Type Hypersensitivity Reaction Research Articles

Hypersensitivity reactions to biologics (part I): allergy as an important differential diagnosis in complex immune-derived adverse events*

Purpose: Biotechnological substances (BSs) are strongly relied upon to prevent rejection of transplanted organs, and to treat oncological, allergological, and other inflammatory diseases. Allergic reactions to partly foreign biologics can occur due to their potential immunogenicity. The severity of an immune response to a biological drug may range from no clinical significance to a severe, life-threatening anaphylactic reaction.Methods: Detailed searches were performed on Pubmed, Web of Science, and Google Scholar to include all available publications. In addition, the Food and Drug Administration, the European Medicines Agency, and British Columbia Cancer Agency Drug Manual databases were screened for hypersensitivity reaction (HSR), infusion reaction, injection site reaction, urticaria, and anaphylaxis for individual BSs.Results: Treatment with BSs can cause various types of HSR. These are mentioned in the literature with definitions such as allergic reactions, anaphylactoid reactions, anaphylaxis, HSR, infusion reactions, injection site reactions, cytokine release syndrome, and urticaria. Due to the overlap in signs and symptoms in the reported descriptions, it is not always possible to differentiate these reactions properly according to their pathomechanism. Similarly, many data reported as anaphylaxis actually describe severe anaphylactic reactions (grades III or IV).Conclusion: There is an urgent need for a simpler symptom- or system-based classification and scoring system to create an awareness for HSRs to BSs. A better understanding of the pathophysiology of HSRs and increased clinical experience in the treatment of side effects will provide timely control of unexpected reactions. As a result, immunotherapy with BSs will become safer in the future.Cite this as Gülsen A, Wedi B, Jappe U. Hypersensitivity reactions to biologics (part I): allergy as an important differential diagnosis in complex immune-derived adverse events. Allergo J Int 2020; 29:97-125https://doi.org/10.1007/s40629-020-00126-6.

SAT0376 DOES SUPPRESSION OF IL-4 AND IL-13 LEAD TO THE DEVELOPMENT OF NEW ONSET SPONDYLO-ARTHRITIS IN SUSCEPTIBLE PATIENTS?

Background:Enthesitis is a key feature of peripheral Spondyloarthritis (SpA). Several pro-inflammatory cytokines including Interleukin-17 and Interleukin-23 are found within the enthesis (1). Dupilumab is a recombinant human monoclonal antibody that inhibits signalling of Interleukin-4 and Interleukin-13, approved for use in patients with moderate- to –severe atopic eczema. Here we describe a cohort of patients with severe atopic eczema who have developed a new peripheral SpA/ enthesitis after receiving Dupilumab.Objectives:To describe the clinical and imaging details of this cohort.Methods:All patients in St John’s Institute of Dermatology who exhibited new arthralgias on Dupilumab therapy were referred for assessment in Guy’s Rheumatology Department. These patients had a focussed history, examination, ultrasound and/or MRI of affected joints and entheseal sites.Results:To date we have seen 12 patients with a history of new inflammatory peripheral SpA type symptoms following onset of Dupilumab therapy. There were 7 males and 5 females all of whom have longstanding severe atopic Eczema. All patients had raised baseline IgE levels of mainly >10000. All patients exhibited a positive response to Dupilumab with a marked improvement in eczema as measured by the EASI score. All patients had normal inflammatory markers and negative immunological screening bloods. Musculoskeletal symptom onset was between 2 and 20 weeks after starting treatment. Typically, these patients had inflammatory symptoms affecting both the small joints and the entheseal sites. 2/12 patients developed inflammatory sounding spinal pain. 2/12 patients had ultrasound evidence of arthritis. 11/12 patients had radiological findings of enthesitis as seen on MRI or ultrasound (power doppler ultrasound signal). 9/12 patients were treated with non-steroidal anti-inflammatories with variable improvement.1 patient required no treatment and 1 patient received low dose prednisolone.Conclusion:In our centre approximately 200 patients have received Dupilumab. These musculoskeletal findings have not been reported previously in clinical trials. We hypothesise that the profound inhibition of IL- 4/13 may allow an inflammatory response at the enthesis presenting with a peripheral SpA pattern. IL-4 has been shown to suppress delayed type hypersensitivity reactions (DTHRs) and psoriasis in both human and mice studies (2). These findings and the demonstratation that IL-23 transcription and secretion can be suppressed by IL-4 with resultant reduction in Th17 function (3) may be key factors as to why a SpA type response is seen in certain subjects.

Hypersensitivity reactions to biologics (partI): allergy as an important differential diagnosis in complex immune-derived adverse events.

PurposeBiotechnological substances (BSs) are strongly relied upon to prevent rejection of transplanted organs, and to treat oncological, allergological, and other inflammatory diseases. Allergic reactions to partly foreign biologics can occur due to their potential immunogenicity. The severity of an immune response to a biological drug may range from no clinical significance to a severe, life-threatening anaphylactic reaction.MethodsDetailed searches were performed on Pubmed, Web of Science, and Google Scholar to include all available publications. In addition, the Food and Drug Administration, the European Medicines Agency, and British Columbia Cancer Agency Drug Manual databases were screened for hypersensitivity reaction (HSR), infusion reaction, injection site reaction, urticaria, and anaphylaxis for individual BSs.ResultsTreatment with BSs can cause various types of HSR. These are mentioned in the literature with definitions such as allergic reactions, anaphylactoid reactions, anaphylaxis, HSR, infusion reactions, injection site reactions, cytokine release syndrome, and urticaria. Due to the overlap in signs and symptoms in the reported descriptions, it is not always possible to differentiate these reactions properly according to their pathomechanism. Similarly, many data reported as anaphylaxis actually describe severe anaphylactic reactions (grades III or IV).ConclusionThere is an urgent need for a simpler symptom- or system-based classification and scoring system to create an awareness for HSRs to BSs. A better understanding of the pathophysiology of HSRs and increased clinical experience in the treatment of side effects will provide timely control of unexpected reactions. As a result, immunotherapy with BSs will become safer in the future.

SAT-504 Delayed Hypersensitivity to Levothyroxine, and Oral Desensitization

Introduction- Hypothyroidism is a common endocrine disorder, affecting about 4.6 percent of the U.S. population aged 12 and older. The most common treatment is synthetic thyroxine hormone supplementation-levothyroxine, starting at 1.6 mcg/kg.Hypersensitivity reactions to levothyroxine are rare. Two cases have been published of successful oral desensitization, for suspected IgE mediated reactions. There are no published protocols describing induction of drug tolerance to immunologic, non-IgE mediated reaction to levothyroxine. The objective of this case report is to describe a novel outpatient protocol, for oral desensitization to levothyroxine, in the setting of a delayed immunologic (non-IgE mediated) reaction.Case report- A 66 year old male with history of hypothyroidism, diagnosed in 2010 presented to outpatient endocrinology. Between 2010 and 2019, the patient was on multiple brands and formulations of levothyroxine. He noticed an itchy, raised rash on abdomen, chest and arms, within a few months after starting each of the above. No mucosal involvement or signs of end organ damage were noted. The rash was deemed a type IV delayed hypersensitivity reaction, based on history and histological findings on biopsy. The patient reported clearance of the rash when he was off any form of thyroid supplementation, and reappearance of the rash when he re-trialed it. The patient had normal thyroid stimulating hormone (TSH) levels while he was on supplementation despite the rash. The patient’s TSH after discontinuing treatment was 104 (uIU/mL) and free thyroxine (T4) was 0.13 ng/dl (0.9–1.7). All components of previous brands of levothyroxine were compared and no common ingredient was thought to be contributing to hypersensitivity reactions. Subsequently, an oral desensitization protocol was initiated at 0.075 mcg daily with weekly increase in doses over seven weeks to reach a target dose of 75 mcg.Discussion- The patient was tried on different brands of levothyroxine and dessicated thyroid hormone. He consistently developed a type IV hypersensitivity reaction within a few months after starting them. The patient had uncontrolled TSH levels after discontinuing the treatment and was at risk of complications of untreated hypothyroidism. This necessitated the need for desensitization. There have been previous case reports of oral or IV desensitization, in suspected IgE mediated reactions, but we describe the first case of induction of levothyroxine tolerance in an immunologic non-IgE mediated reaction. Subsequently, the patient tolerated a therapeutic dose of levothyroxine, with no appearance of rash or itching, for almost 6 months. This case report describes a novel approach to levothyroxine desensitization over a period of seven weeks in an outpatient setting in response to a delayed type hypersensitivity reaction.

Glycopeptide Hypersensitivity and Adverse Reactions.

Glycopeptides, such as vancomycin and teicoplanin, are primarily used in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections, such as cellulitis, endocarditis, meningitis, pneumonia, and septicemia, and are some of the most commonly prescribed parenteral antimicrobials. Parenteral glycopeptides are first-line therapy for severe MRSA infections; however, oral vancomycin is used as a first-line treatment of Clostridioides difficile infections. Also, we currently have the longer-acting lipoglycopeptides, such as dalbavancin, oritavancin, and telavancin to our armamentarium for the treatment of MRSA infections. Lastly, vancomycin is often used as an alternative treatment for patients with β-lactam hypersensitivity. Common adverse effects associated with glycopeptide use include nephrotoxicity, ototoxicity, and Redman Syndrome (RMS). The RMS is often mistaken for a true allergy; however, it is a histamine-related infusion reaction rather than a true immunoglobulin E (IgE)-mediated allergic reaction. Although hypersensitivity to glycopeptides is rare, both immune-mediated and delayed reactions have been reported in the literature. We describe the various types of glycopeptide hypersensitivity reactions associated with glycopeptides and lipoglycopeptides, including IgE-mediated reactions, RMS, and linear immunoglobulin A bullous dermatosis, as well as describe cross-reactivity with other glycopeptides.

P266 IL-4/13 inhibitor dupilumab associated with new onset peripheral axial spondyloarthritis in patients with atopic dermatitis

Abstract Background Dupilumab is a recombinant human monoclonal antibody that inhibits signalling of interleukin-4 and interleukin-13. It has NICE approval for use in patients with moderate to severe atopic eczema who have failed at least one standard therapy. The main reported side effects in clinical trials were allergic conjunctivitis (1-5%), injection site reactions (8-19%) and herpes viral infections (3-7%). Methods Here we report symptoms and signs of a new peripheral axial spondyloarthritis/ psoriatic arthritis type presentation in 8 patients within 16 weeks of commencing dupilumab. This has not been described previously in the clinical trials patient population. Results These patients had a long history of atopy with severe eczema and raised baseline IgE levels of > 12000. A positive response to dupilumab was seen in all patients as evidenced by marked improvements in the Eczema Area and Severity Index (EASI). Musculoskeletal symptom onset began between 2 and 16 weeks after commencement of drug. Patients typically complained of inflammatory type pain in the small joints and entheseal sites. 2/8 patients had inflammatory sounding spinal pain. Early morning stiffness was common. All patients had normal acute phase reactants and one patient had a positive rheumatoid factor. 6/8 patients had radiologically evident enthesitis as seen on MRI or ultrasound (power doppler ultrasound signal-PDUS). 3/8 patients had such severe symptoms that they had to discontinue dupilumab. All patients were commenced on non-steroidal anti inflammatories. One patient was commenced on a low dose JAK inhibitor and exhibited improvement in musculoskeletal symptoms. Conclusion IL-4 has been shown to suppress delayed type hypersensitivity reactions (DTHRs) in both human and mice studies. It has been demonstrated previously that IL-4 can prevent bone erosion and disease progression in animal models of inflammatory arthritis. Guenova et al (2015) showed that IL-4 can selectively suppress IL-23 transcription and secretion with reduced Th17 function. They suggest that administration of IL-4 may be of therapeutic benefit in Th17 mediated inflammatory conditions. Conversely, dupilumab through the inhibition of IL-4 and IL-13 and possible resultant increased IL-17 and IL-23 levels, has perhaps unmasked a tendency towards development of a peripheral axial SpA phenotype in these patients. Disclosures C.D. Hughes None. B. Menon None. Z. Willsmore None. R. Woolf None. C. Smith Grants/research support; CS is a PI/CoPI on a number of commercially supported studie (Abbvie, Janssen, Leo, Sanofi). A. Pink None. B.W. Kirkham Consultancies; BK has worked as a consultant for Eli Lilly, Gilead, Janssen and Novartis. Grants/research support; BK has received research support from Eli Lilly and Novartis.

Ketoprofen hypersensibility and idiosyncratic response – a case report

Context: Ketoprofen is widely used to remove pain. A steady increase on allergic reactions and photoallergic contact dermatitis related to ketoprofen has been reported when there is topical use. However, there are few documented cases of hypersensitivity when it is administered systemically.Objective: Present a case of hypersensitivity reaction after systemic administration of ketoprofen for pain control in nephritis crisis.Case description: A 43-years-old Caucasian man diagnosed with renal colic (kidney lithiasis), who was initially treated with 100 mg of tramadol (IV), followed by 4 mg of thiocolchicoside (IM) which caused no relief. Then 100 mg of ketoprofen was administered (IV). Right after the patient began to show hypersensitivity reaction type I characterized by intense coughing, rhinitis, angioedema, periorbital edema, rash, and scleral jaundice.Discussion and conclusion: Maybe it was a case of drug-induced liver disease, however therapeutic dosages of all administered drugs only once. The mechanisms involved were not investigated, but may be the result of allergic and immunologic aspects caused by ketoprofen and facilitated by a history of hypersensitivity to other NSAIDs as reported by the patient. As for jaundice can be attributed to drug toxicity since laboratory parameters did not reveal any evidence of liver disease.

Pistacia atlantica gum aqueous extract modulates humoral and cellular immune responses in BALB/c mice

Natural herbal products contain different compounds that can modulate immune and inflammatory diseases. This investigation aimed to examine the influence of Pistacia atlantica aqueous extract on cellular and humoral immunity in mice following the exposure to sheep red blood cells (SRBCs). For this purpose, male BALB/c mice (n = 40) were randomly assigned into 4 equivalent groups. The animals received 1 × 109 SRBCs in complete Freund?s adjuvant (CFA) intraperitoneally 3 times with two-week intervals. Five days after the final injection, blood samples were taken from the animals. Additionally, 1 × 109 SRBCs were also injected into the mice?s left hind footpad 48 h before the blood collection. Three groups of mice received various oral doses of the extract (100, 200, and 400 mg/kg) for 52 consecutive days after the study onset. Measurements were performed on the levels of humoral and cellular immune responses, splenocytes? ability to uptake neutral red, respiratory burst, and cell viability. The mice receiving Pistacia atlantica in all concentrations displayed significantly low delayed type hypersensitivity (DTH) reactions in a dose-dependent manner compared to the control animals. The treated mice also presented a dose-dependent, significantly lower average anti-SRBC titer than that in the control animals. IL-17 and IL-10 cytokine levels respectively decreased and increased significantly in the mice that received Pistacia atlantica compared to the control group. Splenocyte proliferation and respiratory burst declined significantly in mice treated with Pistacia atlantica as opposed to the normal control group but phagocytosis ability was significantly decreased. The immunomodulatory impacts of Pistacia atlantica might be partially caused by immunity diversion from proinflammatory cytokine IL-17 into antiinflammatory cytokine IL-10.

A Cross-Sectional Observational Study of Clinical Spectrum and Prevalence of Fixed Food Eruption in a Tertiary Care Hospital.

Background:Fixed food eruption (FFE) is a rare type of hypersensitivity reaction occurring after ingestion of some food items in the form of recurrent erythematous patches, bullae, vesicle, or pustule at the same site after ingestion of same or related food products. Various items listed responsible for causing FFE include tree nuts, groundnuts, legumes, lentils, eggs, fruits like kiwi, strawberry, tonic water, and tartrazine. Its more commonly reported in developed countries with no Indian studies as of yet. We studied the clinical spectrum and prevalence of FFE in a tertiary care hospital.Objective:To study the prevalence and pattern of FFE after eliminating all other possible causes including drug rash.Materials and Methods:A cross-section observational study of 27 consecutive patients suspected to have fixed food eruption after eliminating all possibilities of any drug reaction to the best of our knowledge. Informed consent was obtained from the patients, and ethical clearance was taken from the hospital ethical committee.Results:A total of 27 patients were studied out of which 18 (66.66%) were females and 9 (33.33%) were males. The prevalence of fixed food eruption was calculated to be 0.072%.Fixed food eruption was noted secondary to cashew nuts (14.8%), almonds (7.4%), walnut (7.4%), pistachio (3.7%), strawberry (3.7%), kiwi (3.7%), and cheese crisps (3.7%).Conclusion:This observational study highlights the varied patterns of fixed food eruptions as well as the burden of disease in population secondary to certain diets.

Herpes iris erythema multiforme manifested after human herpes virus type 1 (HHV-1) labial infection

Erythema multiforme (EM) is an acute, self-limiting, often recurrent disease, with or without mucosal involvement, which occurs in an IV type hypersensitivity reaction provoked by infectious, medication, physical, chemical, etc. agents. In erythema multiforme related to the human virus type 1 (HHV-1) infection, the skin and mucosal manifestations are a result from a cell-mediated immune response, directed against HSV-DNA polymerase-positive antigen cells (keratinocytes). We present a clinical case of a 33-year-old female patient with recurrent labial followed by a clinical appearance of EM. About a week after the resolution the recurrence, burning and itchy erythematous target lesions and blisters occurred involving upper and lower limbs, then spread to the face, neck, neckline, typical for EM. In some of the target lesions, a central blister appeared, surrounded by vesicles - iris of EM type. Serology tests established high positive antibodies to HSV-1 of IgG type (154 UI/mL). Based on the characteristic clinical findings we diagnosed iris erythema multiforme, related to HHV1 infection. The presented case is an interesting manifestation of the morphological type of EM, described by Thomas Bateman in 1817, herpes iris, preceded by a relapse of the infection.

Studies on the immunoregulation of Ginseng radix et rhizoma rubra aqueous extract in mice

Objective To investigate the immune enhancement effect of red ginseng aqueous extract in mice. Methods The aqueous extract of red ginseng was obtained by water extraction and concentration, and the aqueous extract 10 ml was equivalent to raw material 2.86 g. The experiment was divided into the blank control group, low dose group of red ginseng aqueous extract 0.24 g/(kg•d), middle dose group 0.48 g/(kg•d) and high dose group 1.43 g/(kg•d). In order to explore the immunoregulation effect of red ginseng aqueous extract, Organ/body weight ratio measurement, the delayed type hypersensitivity (DTH) reaction, the spleen lymphocyte transformation experiment induced by Con A, the detection of antibody-producing, the determination of serum hemolysin experiments, the clearance rate of carbon particles, the phagocytosis effect of macrophages with chicken red blood cell experiments, and the determination of natural killer cell activity were carried out with the mice. Results Compared to the blank control group, the tow edema degree (0.62 ± 0.14 mm, 0.53 ± 0.12 mm vs. 0.36 ± 0.10 mm) of low dose group and medium dose group significantly increased (P<0.05). The ability of proliferation of T lymphocytes (0.173 ± 0.054, 0.189 ± 0.063 vs. 0.098 ± 0.012) of low dose group and high dose group significantly increased (P<0.05). The number of haemolytic empty spots (137.49×103 ± 24.73×103, 148.43×103 ± 27.53×103vs. 112.96×103 ± 26.28×103) of medium dose group and high dose group significantly increased (P<0.05). The phagocytosis rate (35.67% ± 3.82%, 49.26% ± 6.54%, 57.92% ± 7.36% vs. 24.34% ± 4.22%) and index (0.72 ± 0.23, 0.82 ± 0.15, 0.91 ± 0.26 vs. 0.35 ± 0.11) of low-, medium-, high-dose group significantly increased (P<0.05). However, there was no statistical difference in the organ/body weight ratio of the experimental animals, the determination of serum hemolysin experiments, the clearance rate of carbon particles, and NK cells activity. Conclusion Red ginseng aqueous extract has an exact role in immunity improvement in mice. Key words: Ginseng radix et rhizoma; Ginseng radix et rhizoma rubra; Immunoregulation; Mice

2083 Mesalamine-Induced Myocarditis

INTRODUCTION: Mesalamine is a widely used medication for treatment in patients with ulcerative colitis (UC). A rare adverse effect (AE) is mesalamine-induced myocarditis (MIM). A high index of suspicion is essential for prompt diagnosis and prevention of significant morbidity. We present a patient with UC with MIM diagnosis leading to a positive outcome. CASE DESCRIPTION/METHODS: 31-year-old female with UC presented to the emergency department (ED) with a one-week history of progressive, non-exertional CP. The patient had been on prednisone and mesalamine for two weeks for pan-colitis. Labs revealed troponin 6.085 ng/ml, BNP 1,371.7 pg/ml, ESR 73 mmHg/hr, and C-reactive protein 246.4 mg/dl. EKG, Transthoracic echocardiogram, CT angiography of the chest, and left heart catheterization were inconclusive. Due to the ongoing atypical chest pain, lack of cardiac risk factors, patient's age, and elevated inflammatory markers, a cardiac MRI (CMRI) was ordered and was consistent with myocarditis (Figures 1 and 2). Mesalamine was discontinued with complete resolution of CP and normal troponin. The patient was discharged on colonic release budesonide and two weeks later reported no CP. Labs at that time revealed a negative troponin, low CRP 34, and a BNP of 36.7. DISCUSSION: Mesalamine is an effective treatment in UC. Rare AE include blood dyscresias, pleuritis, myocarditis and pancreatitis6. Of these, MIM can be fatal and a high degree of clinical suspicion is required for early diagnosis and management. The pathophysiology of myocardial inflammation with mesalamine remains unclear. A commonly accepted hypothesis is a multisystem cell mediated hypersensitivity type reaction resulting in hypereosinophilia and inflammation4. MIM usually occurs within 2-4 weeks of starting therapy and early diagnosis tends to result in near complete resolution of symptoms after discontinuation of the medication2-5,7. This highlights the importance of prompt diagnosis and management of MIM.

A Systematic Review of the Literature of Delayed Inflammatory Reactions After Hyaluronic Acid Filler Injection to Estimate the Incidence of Delayed Type Hypersensitivity Reaction.

Hyaluronic acid (HA) dermal filler injection is believed to be a safe procedure. However, with the increase in the number of performed procedures and indications, the number of product-related complications, especially delayed inflammatory reactions, has also increased. Delayed-type hypersensitivity (DTH) reaction is one of these delayed inflammatory reactions, which is preventable by performing a pretreatment skin test. The authors sought to find the incidence of delayed inflammatory reactions and DTH reaction after HA injection and to determine whether a pretreatment skin test is worthwhile to be performed. The authors conducted a systematic literature review of all the relevant prospective studies, retrospective studies, and case reports on delayed inflammatory reactions and DTH reaction after HA filler injection. The incidence of delayed inflammatory reactions calculated from the prospective studies was 1.1% per year, and that of possible DTH reaction was 0.06% per year. Most retrospective studies estimated a percentage of delayed inflammatory reactions of less than 1% in 1 to 5.5 years. The incidence of DTH reaction would be lower than that. Among all the DTH cases reported, only about 5% of them were proven to be genuine DTH reactions. The incidence of both delayed inflammatory reactions and DTH reaction is low. There is evidence that genuine DTH reactions caused by HA fillers approved by the Food and Drug Administration do exist. This adverse event can be prevented by performing a pretreatment skin test. However, the incidence of DTH reaction is so low that the pretreatment skin test is not mandatory if Food and Drug Administration-approved HA fillers are used.

Feline asthma and chronic bronchitis - an overview of diagnostics and therapy

Feline asthma and feline chronic bronchitis are considered the most common chronic lower respiratory diseases in cats and are frequently referred to by the term chronic bronchial diseases. In feline asthma, a hypersensitivity reaction type I is suspected. For chronic bronchitis, the aetiology remains largely unknown. Affected cats may suffer from coughing, dyspnoea, and increased respiratory sounds. Both conditions are currently defined by the cytological cell pattern in the bronchoalveolar lavage and may differ in ethology, treatment, and clinical course. For diagnosis, other underlying conditions must be ruled out, in combination with the evidence for non-bacterial, eosinophilic or neutrophilic airway inflammation. In addition to the established therapy with oral or inhaled glucocorticoids and bronchodilators, the article also presents newer therapeutic and diagnostic options.

PS1380 PEPTIDE VACCINATION AGAINST PD‐L1 (IO103) IN MULTIPLE MYELOMA – A PHASE I FIRST IN HUMAN TRIAL

Background:The level of programmed death ligand 1 (PD‐L1) on multiple myeloma (MM) cells is associated with relapse, treatment refractory disease and an aggressive disease phenotype. We have identified naturally occurring T cells specific to PD‐L1. These PD‐L1 specific T cells are naturally present in healthy donors as well as cancer patients. We have previously shown that stimulation of PD‐L1 specific T cells has a boosting effect on anti‐viral immunity (Ahmad et al, Leukemia 2013) and that PD‐L1 specific T‐cells are cytotoxic towards PD‐L1 positive cancer cells (Munir et al, Cancer Res, 2013). Based on these and additional data, we have developed a peptide vaccine against PD‐L1.Aims:The primary endpoint was safety, a secondary endpoint was immunogenicity of the vaccine. An exploratory outcome was efficacy (NCT03042793).Methods:This is a single center first‐in‐human study which included patients from four weeks to one year after high dose chemotherapy with autologous stem cell support (HDT). Apart from the experimental vaccinations, no maintenance treatment was given. All patients received zoledronic acid. Key eligibility criteria were performance status (ECOG) of 2 or less, no severe comorbidities or autoimmune diseases and no signs of relapse of myeloma. The vaccine consists of a 19‐amino acid peptide from the signal peptide of PD‐L1 (IO103). One vaccine contains 100 μg peptide aqueously dissolved and emulsified 1:1 with the adjuvant Montanide ISA‐51 (Seppic Inc. Paris, France) giving a total volume of 1 ml. Vaccinations were given as a subcutaneous injection every two weeks repeating six times and once every four weeks thereafter to reach a total of 15 vaccines. Adverse events were assessed according to CTCAE v.4.03. Bone marrow, serum and peripheral blood mononuclear cells were collected before, during and after the course of vaccines. Delayed type hypersensitivity (DTH) reaction against the vaccine was performed once after 6 injections. 48 hours after DTH‐injection, punch‐biopsies were taken from the sites of DTH‐injections. Skin infiltrating lymphocytes (SKILs) were grown from these biopsies, and their reactivity against the vaccine was tested in enzyme‐linked immune‐spot assays (ELISPOT).Results:Ten patients were included at the department of Hematology at Hospital Herlev, Denmark, between March and November 2017. Four women and six men. Mean age 60.3 (range 39–70). Adverse reactions to the PD‐L1 vaccine (IO103) have been mainly grade 1–2 injection site reactions. The rate of infections was as expected for the population. 8 of 8 patients with evaluable SKILs show strong reactions to the vaccine (Fig 1). Analysis of the remaining immune data is being performed and will be reported. Before start of vaccinations four patients were in complete response (CR) or better and five patients were in very good partial response (VGPR). Since the start of vaccinations, six of the ten patients have experienced relapse of MM. Nine patients are still alive. The rate of relapses was as expected for the population. Interestingly one patient had spontaneous clearance and one patient had significant regression of concurrent basal cell carcinoma during the course of vaccinations.Summary/Conclusion:Vaccinations with the PD‐L1 peptide (IO103) was associated with very limited side effects. The vaccine is highly immunogenic. Two phase IIa studies testing PD‐L1 (IO103) as monotherapy are ongoing, one for patients with high‐risk smoldering multiple myeloma (NCT03850522) and one for patients with basal cell carcinoma before surgery (NCT03714529).image

PS1381 A PHASE 2 TRIAL OF THE COMBINATION OF IXAZOMIB, THALIDOMIDE AND DEXAMETHASONE (ITD) IN RELAPSED AND/OR REFRACTORY MULTIPLE MYELOMA – THE AMARC 16–02 TRIAL

Background: The level of programmed death ligand 1 (PD-L1) on multiple myeloma (MM) cells is associated with relapse, treatment refractory disease and an aggressive disease phenotype. We have identified naturally occurring T cells specific to PD-L1. These PD-L1 specific T cells are naturally present in healthy donors as well as cancer patients. We have previously shown that stimulation of PD-L1 specific T cells has a boosting effect on anti-viral immunity (Ahmad et al, Leukemia 2013) and that PD-L1 specific T-cells are cytotoxic towards PD-L1 positive cancer cells (Munir et al, Cancer Res, 2013). Based on these and additional data, we have developed a peptide vaccine against PD-L1. Aims: The primary endpoint was safety, a secondary endpoint was immunogenicity of the vaccine. An exploratory outcome was efficacy (NCT03042793). Methods: This is a single center first-in-human study which included patients from four weeks to one year after high dose chemotherapy with autologous stem cell support (HDT). Apart from the experimental vaccinations, no maintenance treatment was given. All patients received zoledronic acid. Key eligibility criteria were performance status (ECOG) of 2 or less, no severe comorbidities or autoimmune diseases and no signs of relapse of myeloma. The vaccine consists of a 19-amino acid peptide from the signal peptide of PD-L1 (IO103). One vaccine contains 100 μg peptide aqueously dissolved and emulsified 1:1 with the adjuvant Montanide ISA-51 (Seppic Inc. Paris, France) giving a total volume of 1 ml. Vaccinations were given as a subcutaneous injection every two weeks repeating six times and once every four weeks thereafter to reach a total of 15 vaccines. Adverse events were assessed according to CTCAE v.4.03. Bone marrow, serum and peripheral blood mononuclear cells were collected before, during and after the course of vaccines. Delayed type hypersensitivity (DTH) reaction against the vaccine was performed once after 6 injections. 48 hours after DTH-injection, punch-biopsies were taken from the sites of DTH-injections. Skin infiltrating lymphocytes (SKILs) were grown from these biopsies, and their reactivity against the vaccine was tested in enzyme-linked immune-spot assays (ELISPOT). Results: Ten patients were included at the department of Hematology at Hospital Herlev, Denmark, between March and November 2017. Four women and six men. Mean age 60.3 (range 39–70). Adverse reactions to the PD-L1 vaccine (IO103) have been mainly grade 1–2 injection site reactions. The rate of infections was as expected for the population. 8 of 8 patients with evaluable SKILs show strong reactions to the vaccine (Fig 1). Analysis of the remaining immune data is being performed and will be reported. Before start of vaccinations four patients were in complete response (CR) or better and five patients were in very good partial response (VGPR). Since the start of vaccinations, six of the ten patients have experienced relapse of MM. Nine patients are still alive. The rate of relapses was as expected for the population. Interestingly one patient had spontaneous clearance and one patient had significant regression of concurrent basal cell carcinoma during the course of vaccinations.Summary/Conclusion: Vaccinations with the PD-L1 peptide (IO103) was associated with very limited side effects. The vaccine is highly immunogenic. Two phase IIa studies testing PD-L1 (IO103) as monotherapy are ongoing, one for patients with high-risk smoldering multiple myeloma (NCT03850522) and one for patients with basal cell carcinoma before surgery (NCT03714529).

Immunologic responses in triple-negative breast cancer patients in a randomized phase IIb trial of nelipepimut-S plus trastuzumab versus trastuzumab alone to prevent recurrence.

556 Background: Breast cancer (BC) patients (pts) expressing low levels of HER2 by (immunohistochemistry (IHC) 1-2+) are not eligible for trastuzumab (Tz). However, in a randomized phase 2b trial, triple negative BC (TNBC) pts demonstrated a significantly better DFS with nelipepimut-S (NPS) + Tz vs Tz alone. Here, we assess the ex vivo and in vivo immune responses (IR) in both arms. Methods: Disease-free pts (n = 275) with HER2 IHC 1-2+, non-amplified BC who were node positive and/or had TNBC were randomized 1:1 to granulocyte-macrophage-colony stimulating factor (GM-CSF) or NPS+GM-CSF. ±NPS was given every 3 weeks x 6 followed by 4 boosters every 6 months (mo). All pts received Tz concurrently for 1 year per label regimen and were followed for recurrence. IR were evaluated ex vivo by clonal expansion of NPS-specific cytotoxic T lymphocytes (CTL) by dextramer-staining/flow cytometry at time points over 3 years. In vivo IR were assessed by delayed type hypersensitivity (DTH) reactions periodically. Results: The trial enrolled 97 TNBC pts; 60 had 4 timepoints available for analysis (37 NPS + Tz pts; 23 Tz pts). The NPS+Tz group exhibited increases in CTL frequencies vs baseline: 208%, 303%, 379% at 18, 24 and 30 mo, respectively. NPS+Tz pts’ mean CTL frequencies increased from 0.029 ±0.001% at baseline to 0.112±0.026% at 30 mo (p = 0.01) compared to Tz pts who were 0.027 ±0.001% at baseline and 0.057 ±0.016% at 30 mo (p = 0.71). Only 4 NPS+Tz pts recurred as compared to 13 in the Tz arm. While limited by low numbers, recurrent NPS + Tz pt did not mount an IR by ex vivo assessment (range: 0.0 - 0.026%) or by DTH (all measurements: 0 mm), while non-recurrent pts mounted both clonal CTL expansion (range: 0.000- 0.33%) and enhanced DTH (range: 0.0- 80.5mm). Conclusions: NPS+Tz combination is more efficacious in generating time-dependent antigen (NPS)-specific CTL by both ex vivo and in vivo measures vs Tz. Based on these preliminary data, it appears that both ex vivo and in vivo IR to NPS were attenuated in pts with TNBC recurrence. Further analysis of read-outs from these assays to validate the relationship of IRs to clinical effect seen with NPS+Tz in TNBC pts is underway. Clinical trial information: NCT02297698.

SAT-210 Autoimmune Progesterone Dermatitis: A Rare Case Report in a Young Woman with Chronic Dermatitis

Back ground: Autoimmune progesterone dermatitis (APD) or progesterone hypersensitivity (PH) is a rare hypersensitivity reaction to progestogen that exclusively occur in women of childbearing age of which is the underlying mechanism remains not well understood. Clinical case: A 44 years old lady was referred to our endocrine outpatient clinic by her dermatologist for treatment of a recently diagnosed autoimmune progesterone dermatitis. She was initially evaluated for a skin rash that started during the second trimester of her second pregnancy in 2009. Her initial diagnosis was pregnancy induced eczema which was treated with topical steroid with no significant improvement. Her rash worsens after delivery and had persisted since then. She failed chronic systemic steroid treatment and multiple immunosuppressive medications over the years. She had regular menstrual period since her menarche at age of 11 years old. She was on oral contraceptive medication prior to her second pregnancy which she resumed after delivery. She then switched to IUD. Her rash typically gets worse 7-10 days before the onset of her menstrual period with some improvement after her period. Her initial clinical exam showed erythematous papules over her extensor elbows, thighs and genital area with scattered eczematous excoriated plaques over her extremities and trunk. She underwent skin patch test which showed that she is allergic to class A, B, and D1 steroids PH was suspected based on her history and confirmed by a positive progesterone skin test. She was referred to reproductive endocrinology for consideration of ovulation suppression using GnRH agonist. Conclusion: APD is a rare hypersensitivity reaction that can be triggered by endogenous progesterone (menses, pregnancy) or exogenous progestin (OCP, IUD, IVF) exposure. Women between menarche and menopause can be affected with the average age of onset to be in the third decade of life. The underlying mechanism is not well known with several hypotheses being postulated (e.g hypersensitivity reaction type I and IV, hormone cross reactivity and autoimmunity) Clinical presentation is variable and can range from mild dermatitis to life threatening anaphylaxis with some extra dermal manifestations have been described. Detailed history taking is the key to diagnosis as the most consistent features is the presentation of symptoms during the luteal phase of the menstrual cycle. The goal of treating APD is to suppress ovulation which can be achieved by the use of GnRH agonist, selective estrogen receptor modulator or oophorectomy. Progesterone desensitization has been tried in women desiring pregnancy.

Profile of Drug Hypersensitivity Patients Hospitalized in Dr. Soetomo Hospital, Surabaya, Indonesia: Preliminary Data of 6 Months Observation

Drug hypersensitivity is defined as an untoward response to medication which is noxious and unintended, and which occurs at doses normally used in human either for the prophylaxis, diagnosis, or therapy of disease or for the modification of physiological function. Drug hypersensitivity is common and may cause emergency condition until death. The incidence of drug hypersensitivity-related hospitalizations has usually been assessed within hospitals. The aim of this study is to determine the profile of drug hypersensitivity patients hospitalized at Dr. Soetomo Hospital in 6 months period from January to June 2016. This study was a descriptive retrospective study on medical records of drug hypersensitivity patients hospitalized in Dr. Soetomo Hospital in 6 months period. The patient’s demographic data, the type of hypersensitivity reaction, and the final outcome of the hospitalization were collected. Within the 6 months period, there were 16 drug hypersensitivity patients hospitalized in Dr. Soetomo Hospital. Most of them are female (56.25%), and aged between 46-55 years (25%). There were 4 patients (25%) with type I hypersensitivity: urticaria, angioedema and anaphylaxis; while type IV hypersensitivity occured in 12 patients (75%): Stevens-Johnson syndrome, Stevens-Johnson syndrome-Toxic Epidermal Necrolysis overlap, erythroderma, maculopapular drug eruptions, and DRESS. Most of the patients (87.5%) had favorable outcome after hospitalization. There were 16 patients with drug hypersensitivity reaction hospitalized in Dr. Soetomo Hospital, Surabaya in 6 months period. Most of them were female and had type IV hypersensitivity reactions.

Transition from metal-DTH resistance to susceptibility is facilitated by NLRP3 inflammasome signaling induced Th17 reactivity: Implications for orthopedic implants.

Metal hypersensitivity has been recognized as an adverse biologic reaction that can compromise total joint arthroplasty (TJA) performance. However, the etiology of metal hypersensitivity responses in TJAs remains unclear. Metal implant debris is known to act as a danger signal that drives NLRP3 inflammasome activation. It remains unknown if implant debris induced inflammasome activation regulates T cell lineage in TJA metal hypersensitivity responses. In this study, we show both in vivo and in vitro that the pathogenesis of metal hypersensitivity responses to implant debris are largely dependent on activation of the inflammasome/caspase-1 pathway and subsequent production of IL-17A/F by CD4+ T cells. Inhibiting either the inflammasome pathway or IL-17A bioactivity in vivo and in vitro (in vivo using NLRP3 and Caspase-1 deficient mice or in vitro using blocking agents such as Capase-1 inhibitor, IL-1Ra and anti-IL-17A), significantly (p<0.05) mitigated metal-DTH paw inflammation as well as lymphocyte cytokine (IFN-γ and IL-17) and proliferation responses in metal-sensitized mice and primary human PBMCs. This study provides mechanistic insight into how in vivo exposure to orthopedic implant debris, and metals in general, elicits NLRP3 inflammasome activation that mediates the generation of IL-17A/F producing CD4+ T cells, leading to metal-delayed type hypersensitivity reactions.