Risk Of Immune-related Adverse Events Research Articles

Gut microbiota shifts from onset to remission in immune checkpoint inhibitor-induced enterocolitis: a case report

BackgroundImmune checkpoint inhibitors (ICIs) are crucial in cancer treatment; however, they carry the risk of immune-related adverse events (irAEs), such as enteritis. Case presentation: This study investigated the role of the gut microbiota during the onset and remission of irAE enteritis in a patient with stage IV melanoma undergoing anti-PD-1 and anti-CTLA-4 therapy. Following commencement of ICI treatment, the patient developed severe diarrhea and was diagnosed with grade 3 irAE enteritis. Steroid and probiotic treatments provided swift symptom relief and remission, as confirmed by reduced fecal calprotectin levels and gastrointestinal imaging. Microbiota diversity analysis conducted via 16S rRNA gene sequencing identified a decrease in Streptococcus prevalence with improvement in enteritis symptoms. Conversely, genera Fusobacterium, Faecalibacterium, Bacteroides, Prevotella, and Bifidobacterium showed increased representation after remission. These genera are associated with anti-inflammatory properties and fibrous substrate degradation, aiding gut health. Immunological assessment demonstrated fluctuations in cytokine expression and the modulation of costimulatory molecules, aligning with therapeutic interventions and microbiota alterations.ConclusionsOur findings indicate a significant correlation between gut microbiota and immune responses in irAE enteritis. This underscores the potential utility of microbiome profiling in predicting irAE occurrence and in providing treatment strategies, thereby promoting a more comprehensive approach to managing the adverse effects of ICIs.

Germline variation and risk of immune-related adverse events (irAEs): A real-world BioVU study.

10582 Background: IrAEs are prevalent in patients treated with immune checkpoint inhibitors (ICI) and mimic classical autoimmune diseases. IrAE risk prediction could improve clinical decision making and patient safety for ICI-treated patients. Classical autoimmune diseases show strong associations with germline polymorphisms and with Human Leukocyte Antigen (HLA) variants, though it is unclear if these same genetic risk factors predispose to irAEs. To identify both tolerant and irAE patients, we mined Vanderbilt University Medical Center (VUMC) BioVU, a biorepository of >300K DNA samples linked to de-identified medical records and evaluated genome-wide and imputed HLA class I and II associations with irAE risk. Methods: We identified 1,472 ICI-treated BioVU subjects: 428 with ≥ 1 irAE, and 1044 with no irAEs ≤ 6 months from last ICI treatment. Genotyping was performed by Illumina MEGAEX array. Records were screened for use of irAE therapies ( e.g. systemic corticosteroids, infliximab, levothyroxine) after ICI treatment, with chart adjudication. Association tests were performed using Firth’s logistic regression adjusting for age, sex, ICI regimen, and 3 principal components to assess 1) HLA Class I and II alleles; 2) HLA evolutionary divergence; and 3) GWAS to evaluate total irAEs, organ-specific irAEs, or other specific irAEs (sample size permitting). Endocrine irAEs were excluded to be presented in a separate focused study. Results: In GWAS analyses, 53 SNPs and 23 SNPs were identified significantly (nominal p ≤ 5e-8) associated with GI and neuro-toxicity, respectively. We did not identify any significant HLA class I or II associations with irAE or organ-grouped irAEs, including most evolutionary divergence association tests. We noted marginal association (FDR=0.12, OR=6.85) of rheumatic irAEs with HLA-DRB1*10:01, an HLA class II allele with RA-specific epitope motif. Patients experiencing lung irAEs were more likely to have a high HLA class I and II evolutionary divergence sum (p = 0.013 and p=0.046, respectively). Assessment of associations with specific irAEs, validation of known associations with irAEs or autoimmune disorders, including polygenic risk scores, are underway. Conclusions: We had several SNP-irAE associations, though appropriate classification schemas to maximize power and detect genetic variation remain challenging. We will soon expand with 1,800 additional ICI-treated patients (n=~3,300 in toto), creating a robust resource for irAE genetic associations. [Table: see text]

Effects of pre-treatment on odds of immune-related adverse events.

2540 Background: For many tumor types, there is an option to start an immune checkpoint inhibitor (ICI) at the time of diagnosis or to sequence ICI after chemotherapies or targeted therapies. The risk of immune-related adverse events (irAE) may vary by the line of therapy. Prior systemic therapies might release cancer epitopes and increase the risk of an irAE through awakened subclinical autoimmunity. Conversely, prior systemic therapies may lead to residual immunosuppression and reduce the risk of irAEs. Methods: We created an IRB-approved retrospective registry of all patients who received at least one dose of an ICI for any indication between 2/1/2011 and 4/7/2022 at a comprehensive cancer center and its outreach clinics. Study personnel reviewed the electronic medical record and defined irAEs according to Common Terminology Criteria for Adverse Events. Research specialists at Vasta Global captured most clinical outcomes. Line of therapy was defined ordinal manner, with four or more combined into a single group due to data sparsity. A multivariable logistic regression model was built to assess effect of line of therapy on any irAE while controlling for confounders identified either a priori or in univariate analysis. Given potential for heterogeneity, interaction between tumor primary and line of therapy was tested. SAS v9.4 was used for all analyses. Results: Among the final cohort of 3,101 patients, 1,169 (38%) were noted to have an irAE of any grade. ICI were used as first-line therapy in 1,432 patients and second-, third-, or at least fourth-line in 1,119, 328, and 222 patients, respectively. The most common tumor type was non-small cell lung cancer (36%), followed by melanoma (14%). At baseline, any-grade irAE were more common among first-line ICI with 618 (43.2%) than for second-line (395, 35.3%), third-line (102, 31.1%), or at least fourth-line (54, 24.3%; p<0.01). After adjusting for age (over 65), sex, smoking history, and body mass index, the model revealed significant heterogeneity, indicated by a significant interaction between the ICI line and the primary tumor type (p=0.01). The impact of the ICI line on the odds ratio (OR) of irAE for each primary calculated: melanoma (OR) 0.54 (95% confidence interval [CI] 0.32-0.93), non-small cell lung cancer OR 1.14 (CI 0.96-1.35), head-neck cancer OR 0.82 (CI 0.58-1.14), and renal cell carcinoma OR 0.78 (CI 0.57-1.06). Conclusions: The effect of pre-treatment with prior systemic therapy was significantly associated with the odds of developing an irAE, though this effect was significantly heterogeneous between tumor primaries. Melanoma was significantly less likely to develop irAE when heavily pre-treated. In contrast, NSCLC suggested a trend of increased odds of irAE with more pre-treatment however it was not statistically significant. Further study is indicated to clarify the types of prior systemic therapy that may modulate the risk of irAE and better clarify the optimal sequencing of ICI.

Impact of commonly prescribed medications on immune-related adverse events.

e14704 Background: Commonly used medications may have immune modulating properties that affect the risk of immune-related adverse events (irAEs) after immune checkpoint inhibitor (ICI) therapy. Methods: We identified 27,998 patients who received ICI from 2010 to 2023 in the national Veterans Affairs system, matched to 66,488 historical control patients treated with non-ICI systemic therapies. We extracted medication usage in the year before therapy start. We used propensity-weighted Cox regression analysis to assess the effect of each medication on severe irAE (treatment with prolonged course of high-dose steroids, adrenal insufficiency, or new insulin-dependent diabetes). To identify medication effects specific to ICI vs. other therapies, we report the adjusted hazard ratio (aHR) for each medication stratified by cohort (ICI vs. historical control) and the p-value for the interaction between each medication class and cohort. Results: Among ICI patients, 52% of patients were treated in the first line, 72% received ICI monotherapy, and 95% received PD-1/PD-L1 inhibitors alone. The most common cancer types were NSCLC (46%), melanoma (10%), and liver cancer (8%). Among 15 medication classes, metformin, loop diuretics, and PPIs were associated with small, marginally statistically significant differences in toxicity among ICI patients, but similar associations were observed in historical control patients (p for interaction >0.18; Table). After adjustment for multiple comparisons, no medication classes were associated with increased risk of severe irAE in ICI patients. Conclusions: Commonly prescribed medication classes have no significant effects on toxicity specific to ICI therapy. [Table: see text]

Incidence and time to onset of immunotherapy-related adrenal insufficiency in the I-SPY2 trial.

584 Background: I-SPY2 was the first randomized trial to demonstrate an improvement in pCR and EFS when Immune Checkpoint Inhibitors (ICI) were added to standard neoadjuvant chemotherapy. This finding was validated in the phase 3 KEYNOTE 522 trial for triple-negative breast cancer, leading to approval of pembrolizumab (pembro) in this setting. ICIs add the risk of immune-related adverse events (irAEs); while most irAEs are reversible, endocrinopathies appear to persist. Higher rates of adrenal insufficiency (AI), either from primary adrenalitis or hypophysitis, have been reported with ICI-based therapy (tx) in early breast cancer (EBC) compared to advanced disease. Here we describe the incidence and time of onset of AI with ICI-based tx in I-SPY2. Methods: I-SPY2 is a multicenter, phase 2 trial using response-adaptive randomization within biomarker subtypes defined by hormone receptor, HER2, and MammaPrint status to evaluate novel agents in the neoadjuvant setting in patients (pts) with high-risk EBC. Treatment included weekly paclitaxel (T) plus ICI-based tx x 4 cycles, followed by doxorubicin/cyclophosphamide (AC) every 2-3 weeks x 4. 6 completed investigational arms included ICIs: T+pembro x 4, T+pembro x 8 (+/- AC), T+pembro+SD101 (TLR9 agonist), T+durvalumab+olaparib, T+cemiplimab (cemi), and T+cemi+REGN3767 (anti-LAG-3). AI diagnoses were made by treating providers with review from two board certified endocrinologists. AI was defined as AM serum cortisol level < 3 mcg/dl in absence of recent glucocorticoid treatment. If ACTH was low or normal, pt was dx with hypophysitis; if ACTH was elevated, pt was dx with primary AI. Results: 442 pts in I-SPY2 received ICI-based tx; 11.8% (n=52) developed AI (primary+hypophysitis). Mean age of pts who developed AI was 47.3 vs 48.6 yrs in those who did not (p=0.44). Incidence of AI was highest in arms with dual immune modulation (18.1%) as compared to single ICI tx (8.5%). Median time to onset varied by arm, ranging from 92-204 days from first ICI dose. While some cases occurred during ICI tx (13.5%), the majority occurred between 12-24 wks after tx initiation, with 21.2% diagnosed after completion of all tx. The majority (94.2%) of pts with AI were symptomatic; the most common presenting symptoms included fatigue (59.6%), nausea (48.1%), and vomiting (34.6%). All pts with AI remain on glucocorticoid replacement tx. Conclusions: The incidence of AI in EBC is higher than has previously been reported in advanced disease, with higher rates observed in those tx with dual immune modulation. No correlation was observed with age; correlation of AI with response predictive subtype and other clinicopathologic features is ongoing and will be presented. Given the high incidence of AI in EBC, close monitoring in the peri/postoperative setting and education of pts and providers is critical, as risk persists even after completion of tx. Work to identify risk factors for AI is ongoing. Clinical trial information: NCT01042379 .

Gene network-based and ensemble modeling-based selection of tumor-associated antigens with a predicted low risk of tissue damage for targeted immunotherapy

BackgroundTumor-associated antigens and their derived peptides constitute an opportunity to design off-the-shelf mainline or adjuvant anti-cancer immunotherapies for a broad array of patients. A performant and rational antigen selection pipeline...

Association of Baseline Tumor-Specific Neoantigens and CD8+ T-Cell Infiltration With Immune-Related Adverse Events Secondary to Immune Checkpoint Inhibitors.

Recent evidence has shown that higher tumor mutational burden strongly correlates with an increased risk of immune-related adverse events (irAEs). By using an integrated multiomics approach, we further studied the association between relevant tumor immune microenvironment (TIME) features and irAEs. Leveraging the US Food and Drug Administration Adverse Event Reporting System, we extracted cases of suspected irAEs to calculate the reporting odds ratios (RORs) of irAEs for cancers treated with immune checkpoint inhibitors (ICIs). TIME features for 32 cancer types were calculated on the basis of the cancer genomic atlas cohorts and indirectly correlated with each cancer's ROR for irAEs. A separate ICI-treated cohort of non-small-cell lung cancer (NSCLC) was used to evaluate the correlation between tissue-based immune markers (CD8+, PD-1/L1+, FOXP3+, tumor-infiltrating lymphocytes [TILs]) and irAE occurrence. The analysis of 32 cancers and 33 TIME features demonstrated a significant association between irAE RORs and the median number of base insertions and deletions (INDEL), neoantigens (r = 0.72), single-nucleotide variant neoantigens (r = 0.67), and CD8+ T-cell fraction (r = 0.51). A bivariate model using the median number of INDEL neoantigens and CD8 T-cell fraction had the highest accuracy in predicting RORs (adjusted r2 = 0.52, P = .002). Immunoprofile assessment of 156 patients with NSCLC revealed a strong trend for higher baseline median CD8+ T cells within patients' tumors who experienced any grade irAEs. Using machine learning, an expanded ICI-treated NSCLC cohort (n = 378) further showed a treatment duration-independent association of an increased proportion of high TIL (>median) in patients with irAEs (59.7% v 44%, P = .005). This was confirmed by using the Fine-Gray competing risk approach, demonstrating higher baseline TIL density (>median) associated with a higher cumulative incidence of irAEs (P = .028). Our findings highlight a potential role for TIME features, specifically INDEL neoantigens and baseline-immune infiltration, in enabling optimal irAE risk stratification of patients.

Exploration of Germline Correlates and Risk of Immune-Related Adverse Events in Advanced Cancer Patients Treated with Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors (ICIs) are increasingly used in the treatment of many tumor types, and durable responses can be observed in select populations. However, patients may exhibit significant immune-related adverse events (irAEs) that may lead to morbidity. There is limited information on whether the presence of specific germline mutations may highlight those at elevated risk of irAEs. We evaluated 117 patients with metastatic solid tumors or hematologic malignancies who underwent genomic analysis through the ongoing Personalized OncoGenomics (POG) program at BC Cancer and received an ICI during their treatment history. Charts were reviewed for irAEs. Whole genome sequencing of a fresh biopsy and matched normal specimens (blood) was performed at the time of POG enrollment. Notably, we found that MHC class I alleles in the HLA-B27 family, which have been previously associated with autoimmune conditions, were associated with grade 3 hepatitis and pneumonitis (q = 0.007) in patients treated with combination PD-1/PD-L1 and CTLA-4 inhibitors, and PD-1 inhibitors in combination with IDO-1 inhibitors. These data highlight that some patients may have a genetic predisposition to developing irAEs.

Abstract 2533: In-depth multi-omic profiling of immune cells in cancer patients developing immune-related adverse events

Abstract Background: The clinical efficacy of immune-checkpoint inhibitors is complicated by the risk for immune-related adverse events (irAEs) that can involve any organ systems. To date, (1) we cannot predict irAE risk reliably at patient level and (2) irAEs remain a diagnosis of exclusion as there are no specific clinical or biological markers. The goal of this study was to elucidate intricate transcriptomic and proteomic signatures of immune cells in patients evolving irAEs. Methods: This pilot trial was conducted as part of a prospective multicenter cohort study (NCT04631731). The study cohort consisted of n=71 patients who were treated with ICIs across Blacktown and Westmead Hospitals, NSW, Australia. Peripheral blood mononuclear cells (PBMCs) were collected from both pre-treatment and after 6-8 weeks post-ICI commencement. Samples were further utilized for RNA sequencing, flow cytometry and Chromium 3’ gene expression analysis (10x Genomics). Results: The median age was 67 years old with the 78% (n=56) of Caucasian origin. The predominant number of patients were treated with dual ICIs. N=21 patients experienced irAEs. Firstly, a differential analysis established a set of genes which were significantly (FDR<0.01) dysregulated between patients with (group A) and without irAEs (group B) and were mostly related to cell cycle and regulation. Notably, phospholipase D signaling pathway was exclusively upregulated in group A and is known to be linked to B cell expansion. Secondly, a cell enrichment analysis within the group A revealed a significant increase of CD4+ and CD8+ T central memory (Tcm) cells upon the toxicity onset as compared to baseline stage. Thirdly, the flow cytometry data established that group A had (1) higher expression of CD27 on CD4+ T cells, a member of Traf-linked tumor necrosis factor receptor family essential for T cells’ maturation and (2) lower expression of inhibitory receptor LAG3 (CD223) which is crucial for maintaining homeostasis of immune system through suppression of T cell proliferation. Finally, we sequenced CD45+ cells from n=4 patients from group A and n=4 from group B at both pre- and post-treatment stages. The unsupervised clustering established 17 different clusters in our single cell dataset with cluster 11 was unique only to patients from group A. The differential analysis established that a set of n=62 genes was significantly upregulated (p<0.05) in cluster 11. Functional annotation established that B cell activation and proliferation pathways were enriched by those genes further stressing B cells’ role in irAEs development. Conclusions: Our real-world cohort study established significant molecular and cellular differences between patients with and without irAEs. Further research in larger cohorts is imperative to validate the established findings and to elucidate the precise mechanisms contributing to the development of irAEs. Citation Format: Dmitrii Shek, Bo Gao, Joey Lai, Brian Gloss, Adnan Nagrial, Ines Pires da Silva, Matteo S. Carlino, Scott A. Read, Golo Ahlenstiel. In-depth multi-omic profiling of immune cells in cancer patients developing immune-related adverse events [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 2533.

Impact of immune-related adverse events in patients with hepatocellular carcinoma treated with atezolizumab plus bevacizumab.

Immune checkpoint inhibitors pose the risk of immune-related adverse events (irAEs). Recent data suggest that irAEs may be associated with a favorable prognosis. This study aimed to investigate and analyze the association between these adverse events and the clinical benefits in patients with unresectable hepatocellular carcinoma. The study enrolled 130 patients with advanced hepatocellular carcinoma treated with atezolizumab plus bevacizumab between November 2020 and January 2023 at a single center. The relationship between irAEs and both response rate and post-treatment outcomes was investigated. Out of the 130 patients, irAEs developed in 36 (27.7%) patients. The irAE group exhibited a significantly longer progression-free survival (PFS) than the non-irAE group, with a median PFS of 8.9 compared with 4.6months (P<0.01). No difference was found in the overall survival between the irAE and non-irAE groups. The irAE group demonstrated significantly higher disease control rate (DCR) than the non-irAE group (97.0% vs 65.5%, P<0.01). The analysis by irAE severity revealed that the grade 1/2 group exhibited significantly longer PFS (7.9 vs 4.6months, P=0.007) and higher DCR (100% vs 65.5%, P<0.01) than the non-irAE group. Furthermore, hypothyroidism correlated with a favorable PFS (8.9 vs 5.4months, P=0.02), DCR (100% vs 71.3%, P=0.03), and overall response rate (58.3% vs 18.5%, P=0.005). The presence of irAEs is associated with prolonged PFS and higher DCR. Specifically, mild irAEs (grade 1/2) and hypothyroidism displayed prolonged PFS and higher DCR.

A169 A RARE MANIFESTATION OF ENTERITIS DUE TO IMMUNE CHECKPOINT INHIBITOR: CASE REPORT OF PYLORIC STRICTURE

Abstract Background Immune checkpoint inhibitors (ICI) are immunomodulatory antibodies used to enhance the immune response against tumor cells that have revolutionized the treatment of various malignancies. ICIs pose a risk of immune-related adverse events in various organs including the gastrointestinal tract, with diarrhea and colitis being most common. ICIs can rarely cause involvement of the upper gastrointestinal tract, with case reports of gastritis, duodenitis, and esophagitis. There are very rare reports of strictures caused by ICIs, more frequently in the lower gastrointestinal tract, and only a few reports in the esophagus or duodenum. Aims We report a rare case of an upper gastrointestinal stricture due to ICI at the pylorus. Methods Case report. Results A 38-year-old woman with breast cancer on ICI pembrolizumab presented with several weeks of nausea and early satiety. She had started pembrolizumab 8 months prior, underwent neoadjuvant chemotherapy and mastectomy months ago, and completed radiation 6 weeks earlier. She also described nocturnal reflux and heartburn, but no vomiting, weight loss, or other gastrointestinal symptoms. Her examination was normal and recent bloodwork only showed a mild normocytic anemia. EGD (esophagogastroduodenoscopy) showed friable circumferential ulceration of the distal antrum with surrounding erythema and luminal narrowing from the pyloric channel to duodenum. 1-centimetre gastroscope was not passable but 4.9-millimetre pediatric gastroscope passed into the duodenum where there were no abnormalities past the duodenal bulb. Pathology showed granulation tissue, fibrinopurulent exudate, and antral mucosa with chronic active inflammation negative for Helicobacter pylori and malignancy. Oncology felt that radiation was too far from the pylorus to be responsible for the findings. High-dose proton pump inhibitor (PPI) and soft diet were recommended with minimal symptomatic improvement. 2 months later, she developed weight loss and repeat EGD showed minimal endoscopic improvement (Figure 1). ICI-related enteritis was suspected and she was started on prednisone 50 mg daily. Her appetite and nausea significantly improved. Steroid taper was planned for 8 weeks. At 3 months, symptoms recurred with prednisone taper. EGD showed only mild improvement of the duodenal stricture. Prednisone dose was increased. On repeat EGD at 7 months, the pylorus was patent with only granular inflammation predominantly in the apex of the duodenal bulb. She tolerated a slower prednisone taper thereafter. Conclusions ICI-related inflammation is common in the lower gastrointestinal tract and can less commonly affect the upper gastrointestinal tract. This is a rare report of upper gastrointestinal stricture and the first report known to us of pyloric stricture caused by ICI. Treatment may be challenging, but was achieved with PPI and high-dose steroids with slow taper. Funding Agencies None

Clinical impact on treatment effectiveness of immune-related adverse events in patients with hepatocellular carcinoma treated with atezolizumab plus bevacizumab.

479 Background: Immune checkpoint inhibitors (ICIs) have emerged as the first-line therapy for unresectable hepatocellular carcinoma (HCC). However, their administration poses the risk of immune-related adverse events (irAEs). Recent data suggests that the occurrence of irAEs may be associated with a favorable prognosis. Nevertheless, limited studies have explored the relationship between irAE severity or specific symptoms and clinical outcomes. Therefore, the objective of this study was to investigate and analyze the association between these adverse events and the clinical benefits in patients with unresectable HCC treated with immune checkpoint inhibitors. Methods: We enrolled 130 patients with unresectable HCC treated with atezolizumab plus bevacizumab between November 2022 and January 2023 at a single center. We investigated the relationship between irAEs and both response rate and post-treatment outcomes. Results: Out of the 130 patients, 36 (27.7%) developed irAEs. Patients with irAEs exhibited a significantly longer progression-free survival (PFS) compared to the non-irAE group, with a median PFS of 8.9 months compared to 4.6 months (p &lt; 0.01). There was no difference in overall survival with or without irAEs. The irAE group demonstrated significantly higher disease control rate (DCR) compared to the non-irAE group (97.0% vs 65.5%, p &lt; 0.01). The analysis by the severity of irAE revealed that the grade 1/2 group exhibited significantly longer PFS (7.9 months vs 4.6 months, p =0.007) and higher DCR (100% vs 65.5%, p &lt; 0.01) compared to the non-irAE group. Furthermore, hypothyroidism was correlated with a favorable PFS (8.9 months vs 5.4 months, p = 0.02), DCR (100% vs 71.3%, p = 0.03) and overall response rate (58.3% vs 18.5%, p = 0.005). Conclusions: The presence of irAEs is associated with prolonged PFS and higher DCR. Specifically, mild irAEs (Grade 1/2) and hypothyroidism displayed prolonged PFS and higher DCR.

Lipidomics reveals immune-related adverse events in NSCLC patients receiving immune checkpoint inhibitor

There is a lack of reliable biomarkers to predict and identify the risk of immune-related adverse events (irAEs) in non-small cell lung cancer (NSCLC) patients undergoing immune checkpoint inhibitor (ICI) treatment. This study aims to explore potential biomarkers using lipidomics to identify and predict the risk of irAEs in NSCLC patients receiving ICI treatment. This prospective study enrolled 94 NSCLC patients with IIIB/IV stage NSCLC who underwent first-line chemotherapy in combination with ICI treatment. The prediction cohort consisted of plasma samples collected from 60 patients before ICI treatment, and the occurrence of irAE was monitored within 6 months of initiating first-line ICI therapy. The validation cohort comprised 34 patients, with plasma samples obtained from 15 patients who did not develop irAE at 6 months of ICI treatment and plasma samples collected from 19 irAE patients at the onset of irAE. Through non-targeted lipidomics and semi-targeted lipid quantification analysis, we identify 11 differentially metabolized lipids and further screened these lipids with the area under the curve (AUC) > 0.7 to predict the occurrence of irAEs in NSCLC patients following ICI treatment. The results showed that the biomarker panel consisting of 9 lipids (LPC-18:2, PC-40:6, LPC-22:6, LPC-O-18:0, PS-38:0, PC-38:6, PC-37:6, PC-36:5,LPC-17:0) exhibited a good AUC of 0.859 in the prediction and 0.940 in the validation cohort phase of the receiver operating characteristic curve; The study utilizes plasma lipidomics to develop a rapid and effective prediction model for identifying irAEs in advanced NSCLC patients who treatment with first-line chemotherapy combined with immunotherapy.

Emerging Therapeutic Targets and Drug Resistance Mechanisms in Immunotherapy of Hematological Malignancies.

CAR-T cell therapy has revolutionized the treatment of hematological malignancies with high remission rates in the case of ALL and NHL. This therapy has some limitations such as long manufacturing periods, persistent restricted cell sources and high costs. Moreover, combination regimens increase the risk of immune-related adverse events, so the identification new therapeutic targets is important to minimize the risk of toxicities and to guide more effective approaches. Cancer cells employ several mechanisms to evade immunosurveillance, which causes resistance to immunotherapy; therefore, a very important therapeutic approach is to focus on the development of rational combinations of targeted therapies with non-overlapping toxicities. Recent progress in the development of new inhibitory clusters of differentiation (CDs), signaling pathway molecules, checkpoint inhibitors, and immunosuppressive cell subsets and factors in the tumor microenvironment (TME) has significantly improved anticancer responses. Novel strategies regarding combination immunotherapies with CAR-T cells are the most promising approach to cure cancer.

Progresses in biomarkers for cancer immunotherapy.

Currently, checkpoint inhibitor-based immunotherapy has emerged as prevailing treatment modality for diverse cancers. However, immunotherapy as a first-line therapy has not consistently yielded durable responses. Moreover, the risk of immune-related adverse events increases with combination regimens. Thus, the development of predictive biomarkers is needed to optimize individuals benefit, minimize risk of toxicities, and guide combination approaches. The greatest focus has been on tumor programmed cell death-ligand 1 (PD-L1), microsatellite instability (MSI), and tumor mutational burden (TMB). However, there remains a subject of debate due to thresholds variability and significant heterogeneity. Major unmet challenges in immunotherapy are the discovery and validation of predictive biomarkers. Here, we show the status of tumor PD-L1, MSI, TMB, and emerging data on novel biomarker strategies with oncogenic signaling and epigenetic regulation. Considering the exploration of peripheral and intestinal immunity has served as noninvasive alternative in predicting immunotherapy, this review also summarizes current data in systemic immunity, encompassing solute PD-L1 and TMB, circulating tumor DNA and infiltrating lymphocytes, routine emerging inflammatory markers and cytokines, as well as gut microbiota. This review provides up-to-date information on the evolving field of currently available biomarkers in predicting immunotherapy. Future exploration of novel biomarkers is warranted.

A 71-year-old male with a life-threatening recurrence of hemolytic anemia, thrombocytopenia, and acute kidney injury after pembrolizumab therapy: a case report

BackgroundImmune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. However, their use has been restricted in patients with preexisting autoimmune diseases due to concerns about increased risk of immune-related adverse events (irAEs).Case presentationWe present a case of a patient with stage IV lung adenocarcinoma and a history of complement-mediated autoimmune hemolytic anemia in remission. After receiving a single dose of pembrolizumab, the patient experienced life-threatening recurrent hemolytic anemia, de novo thrombocytopenia, diarrhea, myocarditis, and acute kidney injury. Laboratory tests confirmed the diagnosis of Evan's syndrome, with positive PAIgG and direct antiglobulin test. Treatment with intravenous methylprednisolone at a dose of 2 mg/kg resulted in a favorable response, with resolution of symptoms and rapid recovery of kidney function. The probable cause of pre-renal hypoperfusion (evidenced by a BUN-to-creatinine ratio of 48.1) leading to acute tubular injury was attributed to pembrolizumab-induced diarrhea.ConclusionsThis case illustrates a life-threatening recurrence of complement-mediated autoimmune hemolytic anemia induced by ICIs. Clinicians should carefully consider the expected efficacy and potential toxicity before initiating ICIs therapy in patients with preexisting autoimmune diseases. Additionally, the occurrence of acute kidney injury during ICIs therapy adds complexity and requires careful differential diagnosis.

Abstract P3067: Emerging Immune Checkpoint Therapies Reshape The Cardiac Immune Landscape And Promote Myocardial Vulnerability

Immune checkpoint therapies have shown remarkable efficacy across multiple tumor types by amplifying cancer-immunity and boosting T-cell immune response against tumors. As an increasing number of immune checkpoint molecules have been identified, numerous combination therapeutic strategies are under clinical investigation. For instance, the combination of an OX40 (TNFRSF4) agonist and PD-1 (Programmed cell death protein 1) inhibitor has been shown to have promising anti-tumor effects in pre-clinical studies and early clinical trials. Despite remarkable therapeutic benefit, it has become evident with increasing clinical usage that these agents elevate the risk of immune-related adverse events (irAEs), especially cardiovascular sequelae. Mitigating irAEs is critical for the establishment of efficacious and safe interventions. Currently, little is understood regarding the cardiac effects of combined OX40 activation and PD-1 inhibition. In this study, we observed that PD-1 deletion upregulated OX40 expression on cardiac T-cells. Combined PD1 inhibition (Pdcd1 -/- or PD-1 blocking antibody) and OX40 activation (OX40 agonistic antibody) increased the frequency of splenic and cardiac effector memory CD4 + and CD8 + T-cells, inflammatory monocyte and macrophage infiltration into the heart, and enhanced myocardial expression of numerous chemokines and cytokines in both naïve and tumor bearing mice. Intriguingly, persistent increases in cardiac effector memory CD4 + and CD8 + T-cells and inflammatory macrophages was observed at chronic time points suggesting long term effects on the cardiac immune landscape. Furthermore, OX40 activation aggravates angiotensin II and phenylephrine (AngII/PE) infusion induced cardiac hypertrophy, fibrosis and inflammation in Pdcd1 -/- mice suggesting that the reshaped T-cell and macrophage landscape imparts myocardial vulnerability. This study will also uncover mechanism-based therapeutic targets to prevent or treat cardiac adverse events elicited by combined OX40 activation and PD-1 inhibition.

The Local Microbiome in Esophageal Cancer and Treatment Response: A Review of Emerging Data and Future Directions.

peer-reviewed, published studies describing the role of local, gastrointestinal-specific microbiota or the role of the gut microbiome in treatment responses were reviewed. PubMed was searched from 1 September 2022 to 1 November 2022, using the following terms in combination: "microbiome", "tumor microbiome", "esophageal cancer", "cancer", "cancer treatment", and "immunotherapy". Original research articles were considered, and other reviews or editorials were discarded. In total, approximately 250 articles were considered. over 70 studies describing microbiome research in either gastrointestinal carcinogenesis or the systemic treatment response were identified and reviewed. a growing body of evidence supports the role of the esophageal microbiome in both esophageal tumorigenesis and the immune checkpoint inhibitor response. More well-designed, comprehensive studies are required to collect the appropriate clinical, microbial, and immunophenotype data that are needed to clarify the precise role of the microbiome in esophageal carcinogenesis and treatment.

Construction and Evaluation of Clinical Prediction Model for Immunotherapy-related Adverse Events and Clinical Benefit in Cancer Patients Receiving Immune Checkpoint Inhibitors Based on Serum Cytokine Levels.

Immune checkpoint inhibitors (ICIs) have revolutionized the therapeutic landscape of cancer therapy. This study aimed to develop novel risk classifiers to predict the risk of immune-related adverse events (irAEs) and the probability of clinical benefits. Patients with cancer who received ICIs from the First Affiliated Hospital of Xi 'an Jiaotong University from November 2020 to October 2022 were recruited and followed up. Logistic regression analyses were performed to identify independent predictive factors for irAEs and clinical response. Two nomograms were developed to predict the irAEs and clinical responses of these individuals, with a receiver operating characteristic curve to assess their predictive ability. Decision curve analysis was performed to estimate the clinical utility of the nomogram. This study included 583 patients with cancer. Among them, 111 (19.0%) developed irAEs. Duration of treatment (DOT)>3 cycles, hepatic-metastases, IL2>2.225pg/mL, and IL8>7.39pg/mL were correlated with higher irAEs risk. A total of 347 patients were included in the final efficacy analysis, with an overall clinical benefit rate of 39.7%. DOT>3 cycles, nonhepatic-metastases, and irAEs and IL8>7.39pg/mL were independent predictive factors of clinical benefit. Ultimately, 2 nomograms were successfully established to predict the probability of irAEs and their clinical benefits. Ultimately, 2 nomograms were successfully established to predict the probability of irAEs and clinical benefits. The receiver operating characteristic curves yielded acceptable nomogram performance. Calibration curves and decision curve analysis supported the hypothesis that nomograms could provide more significant net clinical benefits to these patients. Specific baseline plasma cytokines were closely correlated with irAEs and clinical responses in these individuals.

Risk of immune-related adverse events (irAE) with immune checkpoint inhibitors (ICI) in patients (pts) with family history (FH) of autoimmune disease (AID).

2648 Background: Pts with personal history (PH) of AID are at increased risk of irAE following ICI. Risk of irAE in pts with FH of AID is unknown. Methods: In this retrospective cohort study, consecutive pts were recruited from 2 Australian melanoma cancer centers. Pts who received anti-PD-1 (PD1) based ICI with FH of AID were eligible. Pts with PH of AID were excluded. Toxicity data (CTCAE v5.0) was obtained and stratified by FH of AID (first/second/third degree relative). Descriptive statistics and Fisher’s Exact test were used for analysis. Results: 396 melanoma cases were screened, of which 44 (11.1%) were eligible for inclusion. Baseline characteristics are summarized. 57 irAE occurred in 44 pts. The most common irAE were dermatological (n=11; 19.3%), colitis (n=8; 14.0%), endocrinopathies (n=8; 14.0%), hepatitis (n=7; 12.3%) and arthritis (n=7; 12.3%). Among 57 irAE, frequency of Grade 1,2,3 and 4 irAE was 16 (28.1%), 26 (45.6%), 12 (21.0%) and 3 (5.3%) respectively. Corticosteroids were used for 31 (54.4%) irAE. Hospital admission for management of irAE occurred in 11 pts (25.0%). ICI was discontinued in 20 pts (45.5%) due to irAE. In pts with irAE, FH of that irAE/AID was present in 6 pts (13.6%) (n= 2 x arthritis, n= 2 x psoriasis, n= 1 x Crohn’s disease, n= 1 x Grave’s disease), and 4 of these patients had a first-degree relative with an AID. 3/6 pts had ICI ceased due to an irAE (peak toxicity Grade was 3) and 4/6 pts had RECIST response. There was no association in development of irAE between patients with FH of AID in a first-degree relative and those with FH of AID in second or third degree relative (p=0.17). Rate of irAE in pts with FH of AID was not statistically higher to that reported in registration trials of similar regimens (p=0.40). Conclusions: FH of AID is common in melanoma pts and was not associated with higher rate or morbidity of irAE. FH AID should be routinely collected, and larger scale studies need to be performed. [Table: see text]