Pre-existing Autoimmune Disease Research Articles

Immune checkpoint inhibitor therapy in patients with cancer and pre-existing systemic sclerosis

ObjectiveImmune checkpoint inhibitor (ICI) therapies have dramatically improved outcomes in multiple cancers. ICI's mechanism of action involves immune system activation to augment anti-tumor immunity. Patients with pre-existing autoimmune diseases, such as systemic sclerosis (SSc), were excluded from initial ICI clinical trials due to concern that such immune system activation could precipitate an autoimmune disease flare or new, severe immune related adverse events (irAE). In the present study, we report our experience with ICIs in patients with pre-existing SSc. MethodsPatients with SSc who received ICI therapy for cancer were identified from the Johns Hopkins Scleroderma Center Research Registry. Through chart review and prespecified definitions, we identified whether patients experienced worsening SSc activity or new irAEs. SSc disease activity worsening was pre-defined as an increase in modified Rodnan skin score (mRSS), new scleroderma renal crisis, progression of interstitial lung disease (ILD) on CT scan, increased Raynaud's phenomenon frequency or severity, new pulmonary hypertension, or myositis flare. IrAEs also included active inflammatory arthritis and dermatitis. ResultsEight patients with SSc who received ICI therapy for cancer were included. Overall, SSc symptoms remained stable during and after ICI therapy. None of the patients with long-standing sine or limited cutaneous SSc (lcSSc) had progressive skin thickening after ICI therapy. One patient, who was early in his diffuse cutaneous SSc (dcSSc) disease course, experienced worsening skin thickening and renal crisis. Three patients (38 %) experienced a total of five irAEs (grade 2: diarrhea, mucositis and dermatitis; grade 3: pneumonitis, and grade 4: nephritis). The patient with grade 4 nephritis developed scleroderma renal crisis and immune checkpoint related nephritis simultaneously. There were no deaths due to irAEs. ConclusionIn this study, ICI therapy was well tolerated in patients with longstanding, sine or lcSSc. IrAE were common but generally manageable. Patients with early, active SSc may be at greater risk from ICI therapy, but more research is needed.

Herpes Simplex Virus Encephalitis in Patients With Autoimmune Conditions or Exposure to Immunomodulatory Medications.

Among infectious etiologies of encephalitis, herpes simplex virus type 1 (HSV-1) is most common, accounting for ∼15%-40% of adult encephalitis diagnoses. We aim to investigate the association between immune status and HSV encephalitis (HSVE). Using a US Medicaid database of 75.6 million persons, we evaluated the association between HSVE and autoimmune conditions, exposure to immunosuppressive and immunomodulatory medications, and other medical comorbidities. We used the US Medicaid Analytic eXtract data between 2007 and 2010 from the 29 most populated American states. We first examined the crude incidence of HSVE in the population. We then age and sex-matched adult cases of HSVE with a sufficient enrollment period (12 months before HSVE diagnosis) to a larger control population without HSVE. In a case-control analysis, we examined the association between HSVE and exposure to both autoimmune disease and immunosuppressive/immunomodulatory medications. Analyses were conducted with conditional logistic regression progressively adjusting for sociodemographic factors, Charlson Comorbidity Index, and non-autoimmune comorbidities. Incidence of HSVE was ∼3.01 per 105 person-years among adults. A total of 951 HSVE cases and 95,100 age and sex-matched controls were compared. The HSVE population had higher rates of medical comorbidities than the control population. The association of HSVE and autoimmune conditions was strong (adjusted odds ratio (OR) 2.6; 95% CI 2.2-3.2). The association of HSVE and immunomodulating medications had an OR of 2.2 (CI 1.9-2.6), also after covariate adjustment. When both exposures were included in regression models, the associations remained robust: OR 2.3 (CI 1.9-2.7) for autoimmune disease and 2.0 (CI 1.7-2.3) for immunosuppressive and immunomodulatory medications. In a large, national population, HSVE is strongly associated with preexisting autoimmune disease and exposure to immunosuppressive and immunomodulatory medications. The role of antecedent immune-related dysregulation may have been underestimated to date.

HLA inherence as a potential parameter in checkpoint inhibitor-associated autoimmune adverse event assessment.

The success of immunotherapy has made it a lifesaving treatment, but not without side effects. Currently, the risk factors for developing immune-related adverse events (irAEs) in patients who receive immunotherapy are poorly understood, and there is no risk-stratifying mechanism for potentially fatal irAEs. It is postulated that oncology patients with preexisting autoimmune diseases are likely to have flares on immunotherapy. However, some patients develop de novo autoimmune conditions on immunotherapy without a prior history. Literature reports have postulated that human leukocyte antigen (HLA) inherence may play a role in irAEs. However, this potential remains underexplored. The oncology patients who developed autoimmune adverse events on immunotherapy for whom the continuation of treatment was prudent or lifesaving were selected. Of note, all nine patients received checkpoint inhibitors (CIs). Of the nine selected patients, only one had a prior history of an autoimmune condition. None of the nine selected patients had an active autoimmune condition at the time of CI initiation. Their HLA was typed, and the results were cross-referenced with the literature reports in PubMed and Google search with the corresponding autoimmune condition of each patient. Herein, we report nine patients with irAEs for whom retrospective HLA typing revealed the inherence of multiple related HLA alleles that may correspond to the autoimmune condition that they had developed on immunotherapy. It is to be mentioned that the inherence of enriched disease-related HLA alleles was shared among patients with the same irAEs. These patients developed a range of irAEs including bullous pemphigoid, pemphigus foliaceus/vulgaris, thyroiditis, vitiligo, and hepatitis on immunotherapy. Although some combinations of disease-related HLA were well reported in otherwise idiopathic autoimmune diseases, a frequently repeated HLA allele combination in our patient population was found to be rarely seen in the general population. The authors suggest that an enriched inherence of disease-related HLA alleles may play a role in the genetic propensity for the development of irAEs in oncology patients, who receive immunotherapy, including CIs. Inherence of more than one or a cluster of particular autoimmune disease-related HLA alleles in patients who receive immunotherapy may unmask the corresponding autoimmune disease as the genotype inherence presents with the phenotype of the corresponding condition. It is suggested that enriched linked HLA genotypes, which are otherwise rare in the general population, may present as the corresponding phenotype of the autoimmune condition. Such clinical presentation, enhanced by immunotherapy, such as CIs, can play a role in risk stratifying patients for precision medicine and improve the outcome.

Identification of shared mechanisms and targets between immune checkpoint inhibitor-associated myocarditis and autoimmune myocarditis

Objective This study aimed to explore the shared mechanisms and targets between immune checkpoint inhibitor-associated myocarditis (ICIM) and autoimmune myocarditis. Methods Relevant data were retrieved from public datasets and Gene Expression Omnibus (GEO) database. Gene set enrichment analysis (GSEA) of differentially expressed genes (DEGs) was used to identify significant shared signaling pathways between ICIM and non-ICI associated autoimmune myocarditis (NICIAM) represented by ICIM model and experimental autoimmune myocarditis (EAM) model, respectively. Cell type enrichment analysis and immune infiltration analysis by clusterProfiler and ImmuCellAI were performed to identify critical immune cell component involved in ICIM and NICIAM. Additionally, core shared genes across ICIM and NICIAM were identified and validated by various models and methods. Results Interferon-γ response, inflammatory response and allograft rejection signaling were identified as the shared signaling pathways associated with ICIM and NICIAM. Enrichment analysis of cell type supported an important role of increased infiltration of T cells and macrophages in both ICIM and NICIAM. However, the predominant increase of infiltrated T cells was CD4+ T cells in NICIAM, while that were CD8+ T cells in ICIM. Core shared genes Lck and Cd3d expression were found increased in both ICIM and NICIAM, and Lck inhibition was further identified and validated as potential therapeutic approach. Conclusions Our study initially established a comorbidity model to identify potential molecular mechanism including interferon-γ response, inflammatory response and allograft rejection signaling accounting for the concerns of myocarditis risk in patients with preexisting autoimmune disease (PAD) receiving ICI treatment, and supported the therapeutic potential of targeting Lck or Cd3d.

The Impact of Pre-Existing Autoimmune Disease on the Safety and Efficacy of CAR T-Cell Therapy for Non-Hodgkin Lymphoma

Introduction: Chimeric antigen receptor T-cell therapy (CAR-T) has revolutionized the treatment of non-Hodgkin lymphoma (NHL). Despite having an increased risk of NHL, patients with pre-existing autoimmune disease (AID) were excluded from pivotal CAR-T trials due to concerns that CAR-T may exacerbate AID. As a result, there are limited data on the safety and efficacy of CAR-T for NHL in patients with AID. Interestingly, there is also growing evidence that CAR-T can be therapeutically effective for AID, such as in the treatment of systemic lupus erythematosus (SLE). As CAR-T utilization for NHL increases, it is essential to characterize the safety and efficacy of this potentially curative therapy in patients with AID. This study aimed to evaluate the impact of AID on outcomes in patients treated with commercial CD19-targeted CAR-T for NHL. Methods: Following Institutional Review Board approval, we conducted a retrospective analysis of all patients who were treated with commercial CD19-targeted CAR-T for NHL and had a pre-existing AID across the Mayo Clinic Enterprise (Arizona, Florida, and Minnesota) between January 2018 and May 2023. Variables collected included age, gender, NHL type, AID type, and CAR-T product. Efficacy outcomes, including response rates at 6 and 12 months after CAR-T, were collected. Toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), were collected and analyzed. Our chart review for AID included SLE, sarcoidosis, ulcerative colitis, celiac disease, pernicious anemia, Crohn's disease, psoriasis, Sjogren's syndrome, hypothyroidism (Hashimoto's disease), hyperthyroidism (Graves' disease), rheumatoid arthritis (RA), vasculitis, scleroderma, and mixed connective tissue disease (MCTD). Results: A total of 235 patients who received commercial CD19-targeted CAR-T for NHL across the Mayo Clinic Enterprise were identified (Table 1). Of these 235 patients, 27 had a pre-existing AID and 208 did not. The median age was 66 years (range 39-81) for patients with AID and 59 years (range 18-88) for patients without AID. Over half of the patients were male (59% of patients with AID and 51% of patients without AID). The most common NHL type was diffuse large B cell lymphoma (41% of patients with AID and 56% of patients without AID). Most patients received axicabtagene ciloleucel (85% of patients with AID and 84% of patients without AID). The most common AID was hypothyroidism (81%, n=22), although other conditions were also identified, including RA (11%, n=3), SLE (4%, n=1), pulmonary sarcoidosis (4%, n=1), psoriasis (4%, n=1), and MCTD (4%, n=1). Two patients had more than one AID. Median follow-up was 18 months (range 1-36) for patients with AID and 14 months (range 2-49) for patients without AID. Six months after CAR-T, the complete response (CR) rate was 77.2% and 45.1% in patients with AID and without AID, respectively (p=0.0042). Twelve months after CAR-T, the CR rate was 50% and 31.4% in patients with AID and without AID, respectively (p=0.0801). CRS of any grade occurred in 78% and 88% of patients with and without AID, respectively. ICANS of any grade occurred in 41% and 54% of patients with and without AID, respectively. Conclusion: AID did not appear to adversely impact the safety or efficacy of CAR-T for NHL. Limitations of our study include the small number of patients with AID and the fact that the most common AID was hypothyroidism. Larger studies are warranted to confirm these findings. Additional data are needed to characterize the impact of CAR-T for NHL on AID outcomes and to describe the effect of disease-modifying antirheumatic drugs on NHL outcomes after CAR-T.

Characterizing Hematological Changes and Morphological Abnormalities in Hospitalized COVID-19 Patients of Hispanic Descent

Introduction COVID-19 infection is known to significantly impact hematopoiesis and hemostasis, resulting in a wide range of hematological abnormalities. Notably, the pandemic has demonstrated higher mortality rates among the Hispanic population compared to other groups. However, limited comprehensive data exist on specific alterations in COVID-19 patients of Hispanic descent, which could offer valuable insights. This study aims to conduct a thorough examination of hematological changes in hospitalized COVID-19 patients of Hispanic descent, shedding light on unique aspects of the disease within this specific population. Methods We conducted a single-center cross-sectional study in Lima, Peru, analyzing 133 hemogram and blood smear samples collected from hospitalized adult patients (age >18) with confirmed SARS-CoV-2 infection between January and March 2021. Pregnant women and those with pre-existing hematological or autoimmune disorders were excluded. Upon admission, laboratory tests included a complete blood count for assessment, while peripheral blood smears using Wright's staining technique were utilized to observe the morphology and differentiation of the blood cells. Within 24 hours of collection, we recorded basic demographics, blood cell counts, and morphological features. The study focused on hematological examinations taken during the first 4 days of hospitalization. Results Of the samples analyzed, 60.9% (n=81) of samples were from males, with median age 58 (47-68) years. COVID-19 patients showed altered cell counts, with elevated median hemoglobin (12.4 g/dl) and platelets (306 103/μl). White blood cell series had higher median leukocytes (12.4 103/μl), neutrophils (9.5 103/μl), and neutrophil-lymphocyte index (11.5 103/μl), while lymphocyte concentration decreased (0.8 103/μl). Hematological alterations included anemia (64.7%), neutrophilia (65.4%), leukocytosis (60.9%), lymphopenia (59.4%), eosinopenia (51.9%), and thrombocytosis (27.8%). Morphological analysis revealed anisocytosis (18.8%), with smaller proportions of echinocytosis (1.5%) and hypochromia (1.5%) in red blood cells. In the white blood cell lineage, toxic granulations (51.1%) were the most frequently observed characteristic, along with hypersegmentation of neutrophils (32.3%), atypical lymphocytes (15%), acquired Pelger Hüet abnormalities (9%), and circulating myeloblasts (9%). The most common platelet alteration was presence of macroplatelets (33.8%). Conclusion This study offers valuable insights into both quantitative and qualitative hematological alterations observed in hospitalized COVID-19 patients within a specific population. Notably, we identified a higher prevalence of leukocytosis, neutrophilia, lymphopenia, an elevated neutrophil-lymphocyte index, eosinopenia, and anemia, as compared to other cohorts. These alterations have been previously linked to severe cases and have served as prognostic indicators for disease progression and poor outcomes. Recognizing the hematological changes unique to COVID-19 patients of Hispanic descent holds significant importance in tailoring effective healthcare interventions. These findings contribute to the growing body of knowledge, emphasizing the need for further exploration to better inform patient care and global response strategies against COVID-19.

Lymphoma Treatment Alterations in the Context of Autoimmune Disease

Background: Autoimmune disease (AD) confers an increased risk for lymphoma. Several studies have shown that pre-existing AD portends a worse prognosis for lymphoma patients, but the reasons for this are unknown. 1,2,3 We hypothesize that one reason may be poor treatment tolerance in AD patients due to concurrent risk for cytopenias, infections, and immune-related adverse events. Methods: We conducted a retrospective cohort study to understand whether AD is associated with higher risk for treatment alterations, hospitalizations, and transfusions among lymphoma patients. The study population consisted of adult patients (aged 18-74 at lymphoma diagnosis) who underwent lymphoma treatment at one tertiary care center from 2017-2022. Patients who developed AD after or within the 12 months before lymphoma diagnosis were excluded to avoid including patients whose AD was paraneoplastic or a treatment side effect. Subjects were found by using cohort builder in electronic medical record then reviewing records for eligibility. The primary exposure of interest was pre-existing diagnosis of AD and the primary outcome was treatment alteration, such as dose reduction, delay, or discontinuation. The secondary outcomes were hospitalization, and transfusion. Outcomes were compared between groups with non-parametric tests. Logistic regression was used to estimate the association of AD with any treatment alteration. Results: We reviewed 357 records, with 30 eligible for inclusion in AD cohort and 65 eligible for non-AD cohort. There were 17 different lymphoma types with diffuse large B cell lymphoma as the most common (10 in AD cohort, 20 in non-AD). In the AD cohort, there were 12 distinct autoimmune diagnoses and rheumatoid arthritis was the most common (n=11). Baseline patient characteristics did not differ between the AD and non-AD cohorts in age, sex, diagnosis, stage, renal function, hemoglobin or type of treatment received. However, patients in the AD cohort were more likely to be Black or Asian compared to the non-AD cohort (Table 1). There were no differences in frequency of treatment alterations, unplanned hospitalizations, or incidence of transfusion between the AD and non-AD groups. Logistic regression showed no association of study group with incidence of any treatment alteration, even after controlling for baseline characteristics. Discussion: This study examines whether autoimmune disease impacts treatment tolerance among lymphoma patients. In a Swedish retrospective study of lymphoma, worse outcomes were seen among patients with AD due to increased non-lymphoma risk of death, suggesting that AD patients may have more frequent serious and life-threatening complications from lymphoma therapy. 1 In our study, there were no differences in treatment tolerance between the AD and non-AD groups. However, sample size is a limitation, and chart review is ongoing. Notably, treatment alterations were common in both groups, and no increase in unplanned hospitalizations was seen in the AD group. Clinical decisions to dose reduce, delay or discontinue therapy may mitigate against hospitalization from serious treatment related complications even in lymphoma patients with concurrent AD. Future directions include examining interactions between treatment alterations, autoimmune disease, and prognosis in specific lymphoma subtypes. 1. Simard JF, Baecklund F, Chang ET, Baecklund E, Hjalgrim H, et al. Lifestyle factors, autoimmune disease and family history in prognosis of non-hodgkin lymphoma overall and subtypes. Int J Cancer. 2013 Jun 1;132(11):2659-66. doi: 10.1002/ijc.27944. Epub 2012 Dec 3. PMID: 23160780. 2. Jachiet V, Mekinian A, Carrat F, Grignano E, Retbi A, Boffa JJ, et al. Autoimmune manifestations associated with lymphoma: Characteristics and outcome in a multicenter retrospective cohort study. Leuk. Lymphoma. 2018;59:1399-1405 3. Kleinstern G, Averbuch M, Abu Seir R, Perlman R, Ben Yehuda D, Paltiel O. Presence of autoimmune disease affects not only risk but also survival in patients with B-cell non-Hodgkin lymphoma. Hematol. Oncol. 2018;36:457-462.

404. Impact of cross-coronavirus humoral immunity in post-acute sequelae of COVID-19 in systemic autoimmune rheumatic diseases patients

Abstract Background Beyond the acute illness caused by SARS-CoV-2, about one-fifth of infections unpredictably result in long-term persistence of symptoms despite the apparent clearance of infection. Insights into the mechanisms that underlie post-acute sequelae of COVID-19 (PASC) will be critical for the prevention and clinical management of long-term complications of COVID-19. Several hypotheses have been proposed that may account for the development of PASC, including persistence of virus or the dysregulation of immunity. Among the immunological changes noted in PASC, alterations in humoral immunity have been observed in some patient subsets. Methods To begin to determine whether SARS-CoV-2 or other pathogen specific humoral immune responses evolve uniquely in PASC, we performed comprehensive antibody profiling against SARS-CoV-2, a panel of endemic pathogens, and a panel of routine vaccine antigens using Systems Serology in two independent cohorts of patients with pre-existing systemic autoimmune rheumatic disease (SARD) who either developed or did not develop PASC. Results A distinct qualitative shift observed in Fcγ receptor binding was observed in individuals with PASC. Specifically, individuals with PASC harbored weaker Fcγ receptor binding anti-SARS-CoV-2 antibodies and a significantly stronger Fcγ receptor binding antibody response against endemic Coronavirus OC43. Individuals with PASC, further, generated more avid IgM responses and developed an OC43 S2-specific antibody response with stronger Fcγ-receptor binding, linked to cross reactivity across SARS-CoV-2 and common coronaviruses. Conclusion These findings from two independent cohorts implicate previous common Coronavirus imprinting as a marker for the development of PASC in individuals with SARDs. Disclosures Douglas A. Lauffenburger, PhD, Sanofi: Board Member|Sanofi: Honoraria|Sanofi: Honoraria Zachary Wallace, MD, MSc, Bristol-Myers Squibb: Grant/Research Support|Horizon: Advisor/Consultant|MedPace: Advisor/Consultant|Principia/Sanofi: Grant/Research Support|Sanofi: Advisor/Consultant|Shionogi: Advisor/Consultant|Viela Bio: Advisor/Consultant|Zenas BioPharma: Advisor/Consultant Jeffrey Sparks, MD, AbbVie: Advisor/Consultant|Amgen: Advisor/Consultant|Boehringer Ingelheim: Advisor/Consultant|Bristol Myers Squibb: Advisor/Consultant|Bristol Myers Squibb: Grant/Research Support|Gilead: Advisor/Consultant|Inova Diagnostics: Advisor/Consultant|Janssen: Advisor/Consultant|Optum: Advisor/Consultant|Pfizer: Advisor/Consultant Galit Alter, PhD, Leyden Labs: Ownership Interest|Moderna Therapeutics: Employee|Seromyx Systems: Ownership Interest

Effectiveness and Safety of Immune Checkpoint Inhibitors in Cancer Patients With Autoimmune Disease: A Retrospective Cohort Study

Although immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, patients with pre-existing autoimmune diseases (PADs) have largely been excluded from clinical trials evaluating this drug class. This study evaluates the effectiveness and safety of ICI therapy in individuals with PAD in a real-world setting. A retrospective study of patients exposed to ICI therapy between 2012 and 2019 was conducted. Patients with PAD were identified and matched to an ICI-exposed group without PAD based on age, sex, and cancer type. Primary outcomes included toxicity, time to treatment failure, overall survival, and objective response rate. The association between PAD status and outcomes was determined using Cox and logistic regression modeling. A total of 813 patients exposed to ICI therapy were identified, of which 8.2% (N=67) had a PAD. When compared with a matched cohort without PAD (N=132), there was no significant difference in the rates of new immune-related adverse events (irAEs, 42.4% in the non-PAD group vs. 47.8% in the PAD group, P=0.474). After controlling for the type of ICI, there was no significant association between PAD status and irAE (odds ratio 1.67, 95% CI: 0.9–3.21 P=0.1). There was no significant association between overall survival and PAD status (hazard ratio 1.12, 95% CI: 0.76–1.66. P=0.56) or between time to treatment failure and PAD status (hazard ratio 0.82, 95% CI: 0.6–1.12, P=0.22). There was an association between PAD status and objective response rate (odds ratio 3.28, 95% CI: 1.28–8.38, P=0.013). In summary, PAD status was not associated with enhanced toxicity when compared with patients without PAD, with similar oncologic effectiveness between these 2 groups.

Management of autoimmune and viral hepatitis in immunotherapy: a narrative review.

Cancer immunotherapy has firmly established itself as a pillar of cancer care due to its advantages over traditional anti-tumor therapy but also carries limitations due to potential for severe adverse reactions. This review highlights the current understanding and management of patients with autoimmune and viral hepatitis immune in the setting of immune checkpoint inhibitor (ICI) therapy. A literature search was conducted on PubMed, Scopus, Google Scholar SEER*Stat databases (from inception to December 2022) using search terms: "immune checkpoint inhibitor", "autoimmune hepatitis", "viral hepatitis", "HBV pathogenesis", "HCV pathogenesis", "HBV reactivation", "HCV reactivation", "cancer immunotherapy", "immune related adverse events", "immune related hepatitis". Pre-existing autoimmune disease (AD), whether active or inactive, can predispose patients receiving ICI therapy to develop autoimmune disease flares or immune-related adverse events (irAEs). Thus, patients with AD have routinely been excluded from clinical trials and data on safety of ICI therapy are limited. Hepatic irAE can be seen in ICI therapy and is a distinct entity from autoimmune hepatitis (AIH). ICI therapy alters the immune environment in patients with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. Patients who had prior exposure to HBV are at risk for viral reactivation. However, the prevalence of viral hepatitis in patients receiving immunotherapy is underrecognized and can lead to increases in liver biochemical tests as well as deterioration of liver function ultimately limiting treatment. The high morbidity and mortality associated with immune-related hepatitis emphasizes the need for screening of underlying diseases, including autoimmune and viral hepatitis, prior to initiation of ICI. Presence of AIH or chronic viral hepatitis is the most important risk factor for hepatic adverse events in ICI therapy. Screening for AIH, HBV and HCV is paramount in patients who will undergo ICI therapy.

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.

Safety and effectiveness of combination versus monotherapy with immune checkpoint inhibitors in patients with preexisting autoimmune diseases

ABSTRACT Patients with preexisting autoimmune disease (pAID) are generally excluded from clinical trials for immune checkpoint inhibitors (ICIs) for cancer due to concern of flaring pAID. In this multi-center, retrospective observational study, we compared safety of ICI combination (two ICI agents) versus monotherapy in cancer patients with pAIDs. The primary outcome was time to AEs (immune-related adverse events (irAEs) and/or pAID flares), with progression-free survival (PFS) and overall survival as secondary outcomes. Sixty-four of 133 patients (48%) received ICI combination and 69 (52%) monotherapy. Most had melanoma (32%) and lung cancer (31%). Most common pAIDs were rheumatic (28%) and dermatologic (23%). Over a median follow-up of 15 months (95%CI, 11-18 mo), the cumulative incidence of any-grade irAEs was higher for combination compared to monotherapy (subdistribution hazard ratio (sHR) 2.27, 95%CI 1.35–3.82). No statistically significant difference was observed in high-grade irAEs (sHR 2.31 (0.95–5.66), P = .054) or the cumulative incidence of pAID flares. There was no statistically significant difference for melanoma PFS between combination versus monotherapy (23.2 vs. 17.1mo, P = .53). The combination group was more likely to discontinue or hold ICI, but > 50% of the combination group was still able to continue ICI therapy. No treatment-related deaths occurred. In our cohort with pAIDs, patients had a tolerable toxicity profile with ICI combination therapy. Our results support the use of ICI combination if deemed necessary for cancer therapy in patients with pAIDs, since the ICI toxicities were comparable to monotherapy, able to be effectively managed and mostly did not require ICI interruption.

Immunoglobulin G4-Related Lesions in Autoimmune Diseases: Unusual Presentations at Atypical Sites-A Tale of 2 Cases with Literature Review.

Immunoglobulin G4-related disease (IgG4-RD) coexisting with clinically apparent autoimmune diseases, such as rheumatoid arthritis (RA) or antiphospholipid syndrome (APS), is a rarely documented combination in the scientific literature. In this case-based review, we present 2 intriguing cases with preexisting autoimmune diseases, namely, RA and primary APS, who exhibited coexistent IgG4- related lesions at unusual sites. The first case pertains to a patient with known RA who presented with an encasing mass in the esophagus leading to stricture, with histopathological diagnosis of IgG4-RD.The second patient, diagnosed with primary APS, experienced breathlessness, and imaging revealed a right atrial mass. Histopathological examination of the mass confirmed IgG4-RD. Notably, both patients demonstrated significant clinical improvement upon initiation of steroid therapy. Rheumatoid arthritis patients commonly exhibit elevated levels of IgG4 in their sera; however, RA with coexisting IgG4-RD is rarely reported in the literature. Similarly, APS with IgG4-related lesions is exceedingly rare. Although there are few case reports and series on esophageal and cardiac IgG4-RD, the occurrence of such unusual location of IgG4-related lesions in the context of known autoimmunity is presented here for the first time.

Immune Checkpoint Inhibitors in Patients with Pre-existing Neurologic Autoimmune Disorders.

The use of immune checkpoint inhibitors (ICIs) for oncologic indications is associated with immune-related adverse events (irAEs). Patients with pre-existing autoimmune diseases are at increased risk of irAEs and have largely been excluded from clinical trials of ICIs. Therefore, there is limited data on the safety of safety of ICIs in patients with pre-existing neurologic autoimmune diseases (nAIDs) such as myasthenia gravis and multiple sclerosis. This review aims to synthesize the literature on the post-marketing experience with ICI in patients with pre-existing nAID and to discuss possible strategies for mitigating the risk of post-ICI nAID relapses. Patients with pre-existing myasthenia gravis (MG), myositis, and paraneoplastic encephalitis appear highly susceptible to neurologic relapses of their underlying neurologic disorder following ICI initiation; these relapses can cause considerable morbidity and mortality. In patients with multiple sclerosis (MS), the risk and severity of MS relapses following ICI appears to be relatively lower compared to MG. Preliminary evidence suggests that older MS patients with no recent focal neuroinflammatory activity may be safely treated with ICI. Among the several case reports of ICI in patients with a history of Guillain-Barre syndrome (GBS), neurologic worsening was only recorded in one patient who was in the acute phase of GBS at the time of ICI start. Initiating an ICI in a patient with pre-existing nAID involves a complex risk-benefit discussion between the patient, their oncologist, and neurologist. Relevant issues to consider before ICI include the choice of disease-modifying therapy for nAID (if any) and strategies for promptly identifying and managing nAID relapses should they occur. Currently, the literature consists mainly of case reports and case series, subject to publication bias. Prospective studies of ICI in patients with nAID are needed to improve the level of evidence.

Single-cell multi-omics analysis of COVID-19 patients with pre-existing autoimmune diseases shows aberrant immune responses to infection.

In COVID-19, hyperinflammatory and dysregulated immune responses contribute to severity. Patients with pre-existing autoimmune conditions can therefore be at increased risk of severe COVID-19 and/or associated sequelae, yet SARS-CoV-2 infection in this group has been little studied. Here, we performed single-cell analysis of peripheral blood mononuclear cells from patients with three major autoimmune diseases (rheumatoid arthritis, psoriasis, or multiple sclerosis) during SARS-CoV-2 infection. We observed compositional differences between the autoimmune disease groups coupled with altered patterns of gene expression, transcription factor activity, and cell-cell communication that substantially shape the immune response under SARS-CoV-2 infection. While enrichment of HLA-DRlow CD14+ monocytes was observed in all three autoimmune disease groups, type-I interferon signaling as well as inflammatory T cell and monocyte responses varied widely between the three groups of patients. Our results reveal disturbed immune responses to SARS-CoV-2 in patients with pre-existing autoimmunity, highlighting important considerations for disease treatment and follow-up.

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

FRI508 A Case Of Durvalumab Induced Hypothyroidism

Abstract Disclosure: E.D. Cecilio La Riva: None. C. Acosta: None. A.J. Manzano: None. Background: Immune checkpoint inhibitors (ICIs), like Durvalumab, have become a mainstay in cancer treatment as they have significantly improved survival rates, especially for lung cancer. These treatments, however, have been associated with immune-related adverse events (irAEs) including dermatological manifestations, gastrointestinal symptoms, and endocrinopathies. Clinical Case: A 62-year-old male was diagnosed with a poorly differentiated adenocarcinoma with signet ring cell features stage IIIA of the right upper lobe with concurrent prostate cancer who was initially started on chemotherapy with Cisplatin/Pemetrexed for two months (four cycles) and radiation. He was subsequently started on Durvalumab. Thyroid function tests were performed after starting Durvalumab and TSH was 3.46 mlU/L (reference range: 0.40-4.50), Free T4 was 1.2 ng/dL (reference range: 0.8-1.8) and Free T3 was mildly elevated at 4.3 pg/mL (reference range: 2.3-4.2). The patient remained asymptomatic until about 12 weeks later when he began feeling occasional episodes of anxiety and shortness of breath with fatigue that was brought on at random instances. Thyroid function tests at that time showed an undetectable TSH at <0.01, an elevated free T3 at 4.9, and a normal free T4 at 1.6. Immunotherapy was continued and the patient was referred to endocrinology. Repeat thyroid function tests 8 weeks later showed an elevated TSH at 19.55, decreased free T4 at 0.7, and a normal free T3 at 3.1. The patient was started on levothyroxine at that time with improvement of his symptoms. Upon follow-up 4 weeks later, TSH was found at 30.56 and free T4 at 0.9 which improved with levothyroxine dose adjustment. Conclusion: The case of a patient with thyroiditis beginning as transient hyperthyroidism on Durvalumab is described. Hypothyroidism occurs in about 1.82% of patients on ICIs, with more common occurrences on Nivolumab (51.38%) and Pembrolizumab (24.44%). The incidence of hypothyroidism and thyroiditis on Durvalumab is about 3.11% and 2.04% respectively. Thyroid dysfunction with ICIs occurs with PD-1/PD-L1 blockade and an inflammatory, destructive thyroiditis can be seen. Routine monitoring of thyroid function should be performed before and throughout treatment with an ICIs. Preexisting autoimmune thyroid disease may be a risk factor for developing thyroid disease during treatment, but this has not been well studied. Meta-analysis has shown that preexisting autoimmune disease was a risk factor for irAE incidence. This case highlights the importance of proactive monitoring of thyroid function during treatment. Presentation: Friday, June 16, 2023

Refined control of CRISPR-Cas9 gene editing in Clostridium sporogenes: the creation of recombinant strains for therapeutic applications.

Despite considerable clinical success, the potential of cancer immunotherapy is restricted by a lack of tumour-targeting strategies. Treatment requires systemic delivery of cytokines or antibodies at high levels to achieve clinically effective doses at malignant sites. This is exacerbated by poor penetration of tumour tissue by therapeutic antibodies. High-grade immune-related adverse events (irAEs) occur in a significant number of patients (5-15%, cancer- and therapeutic-dependent) that can lead to lifelong issues and can exclude from treatment patients with pre-existing autoimmune diseases. Tumour-homing bacteria, genetically engineered to produce therapeutics, is one of the approaches that seeks to mitigate these drawbacks. The ability of Clostridium sporogenes to form spores that are unable to germinate in the presence of oxygen (typical of healthy tissue) offers a unique advantage over other vectors. However, the limited utility of existing gene editing tools hinders the development of therapeutic strains. To overcome the limitations of previous systems, expression of the Cas9 protein and the gRNA was controlled using tetracycline inducible promoters. Furthermore, the components of the system were divided across two plasmids, improving the efficiency of cloning and conjugation. Genome integrated therapeutic genes were assayed biochemically and in cell-based functional assays. The potency of these strains was further improved through rationally-conceived gene knock-outs. The new system was validated by demonstrating the efficient addition and deletion of large sequences from the genome. This included the creation of recombinant strains expressing two pro-inflammatory cytokines, interleukin-2 (IL-2) and granulocyte macrophage-colony stimulating factor (GM-CSF), and a pro-drug converting enzyme (PCE). A comparative, temporal in vitro analysis of the integrant strains and their plasmid-based equivalents revealed a substantial reduction of cytokine activity in chromosome-based constructs. To compensate for this loss, a 7.6 kb operon of proteolytic genes was deleted from the genome. The resultant knock-out strains showed an 8- to 10-fold increase in cytokine activity compared to parental strains.

Maladies auto-immunes et immunothérapies: Autoimmune diseases and immunotherapies

Immune checkpoint inhibitors are today an essential therapy for the management of primary lung cancer. These monoclonal antibodies nevertheless expose patients to immune-related adverse events. Do patients with preexisting autoimmune disease derive the same benefit from immunotherapy as others? Are they more at risk of toxicity? What is the risk of flare of their underlying autoimmune disease? The aim of this article is to synthesize the data available in the literature on the use of immune checkpoint inhibitors in patients with both lung cancer and autoimmune disease.1877-1203/© 2023 SPLF. Published by Elsevier Masson SAS. All rights reserved.

P18 Bullous leukocytoclastic vasculitis in a patient with known undifferentiated autoimmune rheumatic disease

P18 Bullous leukocytoclastic vasculitis in a patient with known undifferentiated autoimmune rheumatic disease