Tethered IL15-IL15Rα augments antitumor activity of CD19 CAR-T cells but displays long-term toxicity in an immunocompetent lymphoma mouse model.

BACKGROUND: Adoptive cell therapy using genetically modified T cells to express chimeric antigen receptors (CAR-T) has shown encouraging results, particularly in certain blood cancers. Nevertheless, over 40% of B cell malignancy patients experience a relapse after CAR-T therapy, likely due to inadequate persistence of the modified T cells in the body. IL15, known for its pro-survival and proliferative properties, has been suggested for incorporation into the fourth generation of CAR-T cells to enhance their persistence. However, the potential systemic toxicity associated with this cytokine warrants further evaluation. METHODS: We analyzed the persistence, antitumor efficacy and potential toxicity of anti-mouse CD19 CAR-T cells which express a membrane-bound IL15-IL15Rα chimeric protein (CD19/mbIL15q CAR-T), in BALB/c mice challenged with A20 tumor cells as well as in NSG mice. RESULTS: Conventional CD19 CAR-T cells showed low persistence and poor efficacy in BALB/c mice treated with mild lymphodepletion regimens (total body irradiation (TBI) of 1 Gy). CD19/mbIL15q CAR-T exhibits prolonged persistence and enhanced in vivo efficacy, effectively eliminating established A20 B cell lymphoma. However, this CD19/mbIL15q CAR-T displays important long-term toxicities, with marked splenomegaly, weight loss, transaminase elevations, and significant inflammatory findings in some tissues. Mice survival is highly compromised after CD19/mbIL15q CAR-T cell transfer, particularly if a high TBI regimen is applied before CAR-T cell transfer. CONCLUSION: Tethered IL15-IL15Rα augments the antitumor activity of CD19 CAR-T cells but displays long-term toxicity in immunocompetent mice. Inducible systems to regulate IL15-IL15Rα expression could be considered to control this toxicity.

Development and Validation of a Prediction Model for Thyroid Dysfunction in Patients During Immunotherapy.

OBJECTIVE: This study was designed to develop and validate a predictive model for assessing the risk of thyroid toxicity following treatment with immune checkpoint inhibitors (ICIs). METHODS: A retrospective analysis was conducted on a cohort of 586 patients diagnosed with malignant tumors who received programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors. The patients were randomly divided into training and validation cohorts in a 7:3 ratio. Logistic regression analyses were performed on the training set to identify risk factors of thyroid dysfunction, and a nomogram was developed based on these findings. Internal validation was performed using K-fold cross-validation on the validation set. The performance of the nomogram was assessed in terms of discrimination and calibration. Additionally, decision curve analysis (DCA) was utilized to demonstrate the decision efficiency of the model. RESULTS: Our clinical prediction model consisted of four independent predictors of thyroid immune-related adverse events (irAEs), namely baseline thyrotropin (TSH, OR=1.427, 95%CI:1.163-1.876), baseline thyroglobulin antibody (TgAb, OR=1.105, 95%CI:1.035-1.180), baseline thyroid peroxidase antibody (TPOAb, OR=1.172, 95%CI:1.110-1.237), and baseline platelet count (PLT, OR=1.004, 95%CI:1.000-1.007). The developed nomogram achieved excellent discrimination with an area under the curve (AUC) of 0.863 (95%CI: 0.817-0.909) and 0.885 (95%CI: 0.827-0.944) in the training and internal validation cohorts respectively. Calibration curves exhibited a good fit, and the decision curve indicated favorable clinical benefits. CONCLUSION: The proposed nomogram serves as an effective and intuitive tool for predicting the risk of thyroid irAEs, facilitating clinicians making individualized decisions based on patient-specific information.

Management and treatment of severe immune-related hepatotoxicity based on clinical and pathological characteristics.

BACKGROUND: The management of severe immune-related hepatotoxicity (irH) needs to be further optimized. This study aims to analyze the clinical characteristics of severe irH; improve the therapeutic strategy, especially salvage treatment in steroid-refractory irH; and determine the safety of immune checkpoint inhibitor (ICPi)-rechallenge. METHODS: This multicenter retrospective study included patients who developed severe irH and those without irH after immunotherapy between May 2019 and June 2023. Propensity score matching was used to match these two cohorts with similar baseline characteristics. RESULTS: Among 5,326 patients receiving ICPis, 51 patients developed severe irH. irH occurred after a median duration of 36 days and a median of two doses after the first ICPi administration. Patients receiving PD-L1 inhibitors faced a lower risk of developing severe irH. A higher dose of glucocorticoids (GCS) was administered to grade 4 irH than grade 3 irH. For steroid-sensitive patients, grade 4 irH individuals received a higher dosage of GCS than those with grade 3 irH, with no difference in time to resolution. Meanwhile, a significantly higher dose of GCS plus immunosuppression was needed in the steroid-refractory group. Liver biopsy of the steroid-refractory patients exhibited heterogeneous histological features. Twelve patients were retreated with ICPi. No irH reoccurred after a median follow-up of 9.3 months. CONCLUSION: irH requires multidimensional evaluation. PD-L1 inhibitors correlated with a lower risk of severe irH. Grade 4 irH demands a higher dose of GCS than recommended. Pathology may guide the salvage treatment for steroid-refractory irH. ICPi rechallenge in severe irH is feasible and safe.

Chronic immune-related adverse events arising from immune checkpoint inhibitors: an update.

Immune checkpoint inhibitors (ICIs) have transformed cancer treatment, improving outcomes for many patients. However, toxicities termed immune-related adverse events (irAEs) are limitations of these revolutionary treatments. These irAEs may resolve with treatment or ICI cessation (acute) or persist many months beyond therapy cessation (chronic). Acute irAEs were the first to be recognized and are thus more well studied. However, chronic irAEs have been highlighted in recent years and are becoming a topic of more intensive investigation. These chronic irAEs have been noted to affect many different organ systems, including endocrine, rheumatologic, gastrointestinal, dermatologic, neurologic, and cardiovascular systems. In this review, we discuss current knowledge surrounding the frequency, time course, and risk factors associated with chronic irAEs affecting various organ systems, treatment approaches, and future directions.

A Case of Immune Aplastic Anemia during Combined Treatment with Atezolizumab and Chemotherapy for Non-Small Cell Lung Cancer.

Immune check point inhibitors (ICIs) have durable antitumor effects. However, autoimmune toxicities, termed immune-related adverse events, occur in some patients. We report a case of severe immune aplastic anemia (AA) in a patient with non-small cell lung cancer who was receiving atezolizumab with bevacizumab/carboplatin/paclitaxel. Although the cancer has not recurred, his bone marrow is depleted and he did not respond to immunosuppressive therapy. He has survived for 1.5 years with blood transfusions and infection control. Immune AA associated with ICIs is rare, and a treatment has not yet been established. This case report provides information on the management and treatment response of patients with AA caused by ICIs. Further studies should investigate the mechanism and pathogenesis of immune AA caused by ICIs.

Challenges and opportunities in cancer immunotherapy: a Society for Immunotherapy of Cancer (SITC) strategic vision.

Cancer immunotherapy has flourished over the last 10-15 years, transforming the practice of oncology and providing long-term clinical benefit to some patients. During this time, three distinct classes of immune checkpoint inhibitors, chimeric antigen receptor-T cell therapies specific for two targets, and two distinct classes of bispecific T cell engagers, a vaccine, and an oncolytic virus have joined cytokines as a standard of cancer care. At the same time, scientific progress has delivered vast amounts of new knowledge. For example, advances in technologies such as single-cell sequencing and spatial transcriptomics have provided deep insights into the immunobiology of the tumor microenvironment. With this rapid clinical and scientific progress, the field of cancer immunotherapy is currently at a critical inflection point, with potential for exponential growth over the next decade. Recognizing this, the Society for Immunotherapy of Cancer convened a diverse group of experts in cancer immunotherapy representing academia, the pharmaceutical and biotechnology industries, patient advocacy, and the regulatory community to identify current opportunities and challenges with the goal of prioritizing areas with the highest potential for clinical impact. The consensus group identified seven high-priority areas of current opportunity for the field: mechanisms of antitumor activity and toxicity; mechanisms of drug resistance; biomarkers and biospecimens; unique aspects of novel therapeutics; host and environmental interactions; premalignant immunity, immune interception, and immunoprevention; and clinical trial design, endpoints, and conduct. Additionally, potential roadblocks to progress were discussed, and several topics were identified as cross-cutting tools for optimization, each with potential to impact multiple scientific priority areas. These cross-cutting tools include preclinical models, data curation and sharing, biopsies and biospecimens, diversification of funding sources, definitions and standards, and patient engagement. Finally, three key guiding principles were identified that will both optimize and maximize progress in the field. These include engaging the patient community; cultivating diversity, equity, inclusion, and accessibility; and leveraging the power of artificial intelligence to accelerate progress. Here, we present the outcomes of these discussions as a strategic vision to galvanize the field for the next decade of exponential progress in cancer immunotherapy.

Exploring the predictive potential of programmed death ligand 1 expression in healthy organs and lymph nodes as measured by 18F-BMS986-192 PET: pooled analysis of data from four solid tumor types.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) can elicit anticancer immune responses, but predictive biomarkers are needed. We measured programmed death ligand 1 (PD-L1) expression in organs and lymph nodes using 18F-BMS-986192 positron emission tomography (PET)-imaging and looked for correlations with response and immune-related adverse events. METHODS: Four 18F-BMS-986192 PET studies in patients with melanoma, lung, pancreatic and oral cancer, receiving ICI treatment, were combined. Imaging data (organ standardized uptake value (SUV)mean, lymph node SUVmax) and clinical data (response to treatment and incidence of immune-related adverse events) were extracted. RESULTS: Baseline PD-L1 uptake in the spleen was on average higher in non-responding patients than in responders (spleen SUVmean 16.1±4.4 vs 12.5±3.4, p=0.02). This effect was strongest in lung cancer, and not observed in oral cancer. In the oral cancer cohort, benign tumor-draining lymph nodes (TDLNs) had higher PD-L1 uptake (SUVmax 3.3 IQR 2.5-3.9) compared with non-TDLNs (SUVmax 1.8, IQR 1.4-2.8 p=0.04). Furthermore, in the same cohort non-responders showed an increase in PD-L1 uptake in benign TDLNs on-treatment with ICIs (+15%), while for responders the PD-L1 uptake decreased (-11%). PD-L1 uptake did not predict immune-related adverse events, though elevated thyroid uptake on-treatment correlated with pre-existing thyroid disease or toxicity. CONCLUSION: PD-L1 PET uptake in the spleen is a potential negative predictor of response to ICIs. On-treatment with ICIs, PD-L1 uptake in benign TDLNs increases in non-responders, while it decreases in responders, potentially indicating a mechanism for resistance to ICIs in patients with oral cancer.

Thoracic lymphangitis as an immune-related adverse event: a case report.

The efficacy of immune checkpoint inhibitors (ICIs) has been widely recognized in several cancers and is now being used in the perioperative setting for lung cancer.We recently encountered an immune-related adverse event that has not been previously reported: thoracic lymphangitis, which occurred after postoperative ICI treatment for lung cancer. The patient complained of breathlessness and her condition rapidly progressed to hypoxia grade 3. Chest computed tomography revealed significant lymphostasis. With high-dose steroid treatment, the patient showed improvement.Therefore, as the frequency of neoadjuvant, adjuvant, and perioperative ICI use is expected to increase, it is crucial to understand and monitor this adverse event.

Adrenal Insufficiency and Thyrotoxicosis Following Combined Immune Checkpoint Inhibitor Use: A Case Report and Literature Review.

Destructive thyroiditis and secondary adrenal insufficiency are major endocrinological immune-related adverse events of immune checkpoint inhibitors (ICIs). However, the timing at which each event occurs most frequently after drug administration varies, and cases where multiple events occur simultaneously are rare. We encountered a patient who concurrently suffered from thyrotoxicosis and adrenal insufficiency. An 80-year-old woman with a history of type 2 diabetes mellitus (DM) was diagnosed with stage IVA squamous cell carcinoma of the lungs. Treatment with a combination of nivolumab and ipilimumab was initiated. Although she tested positive for thyroglobulin antibody and transient subclinical hyperthyroidism was observed after two courses, treatment with ICIs was continued. Four months later, treatment was discontinued due to drug-induced lung disease. One month after the last administration, the patient became unconscious and was admitted to another hospital, diagnosed with diabetic ketoacidosis, urinary tract infection, and sepsis. After acute-phase treatment, she was transferred to our hospital due to persistent fever and tachycardia. Thyrotoxicosis and adrenal insufficiency were observed, with high levels of free thyroxine, low thyroid-stimulating hormone (TSH), and cortisol levels. Treatment with extracellular fluids, potassium iodide, beta-blockers, and hydrocortisone was initiated, and the patient's condition improved. No other pituitary hormone deficiencies were observed. She was diagnosed with painless thyroiditis and secondary adrenal insufficiency based on the positive thyroglobulin antibody, negative TSH receptor antibody, decreased Doppler flow in thyroid ultrasonography, low adrenocorticotrophic hormone (ACTH), and low response of ACTH and cortisol to corticotropin-releasing hormone loading test. MRI revealed no abnormalities. We report a case of thyrotoxicosis and secondary adrenal insufficiency five months after the first administration of nivolumab and ipilimumab. Careful follow-up and early detection of endocrine disorders are critical in patients treated with a combination of ICIs.

Successful Treatment of Steroid-Refractory Immune Thrombocytopenia in a Patient Developing Multiple Myeloma While on Immune Checkpoint Inhibitor Therapy for Lung Cancer: A Case Report.

Immune checkpoint inhibitor-related thrombocytopenia (irTCP) is a relatively rare immune-related adverse event (irAE); however, overall survival may worsen when it occurs. Prolonged use of high-dose steroids can diminish the effectiveness of immune checkpoint inhibitor (ICI) therapy on the primary disease because of T lymphocyte suppression, thus early tapering is necessary. We experienced a rare case of a 79-year-old male who concurrently developed irTCP and multiple myeloma (MM) during treatment with ICIs for lung adenocarcinoma. The patient exhibited severe thrombocytopenia and elevated serum IgA levels. Based on various tests, we diagnosed MM and irTCP. Despite administering the standard bortezomib plus dexamethasone (Bd therapy) treatment for MM, there was no response and the irTCP was steroid-resistant. Consequently, we administered a regimen including daratumumab (DPd therapy) for steroid-resistant irTCP and refractory MM, which resulted in a response. As a result, we were able to avoid prolonged use of high-dose steroids and the patient is stable without exacerbation of lung adenocarcinoma for 1 year and 5 months after the onset of MM. To our knowledge, there are no cases of MM developing during ICI treatment and this is the first case report in which daratumumab was effective for the treatment of irTCP.

Autoantibody-positivity before and seroconversion during treatment with anti-PD-1 is associated with immune-related adverse events in patients with melanoma.

INTRODUCTION: Treatment with the immune checkpoint inhibitor anti-programmed cell death protein-1 (PD-1) often causes immune-related adverse events (irAEs). Since irAEs resemble autoimmune diseases, autoantibodies might play a role and could potentially be used to identify patients at risk. Therefore, we investigated the association between autoantibody-positivity and toxicity as well as clinical response in patients with melanoma treated with anti-PD-1. MATERIALS AND METHODS: This two-center, retrospective study included 143 patients with melanoma treated with anti-PD-1. Toxicities grade ≥2 and recurrences/responses were captured until 6 months after treatment initiation. Autoantibody measurements were performed at baseline and 3 months after treatment initiation, including IgM-rheumatoid factor (RF), antinuclear antibodies (ANA), extractable nuclear antigen, anti-cyclic citrullinated peptide antibodies (anti-CCP2) and anti-thyroid antibodies. RESULTS: 169 irAEs were experienced by 86/143 patients (137 grades 1-2, 32 grades 3-4), the most common being thyroiditis (n=25), dermatitis (n=24), and sicca problems (n=19). Patients with autoantibodies at baseline experienced more irAEs (p=0.001), predominantly associated with anti-thyroid antibodies and thyroid dysfunction. No association was observed between any irAE and anti-CCP2, RF or ANA. In women, baseline and on-treatment anti-thyroid antibody-positivity as well as seroconversion during treatment was associated with thyroid dysfunction. In men, this association was only observed on-treatment. The presence of autoantibodies was not associated with melanoma recurrence (p=0.776) or response (p=0.597). CONCLUSION: The presence of autoantibodies prior to anti-PD-1 therapy is associated with irAEs in patients with melanoma. Both baseline positivity and seroconversion of anti-thyroid antibodies were strongly associated with thyroid dysfunction. This association was stronger in women, with all women who were baseline positive developing thyroid dysfunction.

Favorable outcome of immunotherapy in a rare subtype of hepatocellular carcinoma: a case report and literature review.

Scirrhous hepatocellular carcinoma (S-HCC) represents an uncommon subtype of HCC. During radiological evaluation this unique subtype is frequently mistaken as cholangiocarcinoma, fibrolamellar HCC, or metastatic adenocarcinoma. Here, we present the case of a 50-year-old woman with a large hepatic mass. A triple-phase computed tomography of the liver revealed an arterial enhancing lesion without portovenous washout at hepatic segment 4a/8. The liver biopsy showed hepatocellular characteristics and was positive for Hep Par 1, CK7, CK19, Arginase 1 and CEA, indicating atypical S-HCC. This patient had achieved tumor control with combined treatment with atezolizumab plus bevacizumab and was then treated with lenvatinib after tumor progression. The patient died 15 months after the initial diagnosis.

Diagnosis, management, and outcomes of immune checkpoint inhibitor induced acute interstitial nephritis: A single-center experience.

BACKGROUND: Immune checkpoint inhibitor (ICI)-associated acute interstitial nephritis (AIN) is a recognized complication of immunotherapy (IO), but literature on its management and outcomes is limited. METHODS: We retrospectively reviewed patients who received ICIs and developed biopsy-proven or clinically-suspected ICI-associated AIN at the University of Virginia Comprehensive Cancer Center from 2012-2023. We analyzed baseline characteristics and clinical outcomes, including treatment interruption and rechallenge rates. Acute kidney injury (AKI) was defined as a ≥ 1.5-fold increase in baseline creatinine under seven days, a two-fold increase above the upper limit of normal, or an increase by ≥0.3 mg/dL. Kidney function returning to within 0.3 mg/dL or less than twice baseline was considered complete (CRc) and partial (PRc) recovery, respectively. RESULTS: We identified 12 cases of ICI-AIN: four by biopsy (33%) and eight (67%) by clinical suspicion. Two patients received anti-CTLA-4 and anti-PD1, six received anti-PD1 alone, and four received chemo-immunotherapy. The majority (58%) of patients developed AIN within the first 5 cycles. Eight patients developed ≥ Grade 3 AKI, and six developed multiple irAEs. ICI was permanently discontinued in seven patients (58%) and temporarily interrupted in four (30%). The CRc and PRc rates were 67% and 8%, respectively. Upon AIN onset, the best disease response was stable disease in five patients, partial response in three, and progressive disease in three. Median overall survival was 4.87 years, and progression-free survival was 1.5 years. CONCLUSIONS: Rechallenge with IO after kidney irAE may be possible in some patients but requires careful evaluation on an individual basis.

Highly variable timing renders immunotherapy efficacy and toxicity impractical biomarkers of one another in clinical practice.

Background: A useful clinical biomarker requires not only association but also a consistent temporal relationship. For instance, chemotherapy-induced neutropenia and epidermal growth-factor inhibitor-related acneiform rash both occur within weeks of treatment initiation, thereby providing information prior to efficacy assessment. Although immune checkpoint inhibitor (ICI)-associated immune-related adverse events (irAE) have been associated with therapeutic benefit, irAE may have delayed and highly variable onset. To determine whether ICI efficacy and irAE could serve as clinically useful biomarkers for predicting each other, we determined the temporal relationship between initial efficacy assessment and irAE onset in a diverse population treated with ICI. Methods: Using two-sided Fisher exact and Cochran-Armitage tests, we determined the relative timing of initial efficacy assessment and irAE occurrence in a cohort of 155 ICI-treated patients (median age 68 years, 40% women). Results: Initial efficacy assessment was performed a median of 50 days [interquartile range (IQR) 39-59 days] after ICI initiation; median time to any irAE was 77 days (IQR 28-145 days) after ICI initiation. Median time to first irAE was 42 days (IQR 20-88 days). Overall, 58% of any irAE and 47% of first irAE occurred after initial efficacy assessment. For clinically significant (grade ≥2) irAE, 60% of any and 53% of first occurred after initial efficacy assessment. The likelihood of any future irAE did not differ according to response (45% for complete or partial response vs. 47% for other cases; P=1). In landmark analyses controlling for clinical and toxicity follow-up, patients demonstrating greater tumor shrinkage at initial efficacy assessment were more likely to develop future grade ≥2 (P=0.05) and multi-organ (P=0.02) irAE. Conclusions: In contrast to that seen with chemotherapy and molecularly targeted therapies, the temporal relationship between ICI efficacy and toxicity is complex and bidirectional. In practice, neither parameter can be routinely relied on as a clinical biomarker to predict the other.

Immune checkpoint inhibitor associated epidermal necrosis, beyond SJS and TEN: a review of 98 cases.

Immune checkpoint inhibitor (ICI) therapies carry the risk of major immune-related adverse events (irAEs). Among the most severe irAEs is epidermal necrosis that may clinically mimic Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN). The aim of this study was to provide a summary of the clinical and histological features of ICI-associated epidermal necrosis, with a special focus on factors associated with fatal outcomes in cases of extensive disease. A total of 98 cases, 2 new cases and 96 reported on PubMed and in the literature, of ICI-associated epidermal necrosis were assessed. Development of epidermal necrosis occurred between 1 day and 3 years after starting ICI therapy, with an average onset of 13.8 weeks for patients with limited (< 30% BSA) and 11.3 weeks for those with extensive (≥ 30% BSA) involvement, and a median onset of 5.8 weeks and 4 weeks respectively. A preceding rash was seen in 52 cases and was more common in extensive cases. Mucosal involvement was only reported in 65% of extensive cases but was significantly associated with fatal reactions. Co-administration of cytotoxic chemotherapy was associated with more extensive disease. Recovery was observed in 96% and 65% of those with limited and extensive involvement respectively and no specific therapy was associated with improved survival. Young age was significantly associated with poor outcomes in extensive disease, the average age of surviving patients was 64.5 years old versus 55.1 years old for deceased patients, p < 0.01. Both superficial perivascular and interface/lichenoid inflammatory infiltrates were commonly seen. These findings suggest that ICI-associated epidermal necrosis should be considered a distinct clinical entity from drug-induced SJS/TEN.

Endocrine immune-related adverse event is a prognostic biomarker independent of lead-time bias.

OBJECTIVES: Immune-related adverse events (irAEs) are known to be associated with clinical efficacy and better prognoses in patients receiving immune checkpoint inhibitors. In particular, endocrine irAE (e-irAE) is related to better prognoses. Since the incidence of irAEs increase as treatment duration becomes longer, we should consider lead-time bias not to overvalue the result. We evaluated the impact of e-irAE on the outcome before and after 6-, 9-, and 12-week landmark analyses. MATERIALS AND METHODS: We evaluated 222 patients with advanced or recurrent non-small cell lung cancer who received anti-PD-1 antibodies such as nivolumab or pembrolizumab from January 2016 to April 2021. Treatment efficacy and outcomes of patients with or without e-irAE (e-irAE group or no e-irAE group) were retrospectively evaluated. In addition, we performed 6-, 9-, and 12-week landmark analyses to exclude the effect of lead-time bias. RESULTS: Median progression free survival (PFS) was significantly longer in the e-irAE group than in the no e-irAE group (overall: 15.3 vs 3.9 months, p < 0.0001; 6-week: 15.3 vs 4.9 months, p < 0.0002; 9-week: 19.8 vs 6.1 months, p = 0.0012, 12-week: 19.8 vs 8.4 months, p = 0.017). Overall survival (OS) was significantly longer in the e-irAE group (overall: not reached (NR) vs 15.4 months, p = 0.0003; 6-week: NR vs 19.1 months, p = 0.0049, 9-week: NR vs 22.2 months, p = 0.006; 12-week: NR vs 23.3 months, p = 0.04). We used the multivariate cox proportional hazard model to adjust for confounding factors and found that e-irAE had better impact on both PFS and OS (PFS: overall: hazard ratio 0.37 [95% confidence interval 0.23-0.56], 6-week: 0.41 [0.26-0.63], 9-week: 0.43 [0.24-0.63], 12-week: 0.52 [0.31-0.84]; OS: overall: 0.40 [0.22-0.68], 6-week: 0.46 [0.25-0.79], 9-week: 0.47 [0.24-0.84], 12-week: 0.58 [0.29-1.08]). CONCLUSION: The occurrence of endocrine irAE was associated with better efficacy and prognoses regardless of the lead-time bias.

Use of artificial intelligence chatbots in clinical management of immune-related adverse events.

BACKGROUND: Artificial intelligence (AI) chatbots have become a major source of general and medical information, though their accuracy and completeness are still being assessed. Their utility to answer questions surrounding immune-related adverse events (irAEs), common and potentially dangerous toxicities from cancer immunotherapy, are not well defined. METHODS: We developed 50 distinct questions with answers in available guidelines surrounding 10 irAE categories and queried two AI chatbots (ChatGPT and Bard), along with an additional 20 patient-specific scenarios. Experts in irAE management scored answers for accuracy and completion using a Likert scale ranging from 1 (least accurate/complete) to 4 (most accurate/complete). Answers across categories and across engines were compared. RESULTS: Overall, both engines scored highly for accuracy (mean scores for ChatGPT and Bard were 3.87 vs 3.5, p<0.01) and completeness (3.83 vs 3.46, p<0.01). Scores of 1-2 (completely or mostly inaccurate or incomplete) were particularly rare for ChatGPT (6/800 answer-ratings, 0.75%). Of the 50 questions, all eight physician raters gave ChatGPT a rating of 4 (fully accurate or complete) for 22 questions (for accuracy) and 16 questions (for completeness). In the 20 patient scenarios, the average accuracy score was 3.725 (median 4) and the average completeness was 3.61 (median 4). CONCLUSIONS: AI chatbots provided largely accurate and complete information regarding irAEs, and wildly inaccurate information ("hallucinations") was uncommon. However, until accuracy and completeness increases further, appropriate guidelines remain the gold standard to follow.

The prognostic impact of peripheral blood eosinophil counts in metastatic renal cell carcinoma patients treated with nivolumab.

Although immune checkpoint inhibitors (ICIs) have gained approval for metastatic renal cell carcinoma (mRCC), the response rate is still limited. Therefore, it is urgent to explore novel markers of responses to ICIs that can help assess clinical benefits. Recently, it has been noted that peripheral blood eosinophil counts are an independent factor correlated with clinical outcome of ICIs in some types of cancer. We investigated peripheral blood absolute eosinophil counts (AECs) at baseline and 4 weeks after the initiation of nivolumab for mRCC patients between February 2016 and May 2022. In addition, we examined clinicopathological features including irAEs and analyzed the correlation between AECs and clinical efficacy of nivolumab. The median progression-free survival (PFS) and overall survival (OS) for all patients were 5.7 and 25.5 months, respectively. The median AECs in patients with irAEs were significantly higher at baseline and 4 weeks after the treatment compared to those without irAEs (p < 0.001 and p = 0.001). With the cutoff value of AECs of 329 cells/µL at 4 weeks after the treatment for prediction of irAEs, high-AECs groups had significantly higher number of responders compared with that in low-AECs group (p < 0.001). Accordingly, the PFS and OS were significantly better in patients with high-AECs group than those in low-AECs group (p = 0.03 and p = 0.009). High-AECs at 4 weeks after the treatment serve as the prominent surrogate marker associated with the incidence of irAEs and better clinical outcome in mRCC patients receiving nivolumab.

Lysosomal degradation of PD-L1 is associated with immune-related adverse events during anti-PD-L1 immunotherapy in NSCLC patients.

Background: Immune checkpoint inhibitors (ICIs) can induce immune-related adverse events (irAEs). Liquid biomarkers to predict irAE occurrence are urgently needed. We previously developed an ELISA system to specifically detect soluble PD-L1 (sPD-L1) with PD-1-binding capacity (bsPD-L1). Here, we investigated the relationship between sPD-L1 and bsPD-L1 in gastric cancer (GC) and non-small cell lung cancer (NSCLC) treated with PD-1/PD-L1 blockade and their association with irAEs. Methods: We examined sPD-L1, bsPD-L1, matrix metalloproteinases (MMPs), and proinflammatory cytokine levels by ELISA in plasma samples from 117 GC patients prior to surgery and 72 NSCLC patients prior to and at 2 months after ICI treatment (anti-PD-1, n = 48; anti-PD-L1, n = 24). In mice treated with anti-PD-1/PD-L1 antibodies (Abs), sPD-L1 levels and localization of Abs were examined by ELISA and immunohistochemistry, respectively. Results:sPD-L1 was detected with higher frequency in GC patients than in NSCLC patients, whereas bsPD-L1 was detected with similar frequencies in GC and NSCLC patients. sPD-L1 levels were correlated with IL-1α, IL-1ß, TNF-α, and IL-6 levels, while bsPD-L1 levels were correlated with MMP13, MMP3, and IFN-γ levels. In NSCLC patients, anti-PD-L1, but not anti-PD-1, treatment increased sPD-L1, which was associated with irAE development, but not with clinical outcomes. In mice, trafficking of anti-PD-L1 Abs to lysosomes in F4/80+ macrophages resulted in sPD-L1 production, which was suppressed by treatment with lysosomal degradation inhibitor chloroquine and macrophage depletion. Conclusion: Anti-PD-L1-mediated lysosomal degradation induces sPD-L1 production, which can serve as an indicator to predict irAE development during anti-PD-L1 treatment.