Autoimmune Events Research Articles

Autoimmune phenomena in treated and naive pediatric patients with chronic viral hepatitis.

Chronic viral hepatitis has been incriminated for inducing autoimmune events, but it is a known fact that interferon-based therapies also promote autoimmunity. We conducted an observational prospective study which included 114 pediatric patients with chronic viral hepatitis B and C. The patients were divided in 2 groups, the first group consisted of treatment-naive patients; the second group included patients who had received interferon-based therapy. We aimed to determine whether the ones who received treatment are more predisposed to developing autoimmune manifestations when compared to those naive. Fifty percent of the study group was found to have serological autoimmune phenomenon. Our research shows that the occurrence of the autoimmune phenomenon is delayed when the patient is treated with interferon-based regimens when compared to naive patients. Hence, even though interferon treatment has been reported to promote autoimmunity, the viruses themselves are more likely to induce the appearance of autoimmune markers over time in patients who do not receive treatment.

Lymphocyte pharmacodynamics are not associated with autoimmunity or efficacy after alemtuzumab

ObjectiveTo examine the association between peripheral blood lymphocyte pharmacodynamics and autoimmune adverse events (AEs) or return of disease activity in alemtuzumab-treated patients with relapsing-remitting MS.MethodsPatients received 2 alemtuzumab courses (12 mg/d IV; 5 days at baseline, 3 days 12 months later) in the 2-year Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis studies (NCT00530348 and NCT00548405) and could then receive as-needed alemtuzumab or other disease-modifying therapy in a 4-year extension (NCT00930553). Lymphocytes were phenotyped quarterly over 2 years using fluorescence-activated cell sorting. Pharmacodynamic assessments included counts of total lymphocytes, CD3+ T cells, CD4+/CD8+ T cells (total/naive/memory/regulatory [Treg]), and CD19+ B cells (total/immature/mature/memory) and ratios of CD19+ (total/immature/mature/memory) to Treg (CD4+/CD8+) counts. Assessed autoimmune AEs included immune thrombocytopenia, nephropathies, and thyroid events. Efficacy assessments included relapses, 6-month confirmed disability worsening (CDW), and MRI disease activity.ResultsLymphocyte repopulation patterns, including ratios between distinct lymphocyte subsets (e.g., CD19+ to Treg cell count ratios), showed no significant differences over 2 years in patients developing/not developing autoimmune AEs, relapses, CDW, or MRI activity through 6 years following alemtuzumab. Lymphocyte kinetics were also unrelated to multiple autoimmune AEs or extreme clinical phenotypes.ConclusionsRepopulation kinetics of the evaluated peripheral lymphocyte subsets did not predict autoimmune AE occurrence or disease activity, including return of disease activity after 2 alemtuzumab courses. Further study is needed to investigate potential antigen-level markers of treatment response.

LBA33 - Lefitolimod vs standard of care (SOC) for patients with metastatic colorectal cancer (mCRC) responding to first-line standard treatment: Results from the randomized phase III IMPALA trial

LBA33 - Lefitolimod vs standard of care (SOC) for patients with metastatic colorectal cancer (mCRC) responding to first-line standard treatment: Results from the randomized phase III IMPALA trial

The Effect of Antibody Fragments on CD25 Targeted Regulatory T Cell Near-Infrared Photoimmunotherapy.

Regulatory T (Treg) cells play a major role in immune suppression permitting tumors to evade immune surveillance. Depletion of intratumoral Treg cells can result in tumor regression. However, systemic depletion of Tregs may also induce autoimmune adverse events. Near-infrared photoimmunotherapy (NIR-PIT) is a newly developed cell-specific cancer therapy that locally kills specific cells in the tumor. Antibody-photoabsorber (IRDye700DX) conjugates (APC) are injected and bind to the tumor, and subsequent administration of NIR light to the tumor results in rapid cell death only in targeted cells. CD25-targeted NIR-PIT has been shown to induce spatially selective depletion of tumor-associated Treg cells. In this study, we compared the efficacy of an antibody fragment, anti-CD25-F(ab')2, and a full antibody, anti-CD25-IgG, as agents for NIR-PIT. Tumor-bearing mice were divided into four groups: (1) no treatment; (2) anti-CD25-IgG-IR700 i.v. only; (3) anti-CD25-F(ab')2-IR700 i.v. with NIR light exposure; and (4) anti-CD25-IgG-IR700 i.v. with NIR light exposure. Although both CD25-targeted NIR-PITs resulted in significant tumor growth inhibition, the anti-CD25-F(ab')2-IR700 based NIR-PIT was superior to the anti-CD25-IgG-IR700 NIR-PIT. The anti-CD25-F(ab')2-IR700 demonstrated faster clearance from the body than the anti-CD25-IgG-IR700. Sustained circulation of anti-CD25-IgG-IR700 may block IL-2 binding on the activated effector T-cells decreasing immune response. In conclusion, anti-CD25-F(ab')2 based NIR-PIT was more effective in reducing tumor growth than anti-CD25-IgG based NIR-PIT. Absence of the Fc portion of the APC leads to faster clearance and therefore promotes a superior activated T cell response in tumors.

Alemtuzumab-induced thyroid events in multiple sclerosis: a systematic review and meta-analysis.

Autoimmune thyroid events (ATEs) are common side effects after alemtuzumab (ALZ) therapy in patients with multiple sclerosis (MS). Our purpose was to reach more robust evidence on prevalence and outcome of the spectrum of alemtuzumab-induced autoimmune thyroid events in patients with multiple sclerosis. PubMed and Scopus were systematically searched through July 2019. Studies dealing with patients without personal history of thyroid dysfunctions and affected by MS treated with ALZ and reporting ATEs were selected. Data on prevalence and outcome of ATEs were extracted. A proportion of meta-analysis with random-effects model was performed. Considering the overall pooled number of 1362 MS patients treated with ALZ (seven included studies), a 33% prevalence of newly diagnosed ATEs was recorded. Among all ATEs, Graves' disease (GD) was the most represented [63% of cases, 95% confidence interval (CI) 52-74%], followed by Hashimoto thyroiditis (15%, 95% CI 10-22%). Interestingly, GD showed a fluctuating course in 15% of cases (95% CI 8-25%). Of all GD, 12% (95% CI 2-42%) likely had spontaneous remission, 56% (95% CI 34-76%) required only antithyroid drugs, 22% (95% CI 13-32%) needed additional RAI, and 11% (95% CI 0.9-29%) underwent definitive surgery. Among different categories of ATEs, Graves' hyperthyroidism was the most common thyroid dysfunction, occurring in more than half of cases. Antithyroid drugs should represent the first-line treatment for ALZ-induced GD patients. However, alemtuzumab-induced GD could not be considered as having a more favourable outcome than conventional GD, given the substantial chance to encounter a fluctuating and unpredictable course.

Abstract 3167: Improving and standardizing TMB assay performance

Abstract Determining and using the most effective and safest treatment is of great importance in cancer disease management. Checkpoint inhibitors that target immune regulatory molecules such as PD-1, PD-L1, and CTLA-4, have successfully improved PFS and OS - but only in some patients and for some cancers. In the case of PD-1 and PD-L1 inhibitors, it is believed that PD-L1 expression by a solid tumor allows it to escape attack from the immune system and that by inhibiting the PD-L1/PD-1 interaction immune evasion is no longer possible. This may then cause some of the mutations that give rise to expressed neoantigens to act as targets for T cells and allow for the gradual elimination of the tumor. Since the risk for developing autoimmune adverse events is not insignificant with the use of checkpoint inhibitors, determining which patients are likely to respond favorably to their use is imperative. Similarly, expanding approved uses to new indications also benefits from the identification of populations that are most likely to show improvement in PFS and OS - generally, through clinically-validated biomarkers. Current indications for the use of PD-1 and PD-L1 inhibitors rely on cancer type and several biomarkers. One of these is the expression (or level of expression) of PD-L1 on the tumor. Another - usually in colorectal cancer - is the presence of microsatellite instability (MSI), which indicates that DNA is not being copied with high fidelity and resulting mutations may lead to the emergence of potential neoantigens. While MSI can be assessed by the PCR amplification of several loci, the presence or absence of neoantigens cannot, and they can also be created in the absence of MSI. This has given rise to a potential biomarker - tumor mutational burden (TMB) - that is an assessment of the number of relevant mutations in a tumor. TMB measurement is challenging since different targeted next generation sequencing (NGS) panels look at different regions and percentages of the genome and use different criteria as to what constitutes a relevant mutation. Presently, there is poor correlation between different TMB assays at mutation levels that may be relevant for a companion diagnostic where patients may be denied treatment. Here, we describe the characterization of a panel of reference materials for the assessment, harmonization, and improvement of TMB measurements by NGS assays. The panel is comprised of cancer cell lines and their SNP-matched normals. DNA from unfixed cells was used to establish a baseline truth set of somatic mutations and germline SNPs, and DNA from FFPE cells was used to determine how TMB assessment is affected by fixation artifacts - especially, at lower variant allele frequencies. We present data from high coverage whole exome sequencing - the current gold standard in TMB assessment - and from targeted NGS panels that are more typical of what may be used clinically. We show that accurate measurements at what may be clinically relevant TMB cutoffs remain a challenge. Citation Format: Matthew G. Butler, Yves Konigshofer, Lequan Nguyen, Shikha Kalotra, Omo Clement, Russell K. Garlick, Bharathi Anekella. Improving and standardizing TMB assay performance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3167.

Melanoma and autoimmunity: spontaneous regressions as a possible model for new therapeutic approaches.

Until now, malignancy has been considered a cellular problem represented by the perturbed (uncontrolled) division of the cells associated with invasion and metastasis. Contrary to this classical approach, a new perspective suggests that cancerous disease is, in fact, a supracellular problem represented by inadequate evolution of complex supracellular processes (embryogenesis, development, regeneration, etc.). Such complex processes would be disconnected from the real needs of the body, inducing unnecessary or even dangerous events such as an exacerbated rate of the cell division, angiogenesis, immunosuppression (specific to embryogenesis and melanoma), invasion (mediated by trophoblastic/placental factors in melanoma), and migration (specific to neural crest cells, which generate melanocytes - the most common origin for melanoma). As a result, a correct and comprehensive interpretation of cancer (causes, evolution, therapy, and prevention) should be conducted from a supracellular perspective. After presenting the supracellular perspective, this article further investigates the favorable evolution of malignant melanoma in two distinct situations: in patients receiving no therapy and in patients treated with immune-checkpoint inhibitors. In patients receiving no therapy, spontaneous regressions of melanoma could be the result of several autoimmune reactions (inducing not only melanoma regression but also vitiligo, an autoimmune event frequently associated with melanoma). Patients treated with immune-checkpoint inhibitors develop similar autoimmune reactions, which are clearly correlated with better therapeutic results. The best example is vitiligo, which is considered a positive prognostic factor for patients receiving immune-checkpoint inhibitors. This finding indicates that immune-checkpoint inhibitors induce distinct types of autoimmune events, some corresponding to specific favorable autoimmune mechanisms (favoring tumor regression) and others to common unfavorable adverse reactions (which should be avoided or minimized). In conclusion, the spectrum of autoimmune reactions induced by immune-checkpoint inhibitors should be restricted in the near future to only these specific favorable autoimmune mechanisms. In this way, the unnecessary autoimmune reactions/autoaggressions could be avoided (a better quality of life), and treatment specificity and efficiency should increase (a higher response rate for melanoma therapy).

PB2002 IMPACT OF AUTOIMMUNE CYTOPENIAS ON THE CLINICAL COURSE AND SURVIVAL OF HODGKIN LYMPHOMA

Background:Autoimmune cytopenias (AICP), namely autoimmune hemolytic anemia (AIHA) and autoimmune thrombocytopenia (AITP) often complicate the course of malignant lymphomas. The incidence and clinical significance of AICPs associated with Hodgkin lymphoma (HL) have not been thoroughly defined.Aims:Our aim was to retrospectively assess the incidence, clinical features and response to treatment of HL‐associated autoimmune phenomena.Methods:Five hundred and sixty‐five HL patients were diagnosed and treated at the University of Debrecen between 1990 and 2017. We compared the clinicopathological characteristics of HL patients developing AICPs with those who had no clinical evidence of autoimmune events. We considered an AICP to be a disease‐defining event if it led to diagnosis or revealed disease progression, relapse or secondary malignancy. Statistical analysis was performed using Fisher's exact test.Results:We identified 8 cases of AIHA and 8 cases of AITP among 14 patients altogether, one of them presented with Evans syndrome. Two AICPs preceded the diagnosis of HL, 2 of them developed simultaneously with the disease and 11 AICPs occurred during follow‐up after first line therapy. During more than 5000 person‐years of follow‐up, the incidence of AICPs in HL patients was 2,8%. Eighty‐one percent of AICPs required treatment, 77% of these patients responded well to intravenous steroid. Treatment of the underlying lymphoma with ABVD combination chemotherapy resulted in the effective control of both the underlying disease and the immune condition, in most cases, where AICPs were identified at the presentation of HL. Almost half of the AICPs (46%) were disease‐defining events: 5 cases led to the diagnosis of HL or indicated relapse and 2 events revealed secondary malignancies. AICPs were more frequently observed in patients with advanced stage disease at initial diagnosis (p < 0.004). The association of HL and AICPs had no effect on long‐term overall‐ (OS) and progression‐free survival, however, short‐term (1 year) mortality of HL patients experiencing AICPs was significantly elevated (p < 0.022) compared to the majority of patients, who did not have AICPs. Also, the OS rate of HL patients with AICPs at initial diagnosis was significantly lower (p = 0.033) compared to patients developing AICPs during follow‐up.Summary/Conclusion:While AICPs are rare complications of HL, these events can imply clinical significance. Those HL patients who experienced AICPs had a particular disease‐related profile. These cytopenias show a good response to steroid treatment. This large series of consecutive, unselected patients demonstrate that the association of HL and AICPs may increase short‐term mortality. Our results emphasize the importance of taking into consideration the possibility of an underlying hematological malignancy in newly diagnosed AIHA/AITP cases.

Phase I (safety assessment) of durvalumab (MEDI4736) with focal sensitizing radiotherapy in platinum resistant ovarian, primary peritoneal or fallopian tube epithelial carcinoma.

TPS5604 Background: Radiation (RT) of malignant neoplasms can induce immunogenic tumor cell death, alter the tumor micro-environment and enhance recruitment of anti-tumor T cells. Co-administration of focal RT and an immune checkpoint-inhibiting agent may overcome immune-suppressive signals and potentiate systemic responses. A phase I study is underway to assess the safety of RT combined with PD-L1 inhibition in patients with recurrent epithelial ovarian/fallopian tube/peritoneal carcinomas (OV). Methods: Women with platinum resistant epithelial OV, ECOG PS 0/1 and ≤ 2 lines of treatment in the platinum-resistant setting are eligible. 1 lesion evaluable by RECIST criteria (v 1.1) and 2 additional lesions suitable for RT (minimal treatment volume 4cc) are required. Pre- and on-treatment biopsies for correlative studies are mandatory. The primary objectives are to assess the safety and tolerability of the focal RT combined with the immune checkpoint inhibitor, durvalumab (D), as defined by dose-limiting toxicities (DLTs), and to define the maximum tolerated RT dose and treatment schedule. The secondary objectives are to evaluate the clinical activity of focal RT and D [RECIST (v 1.1), GCIG CA-125, and immune-related response criteria], progression free survival and overall survival. D 1500 mg delivered intravenously every 28 days = one cycle. RT to the 2 selected target lesions is delivered 24-36 hours prior to the infusion of D. The RT starting dose-level is 24Gy (in 4 fractions) per lesion (given Days -1, 1 and 28 of Cycle 1 and Day 1 of Cycle 2). A 3+3+3 design will permit more extensive exploration of toxicity if DLTs are observed (Table). Investigator assessed DLTs are defined by CTCAE v. 4.03 and include the following: any grade ≥3 adverse event suspected to be related to D or RT (necrosis or recall reactions at previously irradiated sites, RT induced bowel perforation, any unexpected grade 3 or greater toxicity at the site of RT), any grade ≥2 allergic or autoimmune event that involves vital organ function, and any other grade 3 allergic or autoimmune events that do not resolve to grade 1 before the next scheduled dose of D. Treatment may continue up to 12 months. Enrollment began August 2018. To date, no DLTs have been observed at dose level 1 (n= 3) and enrollment is ongoing. Clinical trial information: NCT03283943. [Table: see text]

Immune checkpoint inhibitor toxicity in the clinical practice setting.

e14128 Background: Immune checkpoint inhibitors (ICIs) are changing the landscape of treatment in oncology. The use of ICIs is growing rapidly as the indications for these medications broaden and new ICIs become approved. Given the rapid growth and relative infancy of the use of ICIs, much information stands to be gained on their use in the clinical practice setting, especially regarding toxicity. Methods: The primary objective of this project was to examine the incidence and severity of immune-related adverse events (irAEs), after treatment with single-agent or combination ICIs at a multi-site community cancer center. A retrospective chart review was conducted on all patients who had received ipilimumab, nivolumab, pembrolizumab, atezolizumab, or ipilimumab plus nivolumab from May 1, 2011 to June 30, 2017. Data collected included patient demographics, disease state, treatment information, preexisting autoimmune disease, previous immunotherapy, and adverse event details. The results were analyzed using descriptive statistics. Results: Data was collected on 383 patients. Dermatologic irAEs were common across single agent ICIs (overall incidence 23%). Diarrhea and/or colitis incidence was highest with CTLA-4 inhibitor ipilimumab (26% at 3 mg/kg and 22% at 10 mg/kg) versus the other monotherapy PD-1/PDL-1 inhibitors. Endocrinopathies were most common with ipilimumab 10 mg/kg (55%) and pneumonitis incidence was highest with nivolumab (6%). ICI toxicity occurred in 63% of patients with preexisting autoimmune disease versus 54% of those without a baseline autoimmune disease. Incidence of hospitalization and treatment holds due to irAEs was higher with combination therapy (57% and 66%, respectively) than with monotherapy (10% and 24%, respectively). Conclusions: Overall, there was increased incidence in ICI toxicity in patients at this oncology institution versus what has been reported in clinical trials. Patients with preexisting autoimmune diseases appeared to have mainly low-grade toxicities with slightly increased incidence of irAE compared with those without pre-existing autoimmune disease. Treatment holds and hospitalizations were higher in patients treated with combination therapy ICIs compared to monotherapy ICIs.

Association between past medical history (PMH) of autoimmune events and adverse events of special interest (AESI).

2565 Background: PD-1/L1 inhibitor therapy has become the standard of care for many advanced solid tumors. A notable limitation of PD-1/L1 inhibitor therapy is the concern for AESI that are likely to be immune related. It is unclear whether a history of autoimmune events is a predisposing risk making these adverse events more likely. We aimed to evaluate the association between autoimmune-associated PMH and AESI on PD-1/L1 inhibitors. Methods: We pooled data across seven pivotal trials for PD-1/L1 inhibitors in urothelial cancer (UC) identifying patients with AESI submitted from 2016 - 2017. AESI were determined using a pooled preferred term list for each trial. Information collected from trials included PMH, AESI events and toxicity grade. Results: In total, 1747 immunotherapy treated patients were identified, with 1068 (61%) having an AESI and 277 (26%) having an autoimmune-related PMH. The most common autoimmune-associated events in the PMH were thyroid disorders (64%), asthma (23%), atopic dermatitis/eczema (6%), irritable bowel syndrome (5%), and psoriasis (4%). AESI occurred in 68% of patients with an autoimmune-related PMH and 60% of patients without an autoimmune-related PMH. The most common AESI in patients with an autoimmune-related PMH were diarrhea (35%), rash (27%), renal disorder (27%), and pruritis (23%). The most common AESI in the general trial population were diarrhea (28%), pruritis (26%), rash (25%), increased creatinine (14%), and elevated AST and ALT (10% and 9%). The majority of events were Grade 1-2 (87% in patients with an autoimmune-related PMH and 84% in the general trial population). Conclusions: Pooled clinical trial data shows a slight numeric increase in AESIs in patients with autoimmune-associated PMH. Limitations include potential lack of consistency of PMH documentation and adverse event reporting. There did not appear to be a pattern of association between PMH and type of AESI event. Grades of AESI events in the population with autoimmune-associated PMH were similar to the general trial population. This suggests that PD-1/L1 inhibitors may be safely administered to patients with UC and a PMH of some autoimmune-associated events. Further exploration is needed.

Subclinical Atherosclerosis in Primary Sjögren's Syndrome: Does Inflammation Matter?

Sjögren's syndrome (SS) is a systemic autoimmune disease mainly characterized by inflammatory involvement of exocrine gland. Atherosclerosis is a complex process leading to plaque formation in arterial wall with subsequent cardiovascular (CV) events. Recently, numerous studies demonstrated that SS patients bear an increased CV risk. Since activation of immune system is a key element in atherosclerosis, it is interesting to analyze whether and how the autoimmune and inflammatory events characterizing SS pathogenesis directly or indirectly contribute to atherosclerosis risk in these patients. An increase in circulating endothelial microparticles and integrins, which may be a consequence of endothelial damage and impaired repair mechanisms, has been demonstrated in SS. Increased endothelial expression of adhesion molecules with subsequent infiltration of inflammatory cells into arterial wall is also a critical event in atherosclerosis. The early inflammatory events taking place in the atherosclerotic plaque cause an increase in alarmins, such as S100A8/A9, which seems to be associated with SS disease activity and, in turn, induce up-regulation of interleukin (IL)-1β and other pro-atherogenic cytokines. Interestingly, increased IL-1β levels were also detected in tertiary lymphoid structures developing in vessel adventitia adjacent to the atherosclerotic plaque, suggesting a direct role of IL-1β in this process. Similar to these structures, germinal center-like structures arising in SS exocrine glands are also tertiary lymphoid systems where T-helper (Th) cell subsets govern the adaptive immune response. Th1 cells are the most prevalent subtype and have been shown to be strongly involved in both SS pathogenesis and atherosclerosis. Th17 cells are attracting great interest and few studies showed its importance in SS development. Albeit in low amounts, a Th17 signature was also detected in atherosclerotic plaques and some animal models demonstrated a significant pro-atherogenic role and positive effects of IL-17A blockade. Despite the fact that T cells have a pivotal role in the inflammatory process that ultimately leads to atherosclerosis, B cells have also been detected in atherosclerotic plaques, although their exact role is still mostly unknown with studies showing contrasting results. In this scenario, the role of inflammation in atherosclerosis pathogenesis in patients with SS needs to be further explored.

Platelet-type 12-lipoxygenase deletion provokes a compensatory 12/15-lipoxygenase increase that exacerbates oxidative stress in mouse islet β cells

In type 1 diabetes, an autoimmune event increases oxidative stress in islet β cells, giving rise to cellular dysfunction and apoptosis. Lipoxygenases are enzymes that catalyze the oxygenation of polyunsaturated fatty acids that can form lipid metabolites involved in several biological functions, including oxidative stress. 12-Lipoxygenase and 12/15-lipoxygenase are related but distinct enzymes that are expressed in pancreatic islets, but their relative contributions to oxidative stress in these regions are still being elucidated. In this study, we used mice with global genetic deletion of the genes encoding 12-lipoxygenase (arachidonate 12-lipoxygenase, 12S type [Alox12]) or 12/15-lipoxygenase (Alox15) to compare the influence of each gene deletion on β cell function and survival in response to the β cell toxin streptozotocin. Alox12-/- mice exhibited greater impairment in glucose tolerance following streptozotocin exposure than WT mice, whereas Alox15-/- mice were protected against dysglycemia. These changes were accompanied by evidence of islet oxidative stress in Alox12-/- mice and reduced oxidative stress in Alox15-/- mice, consistent with alterations in the expression of the antioxidant response enzymes in islets from these mice. Additionally, islets from Alox12-/- mice displayed a compensatory increase in Alox15 gene expression, and treatment of these mice with the 12/15-lipoxygenase inhibitor ML-351 rescued the dysglycemic phenotype. Collectively, these results indicate that Alox12 loss activates a compensatory increase in Alox15 that sensitizes mouse β cells to oxidative stress.

Best Practices for Long-Term Monitoring and Follow-Up of Alemtuzumab-Treated MS Patients in Real-World Clinical Settings.

Multiple sclerosis (MS) is a chronic autoimmune neurological disease that typically affects young adults, causing irreversible physical disability and cognitive impairment. Alemtuzumab, administered intravenously as 2 initial courses of 12 mg/day (5 consecutive days at baseline, and 3 consecutive days 12 months later), resulted in significantly greater improvements in clinical and MRI outcomes vs. subcutaneous interferon beta-1a over 2 years in patients with active relapsing-remitting MS (RRMS) who were either treatment-naive (CARE-MS I; NCT00530348) or had an inadequate response to prior therapy (CARE-MS II; NCT00548405). Efficacy with alemtuzumab was maintained over 7 years in subsequent extension studies (NCT00930553; NCT02255656), in the absence of continuous treatment and with a consistent safety profile. There is an increased incidence of autoimmune events in patients treated with alemtuzumab (mainly thyroid events, but also immune thrombocytopenia and nephropathy), which imparts a need for mandatory safety monitoring for 4 years following the last treatment. The risk management strategy for alemtuzumab-treated patients includes laboratory monitoring and a comprehensive patient education and support program that enables early detection and effective management of autoimmune events, yielding optimal outcomes for MS patients. Here we provide an overview of tools and techniques that have been implemented in real-world clinical settings to reduce the burden of monitoring for both patients and healthcare providers, including customized educational materials, the use of social media, and interactive online databases for managing healthcare data. Many practices are also enhancing patient outreach efforts through coordination with specialized nursing services and ancillary caregivers. The best practice recommendations for safety monitoring described in this article, based on experiences in real-world clinical settings, may enable early detection and management of autoimmune events, and help with implementation of monitoring requirements while maximizing the benefits of alemtuzumab treatment for MS patients.

Early Peritoneal CC Chemokine Production Correlates with Divergent Inflammatory Phenotypes and Susceptibility to Experimental Arthritis in Mice.

The inflammatory and autoimmune events preceding clinical symptoms in rheumatoid arthritis (RA) and other autoimmune diseases are difficult to study in human patients. Therefore, animal models that share immunologic and clinical features with human RA, such as pristane-induced arthritis (PIA), are valuable tools for assessing the primordial events related to arthritis susceptibility. PIA-resistant HIII and susceptible LIII mice were injected i.p. with pristane, and peritoneal lavage fluid was harvested in the early (7 days) and late (35 days) preclinical phases of PIA. Chemokine and cytokine levels were measured in lavage supernatant with ELISA, peritoneal inflammatory leukocytes were immunophenotyped by flow cytometry, and gene expression was determined by qRT-PCR. Leukocyte recruitment was quantitatively and qualitatively divergent in the peritoneum of HIII and LIII mice, with an early increase of CC chemokines (CCL2/CCL3/CCL5/CCL12/CCL22) in the susceptible LIII strain. Also, cytokines such as IL-12p40, IL-23, and IL-18 were elevated in LIII mice while IL-6 was increased in HIII animals. The results show that an early peritoneal CC chemokine response is an important feature of arthritis susceptibility and defines potential biomarkers in this model.

Immune system and new avenues in Parkinson's disease research and treatment.

Parkinson's disease (PD) is a progressive neurological disorder characterized by degeneration of dopaminergic neurons in the substantia nigra. However, although 200 years have now passed since the primary clinical description of PD by James Parkinson, the etiology and mechanisms of neuronal loss in this disease are still not fully understood. In addition to genetic and environmental factors, activation of immunologic responses seems to have a crucial role in PD pathology. Intraneuronal accumulation of α-synuclein (α-Syn), as the main pathological hallmark of PD, potentially mediates initiation of the autoimmune and inflammatory events through, possibly, auto-reactive T cells. While current therapeutic regimens are mainly used to symptomatically suppress PD signs, application of the disease-modifying therapies including immunomodulatory strategies may slow down the progressive neurodegeneration process of PD. The aim of this review is to summarize knowledge regarding previous studies on the relationships between autoimmune reactions and PD pathology as well as to discuss current opportunities for immunomodulatory therapy.

Abstract P2-09-08: Imprime PGG, a novel innate immune modulator, combined with pembrolizumab in a phase 2 multicenter, open label study in chemotherapy-resistant metastatic triple negative breast cancer (TNBC)

Abstract Background: CPI monotherapy provides substantial clinical benefit to patients (pts) in multiple cancers, yet response rates are limited (˜15-30%) and fails to benefit the majority. In these pts there is limited or no ongoing T cell-based immune response. Imprime PGG (Imprime), a novel beta glucan derived from Saccharomyces, may expand the clinical benefit of CPI therapy by stimulating an anti-cancer immune response. Acting as a pathogen-associated molecularpattern (PAMP), Imprime enlists innate immune functions including cytotoxic effector mechanisms, reversal of immunosuppression and cross-talk with the adaptive immune system.Imprime-mediated innate immune activation requires formation of an immune complex with naturally-occurring anti-beta glucan antibodies (ABA); sufficient ABA levels is required for complex formation. Imprime is now being studied in combination with pembrolizumab (KEYTRUDA®,Pembro), a humanized mAb against PD-1 which has been previously studied in TNBC pts. Methods: In this study of patients who previously failed chemotherapy for metastatic TNBC, Imprime is being used in combination with Pembro in a Simon 2 stage design. Asample size of 12 evaluable pts in Stage 1 was planned.Evaluable pts received at least one dose of study treatment (tx), had measurable disease at baseline per RECIST v1.1, had at least one post-baseline scan or discontinued tx as a result of progressive disease, death, or a tx-related adverse event before the first post-baseline scan.Pts received Imprime (4 mg/kg IV days 1, 8, 15 of each 3-week cycle) + Pembro 200 mg on D1 of each cycle. Criteria to advance to Stage 2 were ≤4 grade 3/4 AEs during the first tx cycle (other than infusion reactions) and ≥1 objective response. Study primary endpoints are ORR and safety; secondary endpoints are TTR, CRR, DoR, PFS, and OS. Exploratory endpoints include ORR and PFS per irRECIST. Biopsies and blood samples are being collected to assess tx impact on immune activating events at the tumor site and in the periphery. Results: A review of efficacy and safety data was conducted at the end of Stage 1. Thirteen pts (12 evaluable) were enrolled into Stage 1. Safety review noted 2 grade 3 adverse events that met protocol definition of Stage 1 events (1 pt: cellulitis and 1 pt: pleural infusion; both unrelated to treatment). Two events lead to 2 pts discontinuing treatment (infusion reaction and pancreatitis) and only 1 autoimmune event was observed (pancreatitis). Observed efficacy responses in the evaluable pts included 1 complete response (CR; ongoing) and 2 partial responses (PR; ongoing). Secondary efficacy endpoints have not been assessed. Early translational results support proposed MOA and analysis of Stage 1 translational data is ongoing. Conclusion: The use of Imprime with Pembro was well tolerated and met both safety and efficacy requirements to move forward with Stage 2 of the study. No significant safety concerns were identified in Stage 1. Further investigation is thus warranted and enrollment into Stage 2 is ongoing. Updated data will be presented. Citation Format: O'Day S, Borges V, Chmielowski B, Rao R, Abu-Khalaf M, Stopeck A, Lowe J, Mattson P, Breuer K, Gargano M, Bose N, Uhlik M, Graff J, Chisamore M, Cox J, Osterwalder B. Imprime PGG, a novel innate immune modulator, combined with pembrolizumab in a phase 2 multicenter, open label study in chemotherapy-resistant metastatic triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-09-08.

Development and Organization of the Secondary and Tertiary Lymphoid Organs: Influence of Microbial and Food Antigens.

Secondary lymphoid organs (SLO) are distributed in many districts of the body and, especially, lymph nodes, spleen and gut-associated lymphoid tissue are the main cellular sites. On the other hand, tertiary lymphoid organs (TLO) are formed in response to inflammatory, infectious, autoimmune and neoplastic events. Developmental Studies: In the present review, emphasis will be placed on the developmental differences of SLO and TLO between small intestine and colon and on the role played by various chemokines and cell receptors. Undoubtedly, microbiota is indispensable for the formation of SLO and its absence leads to their poor formation, thus indicating its strict interaction with immune and non immune host cells. Furthermore, food antigens (for example, tryptophan derivatives, flavonoids and byphenils) bind the aryl hydrocarbon receptor on innate lymphoid cells (ILCs), thus promoting the development of postnatal lymphoid tissues. Also retinoic acid, a metabolite of vitamin A, contributes to SLO development during embryogenesis. Vitamin A deficiency seems to account for reduction of ILCs and scarce formation of solitary lymphoid tissue. Translational Studies: The role of lymphoid organs with special reference to intestinal TLO in the course of experimental and human disease will also be discussed. Future Perspectives: Finally, a new methodology, the so-called "gut-in-a dish", which has facilitated the in vitro interaction study between microbe and intestinal immune cells, will be described.

A pilot study of interferon-alpha-2b dose reduction in the adjuvant therapy of high-risk melanoma

Melanoma is a highly immunogenic tumor and consequently, efforts have been centered on the development of immune-based treatments for this malignancy [1]. Interferons were initially described in the mid-1950s as proteins that interfere with viral replication [2, 3]. Interferons are cytokines that activate Janus kinases (Jak), which lead to phosphorylation and activation of transcription factors belonging to the signal transducer and activator of transcription (STAT) family [4, 5]. Interferon-alpha (IFN-α) became available for use in clinical trials in the mid-1980s [6]. Results suggested that IFN-α inhibited the proliferation of malignant cells and stimulated immune effectors; therefore, IFN-α was initially used in patients with advanced disease [7, 8]. Since then, several meta-analyses have demonstrated that high-dose adjuvant IFN-α (daily 20 MU/m2 intravenous induction therapy for 1 month followed by maintenance subcutaneous 10 MU/m2 three times per week for at least 1 year) can prolong the disease-free interval in high-risk melanoma patients [9]. The introduction of checkpoint inhibitor therapy has revolutionized the adjuvant therapy of melanoma; however, there remains a role for IFN-α in this setting based on the potential for cancer immune escape or autoimmune events with CTLA-4 and PD-1 blocking antibodies [10–14]. There has also been significant advances in mitogen-activated protein kinase (MAPK) targeted therapies, particularly for BRAF (an intracellular signaling kinase) and MEK (signaling molecule downstream of BRAF). A recent clinical trial demonstrated significant improvement in both relapse-free survival and overall survival with adjuvant dabrafenib (BRAF inhibitor) plus trametinib (MEK inhibitor) in patients with stage III melanoma. These therapies are now approved for adjuvant therapy in BRAF mutated tumors [15]. However, since only approximately 40–50% of melanoma cells harbor an activating BRAF mutation, there still remains a role for IFN-α in this setting as the remaining 50–60% of melanomas would not be susceptible to BRAF-targeted therapies. IFN-α activates the Jak-STAT signaling pathway and induces synthesis of hundreds of different proteins [4, 5]. Our group has shown that STAT1-mediated gene regulation within immune effectors is necessary for mediating the anti-tumor effects of IFN-α and also that the amount IFN-α administered to melanoma patients is likely in excess of the optimal biological dose [4]. Indeed, high doses of IFN-α appear to be no more effective in the induction of phosphorylated STAT1 (p-STAT1) and in the transcription of interferon-stimulated genes (ISGs) than intermediate doses [16, 17]. Our group’s studies in genetically manipulated mice have shown that suppressors of cytokine signaling-1 (SOCS1) and SOCS3 negatively regulate IFN-induced Jak-STAT signal transduction, gene regulation and anti-melanoma activity, and that high doses of IFN-α can induce SOCS proteins [18, 19]. We hypothesized that lower doses of IFN-α would be superior for induction of IFN signal transduction in patient immune cells. A prospective clinical trial was performed wherein patients eligible for adjuvant IFN-α-2b received 1 month of standard intravenous high-dose IFN-α-2b (20 MU/m2) followed by subcutaneous IFN-α-2b at a dose of 10 MU/m2 with dose reductions at set intervals down to a level of 4 MU/m2. Jak-STAT signal transduction and transcription of ISGs in patient peripheral blood mononuclear cells (PBMCs) were monitored during the course of adjuvant IFN-α therapy. The objective of this pilot study was to determine if lower doses of IFN-α were as effective in the induction of IFN signal transduction and gene expression as the standard high dose regimen.

Cancer immunotherapy with check point inhibitor can cause autoimmune adverse events due to loss of Treg homeostasis

Regulatory T-cells (Tregs) can facilitate immune evasion by tumor cells by dampening anti-tumor immunity. Reduced Teff/Treg ratio and enhanced Treg functional activity have been observed in patients suffering from different types of cancers, and attenuated Treg numbers/functions can serve as prognostic indicators. Normally, Tregs play an essential role in the maintenance of immune tolerance and prevention of autoimmunity. The most common immune checkpoint blockers (ICB) targeting co-inhibitory receptors such as anti-CTLA4 (ipilimumab and tremelimumab) and anti-PD1 (pembrolizumab and nivolumab)/anti-PD-L1 (atezolizumab) have achieved unprecedented success in cancer treatment by facilitating an effective anti-tumor immune response, at least in part, by blocking Treg mediated immunosuppression. While ICBs have shown remarkable success in cancer immunotherapy, immune-related adverse events (IRAEs) arising from ICB have forced consideration of ways to maintain immune homeostasis post ICB treatment. Preclinical models of IRAEs have shown a negative correlation between Treg numbers and IRAEs. Therefore, understanding the "ying-yang" role of Tregs in the regulation of autoimmunity and anti-tumor immunity is critical to provoking an effective anti-tumor response while maintaining immune homeostasis. Studies aimed at developing effective approaches to minimize IRAEs without compromising anti-tumor immunity are underway. Herein, we discuss 1) the critical role of key co-inhibitory receptors on Treg homeostasis and tumor tolerance; 2) how co-receptor blockade by cancer immunotherapy can lead to autoimmune adverse events; and 3) recently emerging management strategies to minimize autoimmune adverse events arising from ICB.