immunotherapy in sarcomas.

Combination of plasma MMPs and PD-1-binding soluble PD-L1 predicts recurrence in gastric cancer and the efficacy of immune checkpoint inhibitors in non-small cell lung cancer

BackgroundThe tumor microenvironment (TME) impacts the therapeutic efficacy of immune checkpoint inhibitors (ICIs). No liquid biomarkers are available to evaluate TME heterogeneity. Here, we investigated the clinical significance of PD-1-binding soluble PD-L1 (bsPD-L1) in gastric cancer (GC) patients and non-small cell lung cancer (NSCLC) patients treated with PD-1/PD-L1 blockade.MethodsWe examined bsPD-L1, matrix metalloproteinases (MMPs), and IFN-γ levels in plasma samples from GC patients (n = 117) prior to surgery and NSCLC patients (n = 72) prior to and 2 months after ICI treatment. We also examined extracellular matrix (ECM) integrity, PD-L1 expression, and T cell infiltration in tumor tissues from 25 GC patients by Elastica Masson-Goldner staining and immunohistochemical staining for PD-L1 and CD3, respectively.ResultsbsPD-L1 was detected in 17/117 GC patients and 16/72 NSCLC patients. bsPD-L1 showed strong or moderate correlations with plasma MMP13 or MMP3 levels, respectively, in both GC and NSCLC patients. bsPD-L1 expression in GC was associated with IFN-γ levels and intra-tumoral T cell infiltration, whereas MMP13 levels were associated with loss of ECM integrity, allowing tumor cells to access blood vessels. Plasma MMP3 and MMP13 levels were altered during ICI treatment. Combined bsPD-L1 and MMP status had higher predictive accuracy to identify two patient groups with favorable and poor prognosis than tumor PD-L1 expression: bsPD-L1+MMP13high in GC and bsPD-L1+(MMP3 and MMP13)increased in NSCLC were associated with poor prognosis, whereas bsPD-L1+MMP13low in GC and bsPD-L1+(MMP3 or MMP13)decreased in NSCLC were associated with favorable prognosis.ConclusionPlasma bsPD-L1 and MMP13 levels indicate T cell response and loss of ECM integrity, respectively, in the TME. The combination of bsPD-L1 and MMPs may represent a non-invasive tool to predict recurrence in GC and the efficacy of ICIs in NSCLC.

Impact of metabolic dysfunction-associated steatotic liver disease on the efficacy of immunotherapy in patients with chronic hepatitis B-related hepatocellular carcinoma.

To investigate the impact of metabolic dysfunction-associated steatotic liver disease (MASLD) on the efficacy of immune checkpoint inhibitor (ICI)-based therapy in patients with chronic hepatitis B (CHB)-related hepatocellular carcinoma (HCC). A total of 155 patients with CHB-related HCC who received ICI-based therapy (in the Department of Hepatology, Tianjin Second People's Hospital and Department of Hepatobiliary Oncology, Tianjin Medical University Cancer Institute & Hospital) between April 2021 and December 2023 were evaluated. Patients were divided into two groups: MASLD concurrent with CHB [MASLD-CHB] (n = 38), and CHB (n = 117). The median progression-free survival (PFS, 6.9 months vs. 9.3 months; P = 0.001), progressive disease (57.89% vs. 37.61%; P = 0.028), and disease control rate (42.11% vs. 62.39%; P = 0. 028) in the MASLD-CHB group were significantly worse than the CHB group. The median overall survival was not attained. The percentage of CD4+PD1+ (17. 56% vs. 8.89%; P < 0.001) and CD8+PD1+ T cells (10.50% vs. 7.42%; P = 0.005) in patient samples from the MASLD-CHB group were significantly higher than the CHB group. Concurrent MASLD [hazard ratio (HR) = 1.921; 95% CI, 1.138-3.245; P = 0.015] and alpha-fetoprotein levels after 3 months of treatment (HR = 2.412; 95% CI, 1.360-4.279; P = 0.003) were independent risk factors for PFS in all patients. ICI-based therapy in patients with CHB-related HCC and concurrent MASLD resulted in poorer efficacy and shorter PFS compared to patients with CHB-related HCC alone.

CXCR6-positive circulating mucosal-associated invariant T cells can identify patients with non-small cell lung cancer responding to anti-PD-1 immunotherapy

BackgroundMucosal-associated invariant T (MAIT) cells have been reported to regulate tumor immunity. However, the immune characteristics of MAIT cells in non-small cell lung cancer (NSCLC) and their correlation with the treatment efficacy of immune checkpoint inhibitors (ICIs) remain unclear.Patients and methodsIn this study, we performed single-cell RNA sequencing (scRNA-seq), flow cytometry, and multiplex immunofluorescence assays to determine the proportion and characteristics of CD8+MAIT cells in patients with metastatic NSCLC who did and did not respond to anti-PD-1 therapy. Survival analyses were employed to determine the effects of MAIT proportion and C-X-C chemokine receptor 6 (CXCR6) expression on the prognosis of patients with advanced NSCLC.ResultsThe proportion of activated and proliferating CD8+MAIT cells were significantly higher in responders-derived peripheral blood mononuclear cells (PBMCs) and lung tissues before anti-PD-1 therapy, with enhanced expression of cytotoxicity-related genes including CCL4, KLRG1, PRF1, NCR3, NKG7, GZMB, and KLRK1. The responders’ peripheral and tumor-infiltrating CD8+MAIT cells showed an upregulated CXCR6 expression. Similarly, CXCR6+CD8+MAIT cells from responders showed higher expression of cytotoxicity-related genes, such as CST7, GNLY, KLRG1, NKG7, and PRF1. Patients with ≥15.1% CD8+MAIT cells to CD8+T cells ratio and ≥35.9% CXCR6+CD8+MAIT cells to CD8+MAIT cells ratio in peripheral blood showed better progression-free survival (PFS) after immunotherapy. The role of CD8+MAIT cells in lung cancer immunotherapy was potentially mediated by classical/non-classical monocytes through the CXCL16-CXCR6 axis.ConclusionCD8+MAIT cells are a potential predictive biomarker for patients with NSCLC responding to anti-PD-1 therapy. The correlation between CD8+MAIT cells and immunotherapy sensitivity may be ascribed to high CXCR6 expression.

Abstract PO3-09-03: Dysbiosis of gut microbiota in patients with breast cancer

Abstract [Background] The effects of gut microbiome on various diseases have become widely known, and many studies reported that there was a correlation between the change of gut microbiota, that is dysbiosis, and the progression of digestive tract cancer. In addition, it is well-known that gut microbiota was correlated to the efficacy of immune checkpoint inhibitors for multiple types of cancer. However, the significance of gut microbiota in patients with breast cancer still remains unclear. The aim of this study is to analyze the gut microbiota in patients with breast cancer, compared with healthy women. [Subjects and Methods] We used the pre-treatment feces of 79 patients with primary breast cancer who received treatment at our facility and performed metagenome analysis of the V3-4 region of 16S rDNA. We also analyzed the breast cancer patients' microbiota with QIIME2 analysis method, compared to randomly selected 100 women aged 30-77 years from NIBIOHN's public data . We also assessed the characteristics of the gut microbiota of breast cancer patients by subtypes and its relationship with clinical and pathological factors. [Results] In Japanese gut microbiota, the Firmicutes and Bacteroidetes phyla make up the majority, but Firmicutes was the most common bacterial phylum in 52% of the public cohort, whereas 96.2% (76/79) of the breast cancer patients’ group (BC) showed a significantly higher proportion (p&amp;lt; 0.0001). In addition, ANCOM analysis revealed that the relative bacterial amounts of the Firmicutes, Bacteroidetes, and Proteobacteria phyla were significantly decreased in BC compared to the public cohort (PC), and at the bacterial genus level, the Feacalibacterium genus was significantly decreased in BC. Furthermore, the percentage of Fusobacteria phylum, which is a well-known oral bacteria that exacerbates digestive tract cancer, was 49.3% in BC, compared to 35% in PC (p=0.04). Among BC, the relative frequency of Fusobacteria phylum was significantly higher in the HER2-negative group than in the HER2-positive group (p&amp;lt; 0.0001). In BC, both alpha diversity (p&amp;lt; 0.0001) and beta diversity (p=0.001) were significantly lower than in PC. [Conclusion] An increase in the Firmicutes phylum is known to be associated with obesity, and also likely to affect the incidence risk of breast cancer. The results suggest that the Fusobacteria phylum and Feacalibacterium genus may be risk or preventive factors for breast cancer. Dysbiosis of gut microbiota is suggested to be associated with various diseases, and in this study the decrease in bacterial amount and diversity was observed in BC compared to PC, which may affect the onset and progression of breast cancer. Citation Format: Mai Yamada, Takafumi Morisaki, Yo Sato, Kimihisa Mizoguchi, Yuka Takao, Yurina Ochiai, Yoshiki Ootubo, Saori Hayashi, Masafumi Nakamura, Makoto Kubo. Dysbiosis of gut microbiota in patients with breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-09-03.

Abstract PO2-20-10: Exceptional long-term disease control on pembrolizumab monotherapy in a patient with TMB-high PMS2-mutated MMR-deficient triple negative breast cancer brain metastasis

Abstract Introduction The brain is among the most common sites of breast cancer (BC) spread. Prognosis of BC brain metastasis (BCBM) differs by receptor subtype, with poorest median overall survival (OS) for triple-negative (TN) BCBM at under 5 months. Though treatment guidelines have evolved in recent years, most strategies have focused on local therapies including surgery and stereotactic radiotherapy (SRT), rather than on systemic agents. The 2020 FDA approval of pembrolizumab (pembro) for patients (pts) with metastatic high-tumor mutational burden (TMB-h, ≥ 10 mutations/megabase) solid tumors, agnostic of primary site, combined with clinical trials in melanoma reporting efficacy of immune checkpoint inhibitors (ICI) against BM, suggest a potential use of ICI for pts with TMB-h BCBM. Results of the TAPUR study supported modest therapeutic benefit of pembro for 28 pts with metastatic BC selected for TMB-h, with median OS of 30.6 weeks, but did not include pts with active BCBM. TMB-h is uncommon in BC, and further genomic signatures remain to be elucidated to identify pts with BCBM responsive to ICI. We present a remarkable case of a pt with Lynch Syndrome (LS) due to a germline PMS2 mutation, who developed TMB-h, mismatch repair (MMR)-deficient TN BCBM, and has maintained stable disease for over 6 years on pembro monotherapy. Case description A 62-y.o. woman underwent screening mammography that identified a right breast mass. Pt has a family history of a mother with uterine and pancreatic cancer, and father with bladder cancer. Biopsy confirmed invasive ductal carcinoma (IDC), grade 1 (G1), ER/PR-positive, HER2 score 0. She underwent partial mastectomy, axillary dissection, radiation, and received adjuvant anastrozole. Three years later, while still on anastrozole, she presented with a 6 cm right breast mass. Mastectomy disclosed G3, ER/PR-negative, HER2-positive (3+, Her2:CEP17 ratio 5.6) IDC. She received adjuvant chemotherapy (AC-T) and 1 year of trastuzumab. Seven years later, pt presented with headaches and word finding difficulties. MRI identified a 3.6 cm frontal mass, which biopsy revealed as TN BCBM. Systemic imaging ruled out distant metastases. Pt proceeded with SRT and exemestane (despite receptor staining ER- in case of a possible false negative result). Despite radiotherapy, pt had BCBM progression within the same year with the largest mass diameter grown to 4.8 cm. Resection (followed by SRT) identified the dominant histology as G3 TNBC. Following transition of care to our institution, germline testing revealed a pathogenic mutation in PMS2 (c943C &amp;gt;T). Tumor sequencing of the resected brain metastasis showed TMB of 48 and MMR deficiency. Therefore, systemic therapy with pembro monotherapy was initiated and maintained with good tolerability. Two years later, concern for progression from rising tumor markers led to addition of concurrent carboplatin/gemcitabine for 5 cycles. Imaging and tumor markers stabilized, and pt returned to pembro monotherapy. Today, 3 years later, and over 6.5 years after initial TN BCBM diagnosis, pt continues to have stable disease on pembro with an excellent performance status (ECOG 0) and no evidence of intracranial or extracranial progression. Discussion We document an exceptional case of prolonged benefit to pembro in a pt with TMB-h PMS2-mutated MMR-deficient TN BCBM. This case highlights two major pragmatic points to clinical practice; (i) the significance of germline testing in all pts with metastatic BC, and (ii) the impact of molecular testing of tumor tissue to identify rare alterations which may have dramatic effects on pt outcomes. Altogether, this case is a remarkable addition to growing evidence that TMB could be a biomarker for predicting response to ICI therapy and provides an example of ICI efficacy in the setting of BCBM. Further research on additional genomic, clinical, and pathologic features associated with ICI responsiveness is warranted for greater precision in BCBM management. Citation Format: Jaeyoon Cha, Albert Grinshpun, Lauren Buckley, Brian Alexander, Sara Tolaney, Nancy Lin. Exceptional long-term disease control on pembrolizumab monotherapy in a patient with TMB-high PMS2-mutated MMR-deficient triple negative breast cancer brain metastasis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-20-10.

Abstract PO5-03-11: Ultra-low dose nivolumab added to dose-dense, cisplatin-based neoadjuvant chemotherapy in locally advanced, borderline operable triple negative breast cancer: A matched case-control study

Abstract Background In India, the majority of patients with triple negative breast cancer(TNBC) present with locally advanced and often inoperable disease due to lack of screening, awareness, and social stigma. This makes pathological complete response(pCR) after neoadjuvant chemotherapy(NAC) less likely, leading to early recurrence and poor survival outcomes. Immune checkpoint inhibitors(ICI) in addition to platinum agents have improved both pCR and disease-free survival(DFS). However, these are accessible only to a very small proportion(&amp;lt; 3%) of patients in LMICs due to exorbitant costs. The activity and cost-effectiveness of low dose ICI has been demonstrated in head and neck. The efficacy of low dose ICI in the neoadjuvant setting for TNBC has not been studied. We examined our outcomes with ultra-low dose nivolumab(&amp;lt; 0.6 mg/kg every 2 weeks) added to NAC for locally advanced and borderline operable TNBC. Methods A retrospective analysis of 132 patients with TNBC who received NAC with the ddDCEP regimen(Docetaxel 75mg/m2 and Cyclophosphamide 600 mg/m2 alternating with Epirubicin 90mg/m2 and Cisplatin 60mg/m2 every 2 weeks for 8 cycles) or ddDCEP plus low dose nivolumab(&amp;lt; 0.6mg/kg/2 weeks) and underwent mastectomy at our centre between 2018-2023 was carried out. 105 and 27 patients received ddDCEP alone and ddDCEP + low dose nivolumab respectively. Using rigorous exact matching, 26 matched pairs(52 patients) were obtained based on tumour grade and AJCC TNM stage. pCR in the surgical specimen was the principal outcome assessed. Survival data, adverse events and cost were also analysed. Results The median age of cases and controls was 42 and 40 years respectively. Tumour histology was ductal carcinoma most patients. Across both groups the stage distribution was the same with nearly 85% stage III(IA 3.8%;IIB 7.7%; IIIA 23.1%;IIIB 43.2%;IIIC 19.2%). 92% of cases and 85% of controls had node positive disease. 62% of cases and 46% of controls had T4 disease. At a median follow up of 9 months, there were no recurrences or deaths among the cases. The most common immune mediated adverse event was hypothyroidism seen in 11.5% of cases. The rates of grade 3/4 anaemia, thrombocytopenia and febrile neutropenia were approximately 38%, 10% and 3.8% across cases and controls respectively. The median dose of nivolumab was 0.27mg/kg/2weeks as opposed to the approved dose of 3mg/kg/2weeks for most indications. The range of doses varied from 0.07 to 0.58mg/kg/2weeks. In the overall cohort, the addition of nivolumab did not have any apparent effect on the pCR rates which were identical at 42.3% in both cases and controls. However, there was a positive correlation between the total dose of nivolumab/kg(body weight) and the likelihood of pCR(coefficient 0.34; p-value 0.046). Patients who received higher than the median dose of nivolumab had a significantly higher likelihood of attaining pCR than those who received lower doses (69.2% pCR vs.15.4%;p-value 0.015). The cost of nivolumab at 0.6 mg/kg for 4 doses is approximately USD2000 compared to USD34400 for 8 doses of pembrolizumab in the neoadjuvant component of the KEYNOTE-522 regimen. Conclusion In this cohort with locally advanced/inoperable TNBC, the addition of ultra-low dose nivolumab did not improve pCR overall compared to a matched control set who did not receive ICI. However, in the subset of patients who received between 0.27-0.58 mg/kg/2weeks, the pCR rates were significantly higher at 69%. This presents a promising and cost-effective approach for TNBC management in LMICs. This effect needs verification in larger phase II/III trials. Table. Citation Format: Zachariah Thomas, Josh Georgy, Ashish Singh, Anjana Joel, Divya Thumaty, Ajoy John, Jerryes Wisely, Grace Rebekah, Elanthenral Sigamani, Anish Cherian, Deepak Abraham, Paul Jacob, Rajesh Balakrishnan, Patricia Solomon, Selvamani Backianathan, Raju Chacko. Ultra-low dose nivolumab added to dose-dense, cisplatin-based neoadjuvant chemotherapy in locally advanced, borderline operable triple negative breast cancer: A matched case-control study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-03-11.

Comparative efficacy of immune checkpoint inhibitors combined with chemotherapy in patients with advanced driver-gene negative non-small cell lung cancer: A systematic review and network meta-analysis

ObjectiveTo evaluate the efficacy of different combinations of immune checkpoint inhibitors (ICIs) and chemotherapy (CT) in the treatment of advanced non-small cell lung cancer (NSCLC). MethodsWe obtained relevant randomized controlled trials (RCTs) from databases such as PubMed, Embase, Web of Science, and The Cochrane Library up to May 31, 2023. The analysis of clinical prognostic factors was performed using R 4.2.3 and STATA 15.0. The main outcomes measured were overall survival (OS) and progression-free survival (PFS), while secondary outcomes included the objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events of grade 3–5 severity (Grade ≥3 TRAE). ResultsA total of 17 randomized controlled trials (RCTs) were conducted between 2012 and 2023, involving 7792 patients. These trials evaluated 11 different treatment methods. The results of these trials showed that in terms of overall survival (OS) and progression-free survival (PFS), the combination of tislelizumab with chemotherapy and the combination of camrelizumab with chemotherapy were particularly effective. Moreover, when compared with other combination therapies, pembrolizumab combined with chemotherapy showed superiority in terms of disease control rate (DCR) and objective response rate (ORR). Subgroup analyses further demonstrated that the addition of immune checkpoint inhibitors (ICIs) to chemotherapy significantly improved PFS and OS in patients without liver metastasis and in those with brain metastasis. Additionally, carboplatin-based combination therapy was found to confer favorable survival benefits in terms of PFS, while cisplatin-based combination therapy showed the most favorable outcomes in terms of OS. The results of subgroup analyses for overall survival (OS) showed that the combination of immunotherapy and chemotherapy yielded positive outcomes in specific subgroups. These subgroups were characterized by PD-L1 Tumor Proportion Score (TPS) of 50 % or higher, usage of anti-PD-1 medications, age below 65, male gender, smoking history, and non-squamous cell carcinoma histology. Superior effectiveness was demonstrated only in extending the progression-free survival (PFS) of female patients and patients with squamous carcinoma. Meanwhile, other patient cohorts did not show the same level of improvement. ConclusionsTislelizumab, camrelizumab or pembrolizumab combined with chemotherapy may be the optimal first-line treatment strategies for NSCLC.

A novel Natural killer cell-related gene signature for improving the prediction of prognosis and immunotherapy response in bladder cancer.

Bladder cancer (BLCA) is a commonly diagnosed cancer worldwide that exhibits high rates of recurrence and metastasis. Immunotherapy is increasingly being recognised in the clinical management of bladder cancer. In addition, the prospect of developing Natural Killer (NK) cell-related immunotherapy is promising in BLCA. We established and verified a prognostic signature based on NK cell-related gene expression. We then calculated the NKscore of BLCA samples and correlated it with the clinical outcomes, molecular subtypes of BLCA, tumour microenvironment (TME), and predicted efficacy of immune checkpoint inhibitors (ICI) and chemotherapy drugs to thoroughly explore the implications of the NKscore. Finally, the role of the NK signature gene HECTD1 in BLCA was verified by Quantitative Real-time PCR, Cell Counting Kit-8 Assay (CCK-8), Transwell Assay and Colony Formation Experiment. We analysed NK cell-associated genes and identified six genes with significant prognostic relevance. A high NK score significantly represents a worse prognosis. NKscore was significantly correlated with seven types of classical molecular subtype classifications of BLCA. In addition, NKscore positively correlates with NK-related immune checkpoints, suggesting that emerging NK cell immune checkpoint inhibitors, such as monalizumab, may have potential therapeutic promise for patients with high NKscore. The results of the T cell inflamed score (TIS) and tumour immune dysfunction exclusion (TIDE) score confirmed the suitability of immunotherapy for patients with a high NK score. Likewise, patients with a high NK score may be more suitable for several significant chemotherapeutic drugs. Functional experiments showed that the knockdown of HECTD1 significantly attenuated the proliferation, migration, and invasion ability of tumour cells. to sum up, the capability of our signature to predict prognosis and immunotherapy response was robust. Hopefully, these results will provide new insights for BLCA research and patient immunotherapy.