Joud Hajjar

Targeting the indoleamine 2,3-dioxygenase pathway in cancer

Tumor cells escape the immune surveillance system of the host through a process called immune tolerance. Immunotherapy targets molecules that serve as checks and balances in the regulation of immune response. Indoleamine-2,3-dioxygenase (IDO) is an intracellular enzyme, which through the process of tryptophan depletion exerts an immunosuppressive effect, facilitating immune escape of tumors. This review summarizes our current knowledge on IDO expression in malignancies, the IDO inhibitors that are currently available and those under clinical development.

Haplotype Analysis of the TRB Locus by TCRB Repertoire Sequencing

Polymorphism within the T cell receptor beta variable gene (TRBV) has been implicated in autoimmune disease and immuneCrelated adverse events (IRAEs) during immunotherapy. Previous efforts to evaluate TRBV polymorphism by whole genome sequencing (WGS) have been hampered by the repetitive nature of the TCRB locus. We present a novel longCamplicon TCRB repertoire sequencing approach to evaluate TRBV polymorphism from peripheral blood, which we use to identify TRBV allele haplotypes in 81 Caucasians.

Correction to: Use of Genetic Testing for Primary Immunodeficiency Patients

The original version of this article unfortunately contained mistakes in some of the author names and affiliations. The correct list of author names and affiliations is below, with the corrections in bold.

Use of Genetic Testing for Primary Immunodeficiency Patients

Genetic testing plays a critical role in diagnosis for many primary immunodeficiency diseases. The goals of this report are to outline some of the challenges that clinical immunologists face routinely in the use of genetic testing for patient care. In addition, we provide a review of the types of genetic testing used in the diagnosis of PID, including their strengths and limitations. We describe the strengths and limitations of different genetic testing approaches for specific clinical contexts that raise concern for specific PID disorders in light of the challenges reported by the clinical immunologist members of the CIS in a recent membership survey. Finally, we delineate the CIS’s recommendations for the use of genetic testing in light of these issues.

Biomarkers of response to immune checkpoint blockade in cancer treatment

Immune checkpoint inhibitors (ICPis) are emerging as the new corner stone of cancer treatment due to their ability to produce durable responses in patients with various cancers. But, objective responses to ICPis vary among each type of cancer. Further, treatment with ICPis is often associated with risk of developing immune-related adverse event, which are potentially life-threatening if untreated, indicating a need for patient selection. However, given the complexity of the tumor microenvironment and the dynamic interaction between tumor and immune cells, development of robust biomarkers to predict patients who are likely to respond to treatment with ICPis remains a challenge. In this review we present an overview of the immune monitoring strategies that are currently in use to enable appropriate patient selection.

Fatigue and the wear-off effect in adult patients with common variable immunodeficiency

Patients with common variable immunodeficiency (CVID) have increased fatigue compared with the general population. Fatigue is associated with lower quality of life (QoL), which is associated with higher mortality in CVID. This study aimed to determine the prevalence of self‐reported fatigue for patients with CVID and to identify its possible drivers and burden on QoL. We analysed data from the 2013 Immune Deficiency Foundation (IDF) treatment survey. Answers were included from 873 CVID patients who responded (respondents). Of the 873 respondents included in the analysis, 671 (76·9%) reported fatigue, of whom 400 (83·7%) were receiving intravenous (i.v.) immunoglobulins (IVIG) and 271 (68·6%) were receiving subcutaneous (s.c.) immunoglobulins. This difference in fatigue between patients receiving IVIG and SCIG was statistically significant (P < 0·001). Dose and frequency of immunoglobulin replacement therapy (IgGRT) did not affect fatigue prevalence. Fatigued patients on IVIG reported greater infection rates and required more anti‐microbials during the wear‐off period. Fatigued patients reported worse health status than non‐fatigued patients, and had lower rates of employment, education, household income and school attendance than their non‐fatigued counterparts. Fatigue is increased in CVID, especially among patients receiving IVIG, compared to SCIG. Fatigue has a significant impact on QoL and productivity in patients with CVID. Further studies to identify the mechanisms of fatigue are warranted to help advance therapeutic measures to treat this disease and improve patients’ QoL and wellbeing.

Abstract A44: No tumor or very small tumor burden in on-treatment biopsies is significantly associated with response to Pembrolizumab

Background: In phase I clinical trials, baseline and on-treatment biopsies are increasingly performed to investigate biomarkers correlating, e.g., with therapy response. Prior to use these biopsies for expensive analysis, quality control (QC) is performed regarding, e.g., morphology, tumor content. However, studies to correlate the results obtained from QC evaluation with clinical outcomes are lacking. The purpose of this study was to determine if data from the QC process correlate with therapy response. Method: We investigated 64 baseline and 50 on-treatment (C1D15-21) biopsies from 67 patients participating in an ongoing phase I clinical trial receiving pembrolizumab for their rare tumors such as e.g. adrenocortical carcinoma, angiosarcoma, alveolar rhabdomyosarcoma, carcinoma of unknown primary, epithelioid hemangioendothelioma, malignant neoplasm of tunica vaginalis, paraganglioma, penile carcinoma, pituitary tumor, renal medullary carcinoma, teratoma, and others. Baseline and the on-treatment biopsies were taken in >90% from the same amenable tumor lesion. Matched biopsies were available in n= 48 (71.64%) and data on response was available for 54 (80.60%) patients. From all biopsies the tumor content was estimated by a pathologist on an HE 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A44.

Improved diagnostic clarity in shrimp allergic non‐dust-mite sensitized patients

BACKGROUND Allergen specific immunoglobulin E (sIgE) levels predictive of shrimp allergy have not been identified, but these may be helpful in identifying patients at risk for shrimp-induced allergic reactions. OBJECTIVE This study sought to identify component resolved diagnostic tests useful for diagnosis of shrimp allergy in patients with or without house-dust mite (HDM) sensitization to the major allergen cysteine protease (Der p 1). METHODS Patients with positive skin-prick test (SPT) results and/or sIgE values were recruited. Shrimp allergy was classified by oral food challenge (OFC) or by a clear history of anaphylaxis after shrimp ingestion. Patients with shrimp allergy and patients who were tolerant were further classified based on HDM sensitivity (Der p 1 > 0.35 kUA/L). Testing for sIgE to total shrimp, and shrimp and HDM components was performed. The Fisher exact test, Wilcoxon sum rank test, and receiver operating characteristics analyses were used to compare sIgE levels in patients with allergy and patients who were tolerant. RESULTS Of 79 patients recruited, 12 patients with shrimp allergy (7 with positive OFC results and 5 with a history of anaphylaxis) and 18 patients who were shrimp tolerant were enrolled. Of the patients not HDM sensitized, sIgE levels to shrimp (10.5 kUA/L, p = 0.012) and Der p 10 (4.09 kUA/L, p = 0.035) were higher in patients with shrimp allergy. Shrimp sIgE of ≥3.55 kUA/L had 100% diagnostic sensitivity and 85.7% specificity (receiver operating characteristic 0.94 [0.81, 1.0] 95% CI) and Der p 10 sIgE levels of ≥3.98 kUA/L had a diagnostic sensitivity of 80% and specificity of 100% (receiver operating characteristic 0.86 [0.57, 1.0] 95% CI) for prediction of clinical reactivity. CONCLUSION HDM sensitization influences shrimp and HDM component sIgE levels and, consequently, their diagnostic accuracy in shrimp allergy. In our series, in the patients who were non-HDM sensitized, a shrimp sIgE level of >3.55 kUA/L showed 100% sensitivity and, Der p 10 sIgE of >3.98 kUA/L showed 100% specificity for the diagnosis of shrimp allergy. These levels may not be applicable to every patient and, therefore, may not obviate the need for OFC.

Utility of Shrimp and Der p 10 specific IgE for Shrimp Allergy Diagnosis in Non-House Dust Mite Sensitized Patients

Background There are no set specific IgE (sIgE) to predict shrimp allergy as cross-reactivity with other arthropods play a role in shrimp sensitization. Objective This study identifies the allergens associated with shrimp allergy in house dust mite (HDM) and non-HDM sensitized patients. Methods Patients with shrimp sensitization (positive skin prick test [SPT] and/or sIgE) with/without history of clinical reaction were recruited. Allergy was confirmed by oral food challenge (OFC) except for patients with history of anaphylaxis. Shrimp allergic (SA) and shrimp tolerant (ST) patients were further classified based on HDM sensitivity. The sIgE to shrimp, shrimp and HDM components were performed. Fisher’s exact test, Wilcoxon sum rank test and receiver operating characteristics analyses were done. Results Of 79 patients recruited, 12 SA (7 positive OFC and 5 with history of anaphylaxis), 18 ST and 10 non-shrimp sensitized controls (NC) were enrolled. In non-HDM sensitized patients, sIgE to shrimp (10.5 kUA/L, p=0.012) and Der p 10 (4.09 kUA/L, p=0.035) were higher in SA patients. Shrimp sIgE ≥3.55 kUA/L had 100% sensitivity and 85.71% specificity (ROC=0.94[0.81, 1.0]). Der p 10 sIgE ≥3.98 kUA/L had sensitivity of 80% and specificity of 100% (ROC=0.86[0.57, 1.0]). rPen a 1 ≥1.1 kUA/L had sensitivity of 80% and specificity of 85.7% (ROC=0.80[0.47,1.0]). Conclusions In non-HDM sensitized patients, shrimp sIgE ≥3.55 kUA/L and Der p 10 sIgE≥3.98 kUA/L give 100% sensitivity and specificity, respectively, to diagnose shrimp allergy. HDM sensitivity can influence sIgE levels to shrimp and shrimp/HDM components due to cross-reactivity.

Overview of Basic Immunology for Clinical Investigators

Tumor exists as a complex network of structures with an ability to evolve and evade the host immune surveillance mechanism. The immune milieu which includes macrophages, dendritic cells, natural killer cells, neutrophils, mast cells, B cells, and T cells are found in the core, the invasive margin, or the adjacent stromal or lymphoid component of the tumor. The immune infiltrate is heterogeneous and varies within a patient and between patients of the same tumor histology. The location, density, functionality, and the cross talk between the immune cells in the tumor microenvironment influence the nature of immune response, prognosis, and treatment outcomes in cancer patients. Therefore, an understanding of the characteristics of the immune cells and their role in tumor immune surveillance is of paramount importance to identify immune targets and to develop novel immune therapeutics in the war against cancer. In this chapter, we provide an overview of the individual components of the human immune system and the translational relevance of predictive biomarkers.