Pre-existing Autoimmunity Research Articles

TIGIT acts as an immune checkpoint upon inhibition of PD1 signaling in autoimmune diabetes.

Chronic activation of self-reactive T cells with beta cell antigens results in the upregulation of immune checkpoint molecules that keep self-reactive T cells under control and delay beta cell destruction in autoimmune diabetes. Inhibiting PD1/PD-L1 signaling results in autoimmune diabetes in mice and humans with pre-existing autoimmunity against beta cells. However, it is not known if other immune checkpoint molecules, such as TIGIT, can also negatively regulate self-reactive T cells. TIGIT negatively regulates the CD226 costimulatory pathway, T-cell receptor (TCR) signaling, and hence T-cell function. The phenotype and function of TIGIT expressing islet infiltrating T cells was studied in non-obese diabetic (NOD) mice using flow cytometry and single cell RNA sequencing. To determine if TIGIT restrains self-reactive T cells, we used a TIGIT blocking antibody alone or in combination with anti-PDL1 antibody. We show that TIGIT is highly expressed on activated islet infiltrating T cells in NOD mice. We identified a subset of stem-like memory CD8+ T cells expressing multiple immune checkpoints including TIGIT, PD1 and the transcription factor EOMES, which is linked to dysfunctional CD8+ T cells. A known ligand for TIGIT, CD155 was expressed on beta cells and islet infiltrating dendritic cells. However, despite TIGIT and its ligand being expressed, islet infiltrating PD1+TIGIT+CD8+ T cells were functional. Inhibiting TIGIT in NOD mice did not result in exacerbated autoimmune diabetes while inhibiting PD1-PDL1 resulted in rapid autoimmune diabetes, indicating that TIGIT does not restrain islet infiltrating T cells in autoimmune diabetes to the same degree as PD1. Partial inhibition of PD1-PDL1 in combination with TIGIT inhibition resulted in rapid diabetes in NOD mice. These results suggest that TIGIT and PD1 act in synergy as immune checkpoints when PD1 signaling is partially impaired. Beta cell specific stem-like memory T cells retain their functionality despite expressing multiple immune checkpoints and TIGIT is below PD1 in the hierarchy of immune checkpoints in autoimmune diabetes.

Risk of severe immune-related adverse events in cancer patients with pre-existing autoimmunity receiving immune checkpoint inhibitor therapy.

To evaluate the frequency and severity of irAEs in patients with pre-existing autoimmunity, including irAE-related morbidity and mortality, irAE-related management and resolution, and outcome of ICI rechallenge, to better understand the treatment options for this vulnerable patient population. We designed a retrospective, single-center, case-control study at a large, academic medical center to evaluate the incidence and severity of irAEs in patients with pre-existing autoimmunity compared to controls. Controls were matched 2:1 for age, sex, cancer histology, and ICI class. Patients were identified with ICD 9 and 10 codes followed by manual chart extraction. Cases were defined as patients with pre-existing, systemic autoimmunity. The primary outcome was severe irAE (Grade 3 or higher by Common Terminology Criteria for Adverse Events) within 6 months of ICI therapy. Secondary outcomes included response to ICIs, resolution of the irAE, ICI rechallenge success, and survival. Statistical analyses were performed by Chi-square, Fishers exact, Mann-Whitney, and Log-rank tests. Of 3,130 patients treated with ICIs from 2015-2021, 28 cases with pre-existing autoimmune disease were identified and were matched with 56 controls. Pre-existing autoimmune conditions included antiphospholipid syndrome, inflammatory polyarthritis, juvenile rheumatoid arthritis, multiple sclerosis, psoriatic arthritis, rheumatoid arthritis, and type I diabetes. Multiple cancer histologies, including genitourinary, gynecologic, head & neck, hepatobiliary, lung, melanoma, and pancreatic, were represented. Six of 28 cases (21.4%) experienced severe irAEs compared to 9/56 (16.1%) controls; the odds of developing a severe irAE were not significantly different (OR 0.43, 95% CI 0.083-2.33, p = 0.627, ns). Moreover, there were no significant differences in overall survival or tumor response between the two groups. The majority of irAEs resolved without long-term sequelae (66.7% of cases, 55.6% of controls). The majority of patients who were rechallenged with ICIs were successful in continuing therapy (66.7% of cases, 100% of controls). Our study suggests that patients with pre-existing autoimmune disease can be treated with ICI cancer therapies and experience rates of severe irAEs and overall survival that are similar to those of the general population. These data can aid oncologists in discussing risks and benefits of ICIs when treating patients with pre-existing autoimmunity and solid tumors.

TCDD and CH223191 Alter T Cell Balance but Fail to Induce Anti-Inflammatory Response in Adult Lupus Mice.

Aryl hydrocarbon receptor (AhR) responds to endogenous and exogenous ligands as a cytosolic receptor, transcription factor, and E3 ubiquitin ligase. Several studies support an anti-inflammatory effect of AhR activation. However, exposure to the AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during early stages of development results in an autoimmune phenotype and exacerbates lupus. The effects of TCDD on lupus in adults with pre-existing autoimmunity have not been described. We present novel evidence that AhR stimulation by TCDD alters T cell responses but fails to impact lupus-like disease using an adult mouse model. Interestingly, AhR antagonist CH223191 also changed T cell balance in our model. We next developed a conceptual framework for identifying cellular and molecular factors that contribute to physiological outcomes in lupus and created models that describe cytokine dynamics that were fed into a system of differential equations to predict the kinetics of T follicular helper (Tfh) and regulatory T (Treg) cell populations. The model predicted that Tfh cells expanded to larger values following TCDD exposure compared with vehicle and CH223191. Following the initial elevation, both Tfh and Treg cell populations continuously decayed over time. A function based on the ratio of predicted Treg/Tfh cells showed that Treg cells exceed Tfh cells in all groups, with TCDD and CH223191 showing lower Treg/Tfh cell ratios than the vehicle and that the ratio is relatively constant over time. We conclude that AhR ligands did not induce an anti-inflammatory response to attenuate autoimmunity in adult lupus mice. This study challenges the dogma that TCDD supports an immunosuppressive phenotype.

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.

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.

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

Impact of preexisting autoimmune disease on myelodysplastic syndromes outcomes: a population analysis

AbstractPreexisting autoimmune disease affects between 10% and 30% of patients with myelodysplastic syndromes (MDS). Studies comparing outcomes in patients with MDS with and without autoimmune disease show discordant results. Using the Surveillance, Epidemiology, and End Results Medicare database, we conducted a population analysis to define the impact of autoimmunity on MDS outcomes. Cases were ascertained between 2007 and 2017 and claim algorithms used to identify autoimmune disease, demographic characteristics, comorbidity scores, MDS histology, transfusion burden, treatment with hypomethylating agents, and hematopoietic stem cell transplantation. Cox regression models estimated the impact on survival, and competing-risk regression models defined the effect on leukemic transformation. We analyzed 15 277 patients with MDS, including 2442 (16%) with preexisting autoimmune disease. The epidemiologic profile was distinctive in cases with preexisting autoimmunity, who were younger, were predominantly female, and had higher transfusion burden without difference in MDS histologic distribution. Autoimmune disease was associated with 11% decreased risk of death (hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.85-0.94; P < .001). The effect on risk of leukemic transformation differed based on MDS histology. In low-risk MDS histologies, autoimmunity was associated with a 1.9-fold increased risk of leukemia (HR, 1.87; 95% CI, 1.17-2.99; P = .008), whereas no significant effect was seen in other groups. These results suggest that autoimmune disease affects survival in MDS and is associated with decreased mortality. The survival effect was evident in low-risk histologies despite higher risk of progression to leukemia. This could represent inflammation-driven hematopoiesis, simultaneously favoring less aggressive phenotypes and clonal expansion, which warrants further investigation.

Morphea, Eosinophilic Fasciitis and Cancer: A Scoping Review.

Morphea is an autoimmune fibrotic skin disease. Eosinophilic fasciitis (EF) is considered to belong to the severe spectrum of morphea. We conducted a scoping review assessing the risk of secondary cancer among morphea/EF patients, paraneoplastic morphea/EF and morphea/EF developing secondary to cancer therapy. The search was conducted using MEDLINE, Embase, Cochrane databases for articles published from inception to September 2022 following the Preferred Reporting Items for Systematic reviews and Meta-Analyses for Scoping Reviews (PRISMA-ScR) guidelines with no language or date restrictions. Two hundred and one studies were included. Of these, 32 studies reported on secondary cancer in morphea/EF patients, 45 on paraneoplastic morphea/EF and 125 on cancer-treatment-induced morphea/EF. While the current evidence remains limited, data suggest an increased risk of secondary cutaneous and possibly pancreatic malignancy in morphea patients, particularly the generalized subtype. There were insufficient data for EF. On the other hand, paraneoplastic morphea was anecdotal, whereas several observational studies suggested that ~10% of EF cases may be paraneoplastic, primarily in the context of hematologic malignancies. Radiotherapy-induced morphea is rare, seen in ~0.2% of treated patients and is usually localized to the treatment site, except in patients with pre-existing autoimmunity. While chemotherapy-induced cases are reported, immunotherapy morphea/EF cases are emerging and are preferentially seen with PD-1 and not CTLA-4 inhibitors. This study is limited by the type of articles included (case reports, case series and observational studies), and hence, additional research on this important topic is needed.

Learning Needs of Patients with Cancer and a Pre-Existing Autoimmune Disease Who Are Candidates to Receive Immune Checkpoint Inhibitors.

Patients with pre-existing autoimmune disorders and cancer considering immune checkpoint inhibitors (ICIs) need to receive balanced information about the benefits and risk of developing immune-related adverse events (irAEs) and flare-ups of their autoimmune disease. To assess the learning needs of patients with cancer and pre-existing autoimmune disease regarding ICI treatment, we interviewed 29 patients with autoimmune disease and cancer from a comprehensive cancer center, of whom 20 had received ICI and 9 were candidates to receive ICI at a US Cancer Center. In-depth semi-structured interviews were conducted from August 2021 and January 2022. Interviewee's opinions and preferences about content and information delivery methods were collected. We recorded and transcribed interviews and analyzed them using thematic analysis. Half of the participants were female, and their median (SD) age was 62.9 (±10.9) years. The identified health information needs included the following: (1) information on irAEs and autoimmune disease flare-ups; (2) benefits of ICI; (3) ICI mechanism in the context of autoimmune disease; (4) management of flare-ups; (5) reasons for stopping or modifying cancer or autoimmune disease treatment; (6) likelihood of autoimmune disease progression or organ damage; and (7) lifestyle changes that could help avoid irAEs. Patients who had received ICI and those who had not yet received treatment reported similar needs, although patients who had received ICI had more questions about cancer treatment modifications. Patients also expressed the need to better understand when to contact their provider and how to share information with multiple providers. Most patients wanted to receive information in visual formats for review at home and at their own pace. Patients expressed interest in having educational tools to facilitate shared decision-making with their physicians, and they identified several areas of health information concerning therapy with ICI. They also highlighted the importance of communication among their various providers.

Are severe immune-related adverse events more likely in patients with pre-existing autoimmune disease?

e14599 Background: Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that activate the immune system to treat malignancy. As a consequence of this activation, ICIs may cause autoimmunity in healthy tissues, termed “immune-related Adverse Events” (irAEs). The literature reports a wide range in irAE incidence (10-80%), with a higher incidence in patients exposed to combination therapy. ICI treatment of patients with pre-existing autoimmune disease presents a dilemma for oncologists because of concern that immune activation will lead to more frequent or severe irAEs. As a result, these patients have been excluded from ICI clinical trials. Prior studies suggested that approximately 40% of patients with pre-existing autoimmune disease experience an autoimmune exacerbation during ICI treatment, but more data are needed on the incidence and severity of irAEs in other tissues. Methods: This retrospective case-control study included adult patients who received an FDA-approved ICI for treatment of a solid malignancy (excluding non-melanoma skin cancer) from 2015-2021 at an academic medical center. Cases were patients with pre-existing autoimmune disease. Controls without pre-existing autoimmunity were matched 2:1 based on age, sex, ICI class, and cancer type. Severe IrAEs were defined as grade three or higher by CTCAE definitions and occurring after ICI exposure. ICD-9 and 10 codes were used to identify patients with subsequent data extraction by manual chart review. Results: Of 3,130 adult cancer patients treated with ICIs, 28 cases were identified with pre-existing autoimmune disease: antiphospholipid syndrome (n=1), inflammatory polyarthritis (n=3), juvenile arthritis (n=1), multiple sclerosis (n=3), psoriatic arthritis (n=3), rheumatoid arthritis (n=14), and type I diabetes (n=3). Six out of 28 cases (21.4%) developed severe irAEs, including three (50%) who received anti-PD1/PDL1 monotherapy and three (50%) who received ICI combination therapy. One case experienced a grade five irAE (death) attributed to ICI-colitis; the remaining five patients (83.3%) successfully recovered with suspension of ICI therapy and treatment with immunosuppressive medications. By comparison, 9/56 (16.1%) controls developed severe irAEs. The odds of developing a severe irAE were not significantly different in patients with pre-existing autoimmunity compared to controls (OR 1.42, 95% CI 0.42-4.68, p=ns). Subgroup analysis of 23 cases and 46 controls treated with anti-PD1/PDL1 monotherapy also found no difference in the odds of severe irAE development (OR 0.84, 0.22-3.70, p=ns). Conclusions: Our data suggest that the majority of solid tumor patients with pre-existing autoimmune disease can safely receive ICI monotherapy and combination therapy. Severe (grade 3 or higher) irAEs were infrequent, often treatable, and did not occur more frequently than in patients without pre-existing autoimmunity.

Baseline autoantibody profiling in patients with NSCLC with pre-existing autoimmune diseases or who had received prior anti-PD-1 therapy before enrolling in the TAIL study.

2512 Background: Patients (pts) with pre-existing autoimmune diseases (AID) and prior immune checkpoint inhibitor (ICI) experience were historically excluded from studies with ICIs. Moreover, about 50% pts with pre-existing autoimmunity have a flare up when given ICI therapies (1). In this post-hoc exploratory analysis, we characterized the baseline autoantibody (AAb) profiles and evaluated its correlation with efficacy and safety outcomes in NSCLC pts with either pre-existing AID or who had prior ICI therapy and received atezolizumab in the TAIL study (2). Methods: Plasma samples were obtained from 57 NSCLC pts prior to receiving atezolizumab (TAIL study, NCT03285763). AAb testing was performed using tailored immuno-oncology bead-based antigen arrays comprising 1,340 tumor, AID and immune pathway antigens (3, 4). The cohort includes 39 pts with prior ICI therapy or prior AID (experimental group) and 18 pts without prior ICI therapy or AID (control group). Differences in IgG AAbs were compared between the experimental and control group in pts with or w/o irAE and overall survival (OS) longer or shorter than 11.1 months (median OS in overall population in TAIL). Furthermore, the AAb profiles of a subgroup of pts with therapeutic benefit (OS ≥ 11.1 months) and no or low grade irAEs (standard toxicity grade ≤ 2) were analyzed. Statistical analysis included 2-way permutation-based ANOVA (factors: outcome, study group) and Significance Analysis of Microarrays (SAM). Results: While pre-treatment AAbs were detected in the overall cohort, significant differences in AAb were observed between the experimental and control group at baseline, which were associated with OS and irAEs. In experimental group pts, pre-existing AAbs to AQP4 and NCOA1 predicted the development of irAEs. Differences were also observed in AAbs predicting longer OS. AAbs to CENPT were specifically identified in pts in the experimental group with longer OS, whereas AAbs to SOX5 were elevated in pts of the control group with longer OS. In the subgroup of pts with therapeutic benefit and no or low risk of irAE, AAbs to IL6, CENPT and the cancer testis antigens NY-ESO-2 and MAGEB2 were elevated in the experimental group. Conclusions: This AAb analysis provides important preliminary data in helping to understand the drivers of clinical outcomes with ICIs in pts with pre-existing AID and prior ICI therapy. The findings seem biologically plausible as some of the identified antigens refer to the breach of tolerance to classical AAb targets e.g. CENPT, AQP4 and to an immune response to classic tumor antigens e.g. NY-ESO-2 and MAGEB2. Further validation of the AAb profiling approach is warranted to shed insights on potential therapeutically actionable antigens and generate data orthogonal to efforts to identify biomarkers that are predictive of efficacy and safety outcomes with ICI therapies.

Physician Views on the Provision of Information on Immune Checkpoint Inhibitor Therapy to Patients with Cancer and Pre-Existing Autoimmune Disease: A Qualitative Study.

Immune checkpoint inhibitors (ICIs) have improved cancer outcomes but can cause severe immune-related adverse events (irAEs) and flares of autoimmune conditions in cancer patients with pre-existing autoimmune disease. The objective of this study was to identify the information physicians perceived as most useful for these patients when discussing treatment initiation with ICIs. Twenty physicians at a cancer institution with experience in the treatment of irAEs were interviewed. Qualitative thematic analysis was performed to organize and interpret data. The physicians were 11 medical oncologists and 9 non-oncology specialists. The following themes were identified: (1) current methods used by physicians to provide information to patients and delivery options; (2) factors to make decisions about whether or not to start ICIs in patients who have cancer and pre-existing autoimmune conditions; (3) learning points for patients to understand; (4) preferences for the delivery of ICI information; and (5) barriers to the implementation of ICI information in clinics. Regarding points to discuss with patients, physicians agreed that the benefits of ICIs, the probability of irAEs, and risks of underlying autoimmune condition flares with the use of ICIs were most important. Non-oncologists were additionally concerned about how ICIs affect the autoimmune disease (e.g., impact on disease activity, need for changes in medications for the autoimmune disease, and monitoring of autoimmune conditions).

Iatrogenic endocrine complications of lithium therapy

Lithium is a cation, similar to sodium and potassium, affecting ion transport. It is used in the medical field as a treatment of bipolar disorders. The main endocrine complications of lithium treatment affect thyroid and parathyroid glands, in association with renal complications. Thyroid adverse effects, which are more frequent in women, comprise hypothyroidism, goiter, or sometimes hyperthyroidism, through interference with the iodine symporter. The increase in thyroid volume is early. Prevalence of goiter is 4 times higher than in the general population and hypothyroidism (8–20%) more frequent in case of pre-existing thyroid autoimmunity. Hyperthyroidism likely to worsen mood is reported in 5% of cases but the causal link to lithium is unproven. An increase in serum calcium and PTH occurs in 30% of cases, as lithium stimulates parathyroid cell proliferation by activating the Wnt pathway. The risk of hyperparathyroidism, by adenoma and especially by hyperplasia, is 5 times higher than in the general population, with the particularity of frequent low urine calcium by action on the calcium-sensing receptor (CaSR). Renal complications include risk of acute or chronic renal failure and nephrogenic diabetes insipidus, which is a factor for hypernatremia and hypercalcemia through dehydration. Nephrogenic diabetes insipidus is not always reversible after lithium therapy discontinuation. Metabolically, weight gain can be observed, but rather less than with other psychotropic drugs, and lithium does not in itself induce diabetes. At pituitary level, corticotropic activation is frequent, but implicating the disease rather than lithium. Lithium treatment induces little or no hyperprolactinemia. Regular monitoring of serum calcium, the ionogram, creatinine and TSH is recommended in lithium treatment.

Pre-existing autoimmunity is associated with increased severity of COVID-19: A retrospective cohort study using data from the National COVID Cohort Collaborative (N3C)

Pre-existing autoimmunity is associated with increased severity of COVID-19: A retrospective cohort study using data from the National COVID Cohort Collaborative (N3C)

Pre-Existing Autoimmune Disease Increases the Risk of Cardiovascular and Noncardiovascular Events After Immunotherapy

BackgroundThe use of immune checkpoint inhibitors (ICI) is associated with cardiovascular (CV) events, and patients with pre-existing autoimmune disease are at increased CV risk. ObjectivesThe aim of this study was to characterize the risk for CV events in patients with pre-existing autoimmune disease post-ICI. MethodsThis was a retrospective study of 6,683 patients treated with ICIs within an academic network. Autoimmune disease prior to ICI was confirmed by chart review. Baseline characteristics and risk for CV and non-CV immune-related adverse events were compared with a matched control group (1:1 ratio) of ICI patients without autoimmune disease. Matching was based on age, sex, history of coronary artery disease, history of heart failure, and diabetes mellitus. CV events were a composite of myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft, stroke, transient ischemic attack, deep venous thrombosis, pulmonary embolism, or myocarditis. Univariable and multivariable Cox proportional hazards models were used to determine the association between autoimmune disease and CV events. ResultsAmong 502 patients treated with ICIs, 251 patients with and 251 patients without autoimmune disease were studied. During a median follow-up period of 205 days, there were 45 CV events among patients with autoimmune disease and 22 CV events among control subjects (adjusted HR: 1.77; 95% CI: 1.04-3.03; P = 0.0364). Of the non-CV immune-related adverse events, there were increased rates of psoriasis (11.2% vs 0.4%; P < 0.001) and colitis (24.3% vs 16.7%; P = 0.045) in patients with autoimmune disease. ConclusionsPatients with autoimmune disease have an increased risk for CV and non-CV events post-ICI.

Plasma Exchange for Immune-Related Adverse Events Due to Immune Checkpoint Inhibitor Therapy: Implications for Clinical Care and Clinical Trial Design

Therapeutic plasma exchange (TPE) is increasingly utilized for Grade 3-4 immunotherapy adverse events (irAEs) to accelerate elimination of drug, autoantibodies, and cytokines. Immune checkpoint inhibitors (ICI) are IgG1 or IgG4 constructs with long half-lives (t1/2) and volume of distributions (Vd) favorable for clearance by apheresis. As drug levels are not readily available, the number of sessions needed to eliminate ICIs is estimated based on the interval from last drug dose, drug Vd, and drug t1/2. Increased use of TPE is anticipated as ICIs are now given despite preexisting autoimmunity, prior organ transplantation, and/or prior irAEs. TPE protocols are well established for the management of diseases that can also present as irAEs [e.g. thrombotic thrombocytopenic purpura (TTP), chronic inflammatory demyelinating polyneuropathy (CIDP), myasthenia gravis (MG), hemophagocytic lymphohistiocytosis (HLH)] and for drug removal (e.g. natalizumab). While TPE is included in irAE management guidelines as second line therapy or later (Brahmer JR, et al, J Immunother Cancer, 2021 PMID: 34172516), no randomized controlled trial (RCT) data are available. TPE can reduce the level of clinical biomarkers for irAE monitoring: creatinine kinase (CK), aspartate aminotransferase (AST), alanine aminotransferase (ALT),fibrinogen, platelet count, ferritin. We treated 4 adults (median age 66 years, range 65-77 years) with TPE for steroid-refractory irAEs [myositis (2), myocarditis (1)] and, as part of initial therapy, in combination with dexamethasone and anakinra, for ICI-associated HLH. ICI constructs were IgG1 anti-PD-L1 (envafolimab, durvalumab) and IgG4 anti-PD-1 (nivolumab, cemiplimab). Data collection was IRB approved and with patient written consent. ICI indications were sarcoma, thymic carcinoma, cutaneous squamous cell carcinoma (SCC), and lung SCC. Only one patient (HLH irAE) had preexisting autoimmunity (thyroiditis). Median time from last ICI dose to first irAE symptoms or signs was 16 days (range 5-29 days). Three of 4 patients developed irAE after the first ICI dose. One patient (myocarditis) required full systemic anticoagulation (heparin, then enoxaparin) for atrial fibrillation and deep venous thrombosis, and dual antiplatelet therapy (DAPT) for a new coronary stent. The two myositis patients received prophylactic enoxaparin. All TPE sessions were one plasma volume exchange through central venous access, utilized Anticoagulant Citrate Dextrose Solution A (ACDA), and scheduled daily or every other day. Number of sessions ranged from 2-4. Except for the patient with HLH, TPE was initiated with 5% albumin replacement. Fibrinogen levels and estimated bleeding risk guided the need for fresh frozen plasma (FFP) replacement. Session intervals, exchange fluid, transfusion, biomarkers, changes in fibrinogen and platelet count, anticoagulation, and functional response are detailed in Table 1. Three of 4 patients, who had normal baseline fibrinogen and platelet counts, experienced clinically significant hypofibrinogenemia resulting in discontinuation of chemical DVT prophylaxis and/or cryoprecipitate transfusion, but did not have clinically significant thrombocytopenia. The fourth patient (HLH) required ongoing transfusion support due to pre-TPE hypofibrinogenemia and thrombocytopenia. TPE confounded interpretation of biomarkers in all. All irAEs demonstrated prompt clinical improvement, however, due to rapid corticosteroid tapers, 2 patients (myositis, HLH) relapsed within 1 month from last TPE. Both responded to additional immunosuppression. One patient (myositis) did not relapse. Grade 4 bleeding occurred in the patient receiving enoxaparin and DAPT and led to discontinuation of TPE after 2 sessions. Our experience supports the following when considering TPE for irAEs: 1) exclusion of patients with high bleeding risk, or use of 100% FFP replacement and every other day TPE; 2) meticulous non-biomarker irAE assessment during and after TPE; 3) RCT design includes irAE relapse timing and rates and long term follow-up to assess cumulative immunosuppression and tumor outcome; 4) serial drug levels and correlative studies (e.g. cytokines, autoantibodies) to better understand TPE mechanisms, persistence of irAEs, and long term ICI anti-tumor benefit. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

LBODP093 Evaluation Of The Impact Of Covid-19 Vaccines On Thyroid Function And Autoimmunity And The Potential Influence Of Pre-existing Thyroid Autoimmunity On Neutralizing Antibody Responses

Abstract Objectives There are concerns for COVID-19 vaccination in causing thyroid dysfunction and triggering thyroid autoimmunity. Also, data on the impact of pre-existing thyroid autoimmunity on COVID-19 vaccination efficacy are limited. We evaluated the impact of COVID-19 vaccination on thyroid function and antibodies, and the influence of pre-existing thyroid autoimmunity on neutralizing antibody (NAb) responses. Methods Adults without history of COVID-19 or thyroid disorders who received COVID-19 vaccination between 14 June 2021 and 8 August 2021 at three vaccination centers were recruited. All participants received two doses of vaccines. Thyroid-stimulating hormone (TSH), free thyroxine (fT4), free triiodothyronine (fT3), anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-Tg) antibodies were measured at baseline and 8 weeks after the first dose of vaccination. Post-vaccination NAb against SARS-CoV-2 receptor-binding domain was measured. Results In total, 215 individuals were included (129 BNT162b2 [60%] and 86 CoronaVac [40%] recipients): mean age 49.6 years, 37.2% men, and 12.1% positive for anti-TPO/anti-Tg at baseline. After vaccination, TSH levels did not change (p=0.225), but fT4 slightly increased (from 12. 0±1.1 to 12.2±1.2 pmol/L, p&amp;lt;0. 001) and fT3 slightly decreased (from 4.1±0.4 to 4. 0±0.4 pmol/L, p&amp;lt;0. 001). Only 3 patients (1.4%) had abnormal thyroid function after vaccination: two occurred among BNT162b2 recipients - both were subclinical thyrotoxicosis (TSH 0.32mIU/L, fT4 11.51pmol/L and fT3 4.40pmol/L; TSH 0.34mIU/L, fT4 12.67pmol/L and fT3 4.22pmol/L; both were anti-TPO and anti-Tg negative before and after vaccination); one occurred among CoronaVac recipients - isolated mild low fT3 (TSH 0.90mIU/L, fT4 9.94pmol/L and fT3 2.33pmol/L; anti-TPO/Tg negative before and after vaccination). All three recipients were asymptomatic. Both anti-TPO and anti-Tg titers increased modestly after vaccination (anti-TPO: from 7.50 [IQR: 5.90-11.2] to 9.80 IU/mL [IQR: 7.80-13.1], p&amp;lt;0. 001; anti-Tg: from 12.4 [IQR: 11.1-14.9] to 15.7 IU/mL [IQR: 14.2-18.2], p&amp;lt;0. 001), without significant changes in anti-TPO/Tg positivity. Changes in thyroid function and anti-thyroid antibodies were generally consistent between BNT162b2 and CoronaVac recipients, although anti-TPO titer rise was greater after BNT162b2 (p&amp;lt;0. 001). NAb responses were similar between individuals with and without pre-existing thyroid autoimmunity (p=0.855). Conclusion COVID-19 vaccination was associated with a modest increase in anti-thyroid antibody titers. Anti-TPO increase was greater among BNT162b2 recipients. However, there was no clinically significant thyroid dysfunction 8 weeks post-vaccination. NAb responses were not influenced by pre-existing thyroid autoimmunity. Our results provided important reassurance to people to proceed to COVID-19 vaccination. Presentation: No date and time listed

RF12 | PSUN125 Lymphoma in Congenital Leptin Deficiency: Comorbidity or Adverse Effect?

Abstract Background Congenital leptin deficiency (CLD) is a rare autosomal recessive form of monogenic obesity caused by loss-of-function mutations in the leptin gene. Targeted therapy is available in the form of recombinant human leptin (metreleptin). We previously reported baseline characteristics of one of the first cases of CLD diagnosed in the United States, a patient with a comorbid diagnosis of Hodgkin lymphoma prior to initiation of therapy. Metreleptin has a black box warning for risk of T-cell lymphoma, which has been reported in acquired generalized lipodystrophy patients, both treated and untreated with metreleptin. Clinical Case A 20 yr old female (Pt B) was referred for evaluation of obesity (BMI 45.0 kg/m2) with a history of hyperphagia and excessive weight gain by three months of life. Pt B is of Pakistani origin with a family history of consanguinity. She was treated with combination OCPs in adolescence due to primary amenorrhea and hypogonadotropic hypogonadism. At the time of her initial evaluation, serum leptin levels were undetectable. Pt B was homozygous for the pathogenic variant c398delG in exon 3 of the leptin gene (LEP), which causes a frameshift/premature stop codon. On MR elastography performed for hepatic steatosis, she had an incidental finding of axillary lymphadenopathy. Surgical biopsy and staging work-up confirmed diagnosis of nodular lymphocyte predominant Hodgkin lymphoma, Stage II disease. She was treated with 2 cycles of R-ABVD followed by adjuvant radiation (2000 cGy) to the right supraclavicular and axillary region, achieving clinical remission. Pt B was then treated with 3.75-5 mg metreleptin once daily in an observational treatment protocol for 18 months. With therapy, pt B lost 39.1 kg or 33% of initial body weight. Clinically significant improvements in related parameters were observed, including percent body fat (-18%), estimated visceral adipose tissue (-53%), HOMA2 IR (-80%), ALT (-91%), total cholesterol (-10%), triglycerides (-26%), HDL (+6%), LDL (-19%), and high-sensitivity C-reactive protein (-84%). In addition, prediabetes (with abnormal 2 hour OGTT) resolved, hepatic steatosis improved, bone mineral density increased (+0.6 SD), and pt B developed spontaneous regular menses. She tolerated metreleptin well without serious adverse effects and her lymphoma remained in remission throughout the study. Conclusion To our knowledge, this is the first report of lymphoma in a patient with CLD, occurring prior to treatment with metreleptin. Pt B achieved clinical remission prior to initiation of therapy with metreleptin, with no recurrence on 18 months of therapy. She experienced substantial weight loss and marked improvements in body composition, glucose metabolism, insulin sensitivity, lipid metabolism, liver and reproductive health. Untreated CLD has been associated with impaired lymphocyte production and function. The risk for lymphoma associated with metreleptin may relate to preexisting autoimmunity or immunologic abnormalities related to leptin deficiency rather than medication adverse effect. Presentation: Saturday, June 11, 2022 1:00 p.m. - 1:05 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.