ICI-treated Patients Research Articles

Diagnosing Immune Checkpoint Inhibitor-Induced Myocarditis: Insights, Challenges, and Uncertainties

Recent advancements in immunotherapy have substantially improved overall survival and quality of life among patients with cancer. Notably, immune checkpoint inhibitors (ICIs) have emerged as a revolutionary strategy, particularly in the management of advanced cancers. However, the success of ICIs is accompanied by the challenge of immune-related adverse events. Although rare, cardiovascular adverse events associated with ICIs are associated with high fatality rates and rapid clinical progression, thereby necessitating timely intervention. This review explores the histopathologic characteristics of ICI-induced myocarditis, shedding light on the complexities of diagnosis and management. Several studies examining the histopathologic features of ICI-induced myocarditis have emphasized the roles of macrophages and the potential utility of ancillary tests such as immunohistochemistry. Quantifying CD68+ macrophage abundance may enhance diagnostic sensitivity, thereby providing valuable insights into clinical outcomes. In conclusion, this review underscores the need for a nuanced approach to diagnosing ICI-induced myocarditis. The comprehensive exploration of histopathologic characteristics, ancillary tests, and emerging diagnostic markers provides valuable guidance for practicing pathologists. As the population of ICI-treated patients with cancer continues to grow, optimizing immunohistochemistry panels and refining diagnostic criteria will be crucial to address the unique challenges posed by ICI-induced myocarditis.

TIM-3 transcriptomic landscape with clinical and immunomic correlates in cancer.

TIM-3, an inhibitory checkpoint receptor, may invoke anti-PD-1/anti-PD-L1 immune checkpoint inhibitor (ICI) resistance. The predictive impact of TIM-3 RNA expression in various advanced solid tumors among patients treated with ICIs is yet to be determined, and their prognostic significance also remains unexplored. We investigated TIM-3 transcriptomic expression and clinical outcomes. We examined TIM-3 RNA expression data through the OmniSeq database. TIM-3 transcriptomic patterns were calibrated against a reference population (735 tumors), adjusted to internal housekeeping genes, and calculated as percentiles. Overall, 514 patients (31 cancer types; 489 patients with advanced/metastatic disease and clinical annotation) were assessed. Ninety tumors (17.5% of 514) had high (≥75th percentile RNA rank) TIM-3 expression. Pancreatic cancer had the greatest proportion of TIM-3 high expressors (36% of 55 patients). Still, there was variability within cancer types with, for instance, 12.7% of pancreatic cancers harboring low TIM-3 (<25th percentile) levels. High TIM-3 expression independently and significantly correlated with high PD-L2 RNA expression (odds ratio (OR) 9.63, 95% confidence interval (CI) 4.91-19.4, P<0.001) and high VISTA RNA expression (OR 2.71, 95% CI 1.43-5.13, P=0.002), all in multivariate analysis. High TIM-3 RNA did not correlate with overall survival (OS) from time of metastatic disease in the 272 patients who never received ICIs, suggesting that it is not a prognostic factor. However, high TIM-3 expression predicted longer median OS (but not progression-free survival) in 217 ICI-treated patients (P=0.0033; median OS, 2.84 versus 1.21 years (high versus not-high TIM-3)), albeit not retained in multivariable analysis. In summary, TIM-3 RNA expression was variable between and within malignancies, and high levels associated with high PD-L2 and VISTA checkpoints and with pancreatic cancer. Individual tumor immunomic assessment and co-targeting co-expressed checkpoints merits exploration in prospective trials as part of a precision immunotherapy strategy.

A Large-Scale Meta-Analysis Reveals Positive Feedback between Macrophages and T Cells That Sensitizes Tumors to Immunotherapy.

Identification of robust immunogenomic connections, particularly macrophage T-cell interactions, in a large-scale pan-cancer meta-analysis and development of a predictive model for immunotherapy response that outperformed existing models could facilitate clinical decision-making.

Safety and Efficacy Outcomes in Immune Checkpoint Inhibitor-Treated Patients With Metastatic Urothelial Carcinoma Requiring Treatment Interruption or Discontinuation Due to Immune-Related Adverse Events

IntroductionAs most patients with metastatic urothelial carcinoma (mUC) will be treated with immune checkpoint inhibitors (ICI), familiarity with their associated immune-related adverse events (irAEs) is critical. We describe the characteristics and outcomes of ICI-treated mUC patients who experienced irAEs requiring treatment interruption (TI) or permanent discontinuation. Materials and MethodsICI-treated mUC patients who developed grade ≥2 irAEs were reviewed. Clinical-, treatment-, and toxicity-related data were evaluated. Toxicity was graded per common terminology for categorization of adverse events v5.0. Cohorts were divided into patients who underwent ICI rechallenge and those who required permanent ICI discontinuation. Time to treatment interruption (TTI), time to next treatment, and duration of clinical benefit were assessed descriptively. Progression-free survival and overall survival (OS) were estimated using Kaplan-Meier methodology. ResultsOf 200 ICI-treated mUC patients at Cleveland Clinic between October 2015 and October 2020, 16 (8%) experienced ≥ grade 2 irAEs necessitating TI. Median TTI among all patients was 6.5 months (range, 1-19). Eleven patients (69%) required corticosteroids. ICI were held and rechallenged in 10 patients (62%) and permanently discontinued in 6 patients (38%). Of the 10 ICI-rechallenged patients, 7 (70%) experienced another irAE upon rechallenge with median time to irAE recurrence of 2.9 months (range, 0.1-10.9); 3 (30%) eventually discontinued ICI due to recrudescent irAEs. Four (40%) of the 10 ICI-rechallenged patients received subsequent therapy. Five (83%) of the 6 patients who permanently discontinued ICI demonstrated durable clinical benefit off therapy with median duration of clinical benefit 17.7 months (range, 14.2-55.2). Two-year OS was 40% (95% CI: 19%-86%) in the ICI rechallenge cohort and 67% (95% CI: 38%-100%) in the permanent discontinuation cohort. ConclusionICI-treated mUC patients who developed irAEs requiring TI had a high rate of subsequent irAEs upon ICI rechallenge. Importantly, patients who permanently discontinued ICI due to irAE demonstrated durable clinical benefit off treatment.

Antibiotic use reduces the efficacy of immune checkpoint inhibitors in patients with urothelial carcinoma: A systematic review and meta-analysis

ContextAntibiotics have been suggested to diminish the efficacy of immune checkpoint inhibitors (ICIs) by alterations of the gut microbiota. ObjectiveTo perform a meta-analysis summarizing the effect of antibiotics on the overall survival (OS) and progression-free survival (PFS) of urothelial cancer (UC) patients receiving ICI. Evidence acquisitionPubMed, EMBASE (Ovid), and the Cochrane Library were searched to identify studies published up to July 14, 2023. Studies reporting the associations between antibiotics use and OS and PFS in UC patients treated with ICI were included in this systematic review and meta-analysis. The random-effect model was used to pool the Hazard Ratios (HRs) for OS and PFS with 95% confidence interval (95%CI). The ROBINS-I was used to assess the risk of bias in the included studies, while the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework was used to inform the quality of evidence. Evidence synthesisThirteen nonrandomized studies involving a total of 5,095 ICI-treated UC patients were included in this review, of which 1434 (28%) received antibiotics. Overall, compared to patients who did not receive antibiotics, the pooled HRs for OS and PFS in those who received antibiotics were 1.45 [95% CI 1.25–1.68] and 1.40 [95% CI 1.05–1.87], respectively. Subgroup analysis revealed that the types of ICI and timing of antibiotic initiation did not influence the effect of antibiotics on OS and PFS in UC patients (P > 0.05). ConclusionsAntibiotic use significantly reduced OS and PFS in UC patients receiving ICI. While antibiotics remain crucial for the treatment of infections in UC patients, antibiotics should be prescribed cautiously in UC patients receiving ICI. Patient summaryAntibiotic use is associated with worsened survival in UC patients receiving immune checkpoint inhibitors.

An increased relative eosinophil count as a predictive dynamic biomarker in non-small cell lung cancer patients treated with immune checkpoint inhibitors.

An increased relative eosinophil count (REC) has potential as a predictive biomarker for a beneficial clinical response and outcome to cancer immunotherapies. Therefore, the present study investigated the impact of an increased posttreatment REC on the prognosis of non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs). We retrospectively reviewed all 151 patients diagnosed with NSCLC and treated with ICI monotherapy and blood test data between March 2016 and August 2021 at National Hospital Organization Kochi Hospital and Tokushima University. A total of 151 patients with a mean age of 69 years were included. REC after 4 weeks of initial ICI monotherapy was higher than pretreatment REC in 87 patients but not in 64. REC after 4 weeks of the ICI treatment with and without an increased REC were 4.4 and 1.8%, respectively (p < 0.001). Disease control rates (DCR) were significantly higher in patients with than in those without an increased REC (84% vs. 47%, p < 0.001). The median overall survival (OS) of lung cancer patients with or without an increased REC were 674 and 234 days, respectively. A Kaplan-Meier univariate analysis revealed a significant difference in OS between the two groups (p < 0.001). A Cox proportional regression analysis identified an increased REC as an independent predictor of OS (p = 0.003). ICI-treated NSCLC patients with an increased REC after 4 weeks of treatment had a better DCR and prognosis than the other patients examined.

A practical prognostic peripheral blood-based risk model for the evaluation of the likelihood of a response and survival of metastatic cancer patients treated with immune checkpoint inhibitors

BackgroundLess than half of unselected metastatic cancer patients benefit from the immune checkpoint inhibitor (ICI) therapy. Systemic cancer-related inflammation may influence the efficacy of ICIs and thus, systemic inflammatory markers could have prognostic and/or predictive potential in ICI therapy. Here, we aimed to identify a combination of inflammation-related laboratory parameters to establish a practical prognostic risk model for the pretreatment evaluation of a response and survival of ICI-treated patients with different types of metastatic cancers.MethodsThe study-cohort consisted of a real-world patient population receiving ICIs for metastatic cancers of different origins (n = 158). Laboratory parameters determined before the initiation of the ICI treatment were retrospectively collected. Six inflammation-related parameters i.e., elevated values of neutrophils, platelets, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and lactate dehydrogenase (LDH), and the presence of anemia, were each scored with one point, giving 0–6 risk points for each patient. The patients with information of all these six parameters (n = 109) were then stratified into low-risk (0–3 points) and high-risk (4–6 points) groups. The overall response rate (ORR), overall survival (OS), and progression-free survival (PFS) according to the risk scores were determined.ResultsThe risk model was strongly associated with the outcome of the patients. The ORR to ICI treatment in the high-risk group was 30.3% in comparison to 53.9% in the low-risk group (p = 0.023). The medians for OS were 10.0 months and 27.3 months, respectively (p < 0.001), and the corresponding medians for PFS were 3.9 months and 6.3 months (p = 0.002). The risk group remained as a significant prognostic factor for both OS (HR 3.04, 95% CI 1.64–5.64, p < 0.001) and PFS (HR 1.79, 95% CI 1.04–3.06, p = 0.035) in the Cox multivariate analyses.ConclusionsWe propose a readily feasible, practical risk model consisted of six inflammation-related laboratory parameters as a tool for outcome prediction in metastatic cancer patients treated with ICIs. The risk model was strongly associated with the outcome of the patients in terms of all the evaluated indicators i.e., ORR, OS and PFS. Yet, further studies are needed to validate the risk model.

The immunogenicity and the safety of the adjuvanted glycoprotein E (gE)-based recombinant vaccine against herpes zoster (RZV) in cancer patients during immunotherapy

ABSTRACT Herpes zoster (HZ) is caused by the reactivation of latent varicella zoster virus (VZV). Severe immunocompromising conditions, such as solid tumors, have been largely associated with an increased risk for HZ due to waning VZV-specific cellular immunity. With the approval of the adjuvanted glycoprotein E (gE)-based recombinant vaccine (RZV; Shingrix™, GSK) also in immunocompromised subjects, HZ is considered a vaccine-preventable disease changing perspectives in immunocompromised subjects. To date, no clinical trial has evaluated the immunogenicity in the patients with cancer undergoing immunotherapy. In this study, we describe the humoral and cell-mediated immune responses in 38 cancer patients treated with immune checkpoint inhibitors (ICIs) and receiving RZV. We used samples collected at baseline (T0), 3 weeks (T2), and 6 months (T3) after the complete RV vaccination schedule. Our data showed that a significant proportion (40,5%) of RZV recipients mounted a stronger humoral and cell-mediated immune response at 3 weeks (T2) after complete RZV vaccination schedule. Interestingly, both humoral and cell-mediated immune responses were mostly stable over 6 months (T3). Interestingly, the overall IFNγ-producing lymphocytes was mainly associated with CD4 T cell response (p = .0012). In conclusion, data from our pilot study suggest a strong and long-lasting immunogenicity of RZV in ICI-treated patients. Prospective analyses at 1 year after vaccination will be performed in order to evaluate the long-term persistence of humoral and cell-mediated response against RZV.

Immune mediators as predictive biomarkers for anti-PD-1 antibody therapy in urothelial carcinoma.

Introduction: This study aimed to identify immune mediators, including cytokines, chemokines, and growth factors, in the plasma for predicting treatment efficacy and immune-related adverse events (irAEs) in advanced urothelial carcinoma (aUC) treated with immune checkpoint inhibitors (ICIs). Methods: We enrolled 57 patients with aUC who were treated with the anti-programmed cell death protein 1 (PD-1) antibody pembrolizumab after the failure of platinum-based chemotherapy between February 2018 and December 2020. Plasma levels of 73 soluble immune mediators were measured before and 6weeks after initiating pembrolizumab therapy. The association of estimated soluble immune mediators with clinical outcomes, including overall survival (OS), progression-free survival (PFS), anti-tumor responses, and irAEs, were statistically evaluated. Results: In the multivariate analysis, levels of 18 factors at baseline and 12 factors during treatment were significantly associated with OS. Regarding PFS, baseline levels of 17 factors were significantly associated with PFS. Higher levels of interleukin (IL)-6, IL-8, soluble tumor necrosis factor receptor 1 (sTNF-R1), and IL-12 (p40), both at baseline and post-treatment, were significantly associated with worse OS. Conversely, low IL-6 and high TWEAK levels at baseline were associated with irAEs. Among identified factors, interferon (IFN) γ and IL-12 (p40) were repeatedly identified; high baseline levels of these factors were risk factors for worse OS and PFS, as well as progressive disease. Notably, using correlation and principal component analysis, factors significantly associated with clinical outcomes were broadly classified into three groups exhibiting similar expression patterns. Discussion: Measuring plasma levels of soluble immune mediators, such as IL-6, IL-8, sTNF-R1, IFNγ, and IL-12 (p40), could be recommended for predicting prognosis and irAEs in ICI-treated patients with aUC.

Abstract 16478: Effect of Sodium Glucose Cotransporter 2 Inhibitors on Major Adverse Cardiovascular Events in Cancer Patients Treated With Immune Checkpoint Inhibitors

Introduction: The cardiac adverse events (irAEs) secondary to immune checkpoint inhibitors (ICI) are associated with a high rate of morbidity and mortality. There are no data on the effect of concomitant sodium glucose cotransporter 2 inhibitors (SGLT2i) on the rates of major adverse cardiovascular events (MACE) among patients treated with an ICI. Hypothesis: Whether, the use of SGLT2i among ICI-treated patients may reduce MACE. Methods: This was a population-based cohort study between 2014 and 2023 including cancer patients treated with ICI aged over 18 years across the United States. SGLT2i use while on an ICI was defined as the initiation of SGLT2i therapy after the first record of ICI treatment among patients currently undergoing ICI therapy. The risk of incident MACE in patients on an ICI who were also prescribed an SGLT2i therapy was compared with 1:1 propensity score-matched patients on ICI who were never prescribed an SGLT2i. Hazard ratios (HRs) and 95% confidence intervals (CIs) for MACE were estimated using Cox proportional hazards regression. MACE was defined as a composite of myocardial infarction, heart failure (HF), and ischemic stroke. Results: There were 216 cancer patients undergoing ICI therapy who were newly treated with SGLT2i. These were compared to 216 controls. Over a mean follow-up period of six years, there were 107 MACE events. There were 44 events (20.4%) among those on an SGLT2i and 63 among controls (HR=0.61, 95% CI: 0.41-0.90; log-rank test p=0.011). Of the individual components of MACE, rates of HF were lower where there were 22 HF events (20.4%) among those on an SGLT2i and 37 among controls (HR=0.51, 95% CI: 0.30-0.86; log-rank test p=0.010). There were no differences in the rates of stroke (HR: 0.55, 95% CI: 0.29-1.04) and myocardial infarction (HR: 0.97, 95% CI: 0.38-2.43). Conclusions: In an observational, retrospective study, SGLT2i therapy was associated with a reduced risk for cardiac events compared to those who never treated with SGLT2i. These findings underscore the potential therapeutic value of SGLT2i in the prevention of MACE in cancer patients receiving immunotherapy and warrant further research.

Safety and efficacy of immune checkpoint inhibitor cancer therapy in patients with preexisting type 1 diabetes mellitus.

Immune checkpoint inhibitors (ICI) produce dramatic tumor shrinkage and durable responses in many advanced malignancies, but their use is limited by the development of immune-related adverse events (IRAEs) that occur in up to 60% of patients and often affect endocrine organs. Concern for more severe IRAEs in patients with preexisting autoimmune diseases, including type 1 diabetes mellitus (T1DM), has led to the exclusion of such individuals from clinical trials of ICI therapy. As a result, little is known about the safety and efficacy of ICI in this population. Here, we report safety and treatments outcomes in ICI-treated patients with preexisting T1DM. This retrospective case-controlled study evaluated adult patients with T1DM who received ICI therapy for solid malignancies from 2015 to 2021 at four academic medical centers. Patients with prior ICI therapy, bone marrow transplantation, or pregnancy were excluded. We collected data on demographics, cancer diagnosis and treatment, IRAE incidence and severity, and diabetes management. Controls were matched 2:1 by age, sex, cancer diagnosis, and ICI therapy class. Of 12,142 cancer patients treated with ICI therapy, we identified 11 with a preexisting confirmed diagnosis of T1DM prior to starting ICI therapy. Mean age was 50.6 years, 63.6% were women, and most received anti-PD1/PDL1 monotherapy (10/11) compared with combination therapy (1/11). Grade 3/4 IRAEs were seen in 3/11 subjects with preexisting T1DM and were hepatitis, myositis, and myasthenia gravis. All three cases had interruption of ICI therapy and administration of adjunct therapies, including steroids, IVIG, or mycophenolate mofetil with resolution of the IRAE. The odds of all-grade IRAEs and of severe IRAEs were comparable between cases and controls matched for age, sex, cancer type, and ICI therapy [OR 0.83 (95% CI 0.2-3.56), p = 0.81, and OR 1.69 (0.31-9.36), p = 0.55, respectively]. Overall survival was not different between patients with T1DM and controls (p = 0.54). No patients had hospitalizations for diabetes-related complications during therapy. These data suggest that ICI monotherapy can successfully be used in patients with preexisting T1DM, with IRAE rates comparable with individuals without preexisting T1DM. Larger, prospective studies of these potentially life-saving ICI therapies that include patients with preexisting autoimmunity are warranted.

High bone tumor burden to identify advanced non-small cell lung cancer patients with survival benefit upon bone targeted agents and immune checkpoint inhibitors

BackgroundBone-targeted agents (BTA), such as denosumab (DN) and zoledronic acid (ZA), have historically reduced the risk of skeletal related events in cancer patients with bone metastases (BM), with no improvement in survival outcomes. In the immunotherapy era, BM have been associated with poor prognosis upon immune-checkpoint inhibitors (ICI). Currently, the impact of bone tumor burden on survival upon BTAs in advanced non-small cell lung cancer (aNSCLC) patients treated with ICI remains unknown. MethodsData from ICI-treated aNSCLC patients with BM (4/2013-5/2022) in one institution were retrospectively collected. BTA-ICI concurrent treatment was defined as BTA administration at any time before or within 90 days from ICI start. High bone tumor burden (HBTB) was defined as ≥ 3 sites of BM. Median OS (mOS) was estimated with Kaplan-Meier. Aikaike’s information criterion (AIC) was used to select the best model for data analysis adjusted for clinical variables. ResultsOf 134 patients included, 51 (38 %) received BTA. At a mFU of 39.6 months (m), BTA-ICIs concurrent treatment did not significantly impact on mOS [8.3 m (95% CI 3.9–12.8) versus (vs) 6.8 m (95% CI 4.0–9.6) p = 0.36]; these results were confirmed after adjustment for clinical variables selected by AIC. A multivariate model showed a significant interaction between BTA use and HBTB or radiation therapy to BM. In subgroup analyses, only HBTB confirmed to be associated with significantly longer mOS [8.3 m (95% CI 2.4–14.2) vs 3.5 m (95% CI 2.9–4.1), p = 0.003] and mPFS [3.0 m (95% CI 1.6–4.4) vs 1.8 m (95% CI 1.6–2.0) p = 0.001] upon BTA-ICI concurrent treatment, with the most pronounced OS benefit observed for DN-ICI concurrent regimen [15.2 m (95% CI 0.1–30.7) vs 3.5 m (95% CI 2.9–4.1) p = 0.002]. ConclusionsIn the immunotherapy era, HBTB can identify patients experiencing survival benefit with BTA, especially with DN-ICI combination. HBTB should be included as a stratification factor in the upcoming trials assessing BTA and ICI combinations in patients with aNSCLC and BM.

Prognostic utility of body composition parameters based on computed tomography analysis of advanced non-small cell lung cancer treated with immune checkpoint inhibitors

ObjectiveThe purpose of this study was to evaluate the prognostic impact of body composition parameters based on computed tomography (CT) in patients with non-small cell lung cancer (NSCLC) who received ICI treatment.MethodsThis retrospective study analyzed the data from advanced NSCLC patients treated with ICI therapy between 2013 and 2019. We included patients with NSCLC who underwent baseline CT scans. The exclusion criteria included patients who received three or more lines of chemotherapy, those with insufficient clinical information, or those without treatment response evaluation.ResultsA total of 136 patients were enrolled. Among the volumetric body composition parameters, patients in the highest quartiles (Q2–4) of the visceral fat index (VFI) exhibited a higher response rate to ICI therapy than those in the lowest quartile (Q1) of VFI (Q1 vs. Q2–4: 18.2% vs. 43.1%, p = 0.012). Patients with a VFI in Q2–4 had significantly prolonged progression-free survival (PFS) and overall survival (OS) (PFS, Q1 vs. Q2–4: 3.0 months vs. 6.4 months, p = 0.043; OS, Q1 vs. Q2–4: 5.6 months vs. 16.3 months, p = 0.004). Kaplan–Meier analysis based on the VFI and visceral fat Hounsfield unit (HU) revealed that patients with VFI in Q1 and HU in Q2–4 had the worst prognosis.ConclusionsVisceral fat volume is significantly associated with treatment outcomes in ICI-treated patients with NSCLC. Moreover, fat quality may impact the treatment outcomes. This finding underscores the potential significance of both fat compartments and fat quality as prognostic indicators.Critical relevance statementVisceral fat volume is significantly associated with treatment outcomes in ICI-treated patients with non-small cell lung cancer. Moreover, fat quality may impact the treatment outcomes. This finding underscores the potential significance of both fat compartments and fat quality as prognostic indicators.Graphical Key points• We found that visceral fat volume positively correlated with treatment response and survival in patients with non-small cell lung cancer receiving immune checkpoint inhibitors.• Additionally, a trend toward a negative correlation between visceral fat attenuation and survival was observed.• The findings highlight the prognostic utility of fat compartments and fat quality.

Thymus alterations and susceptibility to immune checkpoint inhibitor myocarditis.

Immune checkpoint inhibitors (ICI) have transformed the therapeutic landscape in oncology. However, ICI can induce uncommon life-threatening autoimmune T-cell-mediated myotoxicities, including myocarditis and myositis. The thymus plays a critical role in T cell maturation. Here we demonstrate that thymic alterations are associated with increased incidence and severity of ICI myotoxicities. First, using the international pharmacovigilance database VigiBase, the Assistance Publique Hôpitaux de Paris-Sorbonne University data warehouse (Paris, France) and a meta-analysis of clinical trials, we show that ICI treatment of thymic epithelial tumors (TET, and particularly thymoma) was more frequently associated with ICI myotoxicities than other ICI-treated cancers. Second, in an international ICI myocarditis registry, we established that myocarditis occurred earlier after ICI initiation in patients with TET (including active or prior history of TET) compared to other cancers and was more severe in terms of life-threatening arrythmias and concurrent myositis, leading to respiratory muscle failure and death. Lastly, we show that presence of anti-acetylcholine-receptor antibodies (a biological proxy of thymic-associated autoimmunity) was more prevalent in patients with ICI myocarditis than in ICI-treated control patients. Altogether, our results highlight that thymic alterations are associated with incidence and seriousness of ICI myotoxicities. Clinico-radio-biological workup evaluating the thymus may help in predicting ICI myotoxicities.

Retrospective study of efficacy and adverse events of immune checkpoint inhibitors in 22 xeroderma pigmentosum patients with metastatic or unresectable cancers.

Xeroderma pigmentosum (XP), a rare disease with defects in DNA repair genes, has >1,000-fold increased risk of ultraviolet-induced skin cancers. Immune checkpoint inhibitors (ICIs) are used for treating cancers with large numbers of mutations but may also promote adverse events (AEs). Deficient DNA repair in XP patients may lead to increased numbers of mutations, leading to enhanced efficacy of cancer response or, alternatively, to increased AE in response to ICI. We sought to compare the efficacy and AE of ICI in XP patients with metastatic or unresectable cancers to that of ICI-treated patients in the general population. In this retrospective study, we reviewed medical records of XP patients treated in the United States and in London (UK). We also reviewed published reports of ICI-treated XP patients and patients in the general population. Metastatic or unresectable cancers in all 22 (100%) XP patients showed regression or remission in response to ICI. The types and frequencies of AE in XP patients were similar to those reported among ICI-treated patients in the general population. However, two XP patients had concurrent additional cancers that did not respond to ICI, two XP patients had cancer recurrence or progression after initial response, and eight XP patients developed new skin cancers during or after ICI treatment. In this retrospective study with small sample size, XP patients demonstrated positive responses to ICI and the treatment was well tolerated but some patients developed new skin cancers while being treated. ICIs can be considered in treating metastatic or unresectable cancers in XP patients.

Two cases of COVID-19 vaccine-related erythema multiforme under the administration of immune checkpoint inhibitors

The COVID-19 pandemic has increased mRNA vaccine usage and revealed various cutaneous adverse events, such as injection site reactions, urticaria, and morbilliform eruptions. Multiple centers have reported erythema multiforme (EM) as a COVID-19 vaccine-associated adverse event. Our center observed two cases of EM in patients receiving immune checkpoint inhibitors (ICI) after COVID-19 vaccination. Notably, ICI administration is known to cause cutaneous adverse events, including EM. A previous report indicated that administering COVID-19 vaccination to patients receiving ICI treatment could promote severe systemic symptoms. This raise concerns that COVID-19 vaccination might rapidly worsen skin rashes in these patients. Our report demonstrates that skin rash related to COVID-19 vaccine-induced EM in ICI-treated patients does not significantly differ from that of COVID-19 vaccine-related EM. Additionally, in both cases, the skin rash resolved without exacerbation. Further research is necessary to determine optimal management strategies. However, our findings provide reassurance that COVID-19 vaccination is safe in ICI-treated patients and should not be avoided.

Antiplatelet drugs may increase the risk for checkpoint inhibitor-related pneumonitis in advanced cancer patients

Immune checkpoint inhibitors (ICIs) are indicated for various cancers and are the mainstay of cancer immunotherapy. They are often associated with ICI-related pneumonitis (CIP), however, hindering a favorable clinical course. Recently, non-oncology concomitant drugs have been reported to affect the efficacy and toxicity of ICIs; however, the association between these drugs and the risk for CIP is uncertain. The aim of this study was to assess the impact of baseline concomitant drugs on CIP incidence in ICI-treated advanced cancer patients. This was a single-center retrospective study that included a cohort of 511 patients with advanced cancer (melanoma and non-small-cell lung, head and neck, genitourinary, and other types of cancer) treated with ICIs. Univariable analysis was conducted to identify baseline co-medications associated with CIP incidence. A propensity score matching analysis was used to adjust for potential CIP risk factors, and multivariable analysis was carried out to assess the impact of the identified co-medications on CIP risk. Forty-seven (9.2%) patients developed CIP. In these patients, the organizing pneumonia pattern was the dominant radiological phenotype, and 42.6% had grade ≥3 CIP, including one patient with grade 5. Of the investigated baseline co-medications, the proportion of antiplatelet drugs (n= 50, 9.8%) was higher in patients with CIP (23.4% versus 8.4%). After propensity score matching, the CIP incidence was higher in patients with baseline antiplatelet drugs (22% versus 6%). Finally, baseline antiplatelet drug use was demonstrated to increase the risk for CIP incidence regardless of cancer type (hazard ratio, 3.46; 95% confidence interval 1.21-9.86). An association between concomitant antiplatelet drug use at baseline and an increased risk for CIP was seen in our database. This implies the importance of assessing concomitant medications for CIP risk management.

THU299 Safety Of Immune Checkpoint Inhibitor Cancer Therapy In Patients With Pre-existing Type 1 Diabetes Mellitus: A Multi-Center Cohort Study

Abstract Disclosure: R. Hilder: None. T. Karen: None. D. Isaacs: None. A. Drakaki: None. M.G. Lechner: None. Introduction: Immune checkpoint inhibitors have revolutionized cancer therapy, producing dramatic tumor shrinkage and durable responses in many advanced malignancies. A limitation of their use is the development of unwanted autoimmunity in healthy tissues, known as Immune Related Adverse Effects (IRAEs), that occur in up to 60% of patients and often affect endocrine organs. For this reason, patients with pre-existing autoimmune diseases, including type 1 diabetes mellitus, have systemically been excluded from clinical trials of ICI therapy. This exclusion has translated to current clinical practice and therefore little is known about the safety and efficacy of ICI in this population. Here we report, for the first time, outcomes in ICI-treated patients with pre-existing T1DM. Methods: This retrospective cohort study included adult patients who received an-FDA approved ICI therapy for solid malignancies from 2015-2021 at two academic medical centers (UCLA Health and City of Hope) and had a diagnosis of T1DM prior to starting ICI. ICD-10 codes E10.9 and E10.65 identified 58 patients with T1DM, screened by manual chart review for inclusion. Patients with prior ICI therapy, bone marrow transplant, or pregnancy were excluded. We collected data on demographic, cancer diagnosis and treatment (stage, ICI therapy, response), Grade 3 or 4 IRAEs [classified by the NIH Common Terminology Criteria for Adverse Events (CTCAE) V5] and diabetes management during ICI therapy, including the incidence of significant hyperglycemia, diabetic ketoacidosis (DKA), and the use of technology. Results: Of 7545 ICI treated cancer patients, we identified five with a pre-existing diagnosis of T1DM. Three were female and mean age was 58 years (range 37-79). All patients were diagnosed with metastatic cancer (cervical, lung and breast) and were treated with anti-PD1/PDL1 monotherapy: Nivolumab, Durvalumab, or Pembrolizumab. Two patients had Grade 3 hepatitis, one of which with concurrent myositis requiring prolonged corticosteroids and IVIG. Both patients recovered with cessation of ICI. Regarding other endocrine IRAEs, one patient had pre-existing hypothyroidism and another developed ICI-thyroiditis during ICI therapy; both were treated with thyroid hormone replacement. Four (80%) utilized insulin pump therapy while on immunotherapy. No patients were hospitalized for DKA or complications of hyperglycemia during ICI therapy. Regarding tumor response to ICI, two patients had complete response, two with partial response, and one was deceased shortly after starting therapy. Discussion: Based on this data, ICI monotherapy can successfully be used in patients with pre-existing T1DM, but patients should be counseled on the risk of IRAEs; in particular hepatitis. Larger, prospective studies of these potentially life-saving ICI therapies that include patients with pre-existing autoimmunity are warranted. Presentation: Thursday, June 15, 2023

Toxicity-specific peripheral blood T and B cell dynamics in anti-PD-1 and combined immune checkpoint inhibition

Immune checkpoint inhibitors (ICI) have revolutionized the treatment landscape of advanced malignancies, but come with a diverse spectrum of immune-related adverse events (irAEs). Mechanistic studies can aid the transition from expert-opinion to evidence-based irAE treatment strategies. We aimed to longitudinally characterize peripheral blood T and B cell dynamics in ICI-treated patients by multicolor flow cytometry and serum multiplex immunoassay at baseline, ± 3 weeks and ± 6 weeks or upon clinically relevant irAEs. We analyzed samples from 44 ICI-treated patients (24 anti-PD-1 monotherapy, 20 combined anti-PD-1/anti-CTLA-4; cICI), of whom 21 developed irAEs, and 10 healthy donors. IrAEs after cICI were characterized by significantly enhanced proliferation of Th1-associated, mainly (CD4+) CD27− effector memory T cells, as well as Th17-associated immune responses and germinal center activation (reflected by CXCL13 and IL-21 increases). We observed no changes in CD21lo, memory, class-switched or newly activated B cell subsets. Particularly double-positive PD-1+LAG-3+ CD8+ T cells showed enhanced cytotoxic capacity in patients with irAEs after cICI. Within anti-PD-1 monotherapy, irAEs were associated with modestly enhanced Th1-associated responses reflected by increased serum CXCL9 and CXCL10. In conclusion, ICI-induced toxicity is dominated by enhanced Th1-associated responses, but in cICI we also found evidence for Th17-associated responses and germinal center activation. Together, our data add to the growing body of evidence that irAEs may be driven by newly activated CD4+ helper T cells, specifically after cICI. This study also supports tailored irAE treatment, based on ICI regimen, and to deploy specific strategies such as Th17 inhibition especially in cICI-associated irAEs.Graphical abstract

Impact of Helicobacter pylori infection status on outcomes among patients with advanced gastric cancer treated with immune checkpoint inhibitors

BackgroundGut microbiota composition can influence cancer immunotherapy response. Recent evidence suggests Helicobacter pylori infection may reduce immune checkpoint inhibitor (ICI) efficacy in lung cancer and melanoma, but thorough characterization of...