Thanarajasingam, Uma

ObjectiveTo determine the risk of rheumatic disease flare and adverse effects in patients with preexisting rheumatic disease who were receiving immune checkpoint inhibitor (ICI) therapy.MethodsA retrospective medical record review was performed to identify all patients who received ICI therapy at Mayo Clinic in Rochester, Minnesota between 2011 and 2016 (~700 patients). Those with a preexisting rheumatic disease were identified using specific diagnostic codes.ResultsSixteen patients were identified (81% female, median age 68.5 years). The most common rheumatic diseases were rheumatoid arthritis (n = 5), polymyalgia rheumatica (n = 5), Sjögren's syndrome (n = 2), and systemic lupus erythematosus (n = 2). Seven patients were receiving immunosuppressive therapy or glucocorticoids for their rheumatic disease at the time of initiation of the ICI. The primary malignancies were melanoma (n = 10), pulmonary (n = 4), or hematologic (n = 2). In most cases, ICIs were offered only after failure of several other therapies. Immune‐related adverse effects (IRAEs) occurred in 6 patients, and all were treated successfully with glucocorticoids and discontinuation of the ICI therapy. There were no significant differences in time from cancer diagnosis to immunotherapy, duration of immunotherapy, age, or sex between the patients with and those without IRAEs.ConclusionTo our knowledge, this represents the largest single‐center cohort of patients with rheumatic diseases who were exposed to modern cancer immunotherapy. Only a minority of these patients experienced a flare of their preexisting rheumatic disease or any other IRAE.

ObjectiveWe describe a 38‐year‐old woman who presented with a history of inflammatory arthritis, rash, and daily fevers. She was noted to have chronic parvovirus infection with persistently detectable viral titers and a novel mutation in the ELANE gene. ELANE encodes neutrophil elastase, a neutrophil serine protease with important antimicrobial effects, and is found as part of neutrophil extracellular trap (NET) complexes. Pathogenic ELANE mutations have been identified in forms of hereditary neutropenia. However, our patient never had neutropenia. Because of the striking clinical scenario, we investigated this mutation functionally.MethodsNET formation by neutrophils was assessed by scanning electron microscopy. Neutrophil activation and neutrophil elastase production were evaluated by flow cytometry and fluorescent substrate–based functional assay, respectively. A multiplex assay was used to quantitate neutrophil inflammatory cytokine production. PyMOL software was used to generate 3‐dimensional models of mutant elastase.ResultsActivated neutrophils from the patient demonstrated a significantly decreased ability to form NETs on scanning electron microscopy, as well as quantitative defects in neutrophil activation and neutrophil elastase activity. The patient's neutrophils showed altered levels of interleukin‐12 (IL‐12) and IL‐8, which are key cytokines for antiviral immunity and neutrophil chemotaxis. Three‐dimensional mapping revealed that the mutation could alter protein folding and surface charge distribution, potentially perturbing protein trafficking. Thus, the mutation could affect neutrophil function by decreasing NETosis and altering key antiviral activities of neutrophils.ConclusionThis is the first report of a human pathogenic ELANE mutation associated with a defect in NETosis and a distinct syndrome of recurrent viral infection and chronic inflammation.

Malignant cells may subvert and escape endogenous host immune surveillance by up‐regulation of immune inhibitory signals known as immune checkpoints. These checkpoints are important therapeutic targets, and antibodies that block checkpoint signaling have shown remarkable efficacy in some solid tumors as well as in some refractory hematologic malignancies. In hematologic cancers, the mechanism of these checkpoints is complex, as the tumor and immune system are one and the same. In this review, we evaluate the biology of checkpoint inhibition, review the current data on its efficacy in lymphoid tumors, and explore uncertainties in the field, including those involving the precise mechanisms of action, the appropriate timing of therapy, and the differences in response rate between lymphoid tumor types.

Abstract Strategies that generate tumor Ag-specific effector cells do not necessarily cure established tumors. We hypothesized that the relative efficiency with which tumor-specific effector cells reach the tumor is critical for therapy. We demonstrate in this study that activated T cells respond to the chemokine CCL3, both in vitro and in vivo, and we further demonstrate that expression of CCL3 within tumors increases the effector T cell infiltrate in those tumors. Importantly, we show that adenoviral gene transfer to cause expression of CCL3 within B16ova tumors in vivo increases the efficacy of adoptive transfer of tumor-specific effector OT1 T cells. We additionally demonstrate that such therapies result in endogenous immune responses to tumor Ags that are capable of protecting animals against subsequent tumor challenge. Strategies that modify the “visibility” of tumors have the potential to significantly enhance the efficacy of both vaccine and adoptive transfer therapies currently in development.

Relapsing polychondritis (RP) is an inflammatory disease of the cartilaginous tissue primarily affecting the cartilaginous structures of the ear, nose, joints, and the respiratory system. Cardiovascular complications of RP are associated with high morbidity and mortality and occur most commonly as valvular disease. Pericarditis is a less common complication, occurring in 4% of patients with RP and has not previously been described at presentation. We describe a case of relapsing polychondritis with acute pericarditis at presentation.

Diabetic mastopathy is an uncommon, benign disease of the breast that can occur in women with diabetes and clinically mimic breast cancer. We describe a patient with long-standing type 1 diabetes who presented with a palpable breast mass with negative imaging findings on mammography, ultrasonography, and breast MRI. Surgical biopsy and histopathology confirmed diabetic mastopathy. We use this case to highlight the recognition, radiographic features, pathology, and management of this benign breast condition and emphasize that, in diabetic patients, the differential diagnosis of a new breast mass should include diabetic mastopathy.

AbstractAdoptive T-cell transfer has achieved significant clinical success in advanced melanoma. However, therapeutic efficacy is limited by poor T-cell survival after adoptive transfer and by inefficient trafficking to tumor sites. Here, we report that intratumoral expression of the chemokine CCL21 enhances the efficacy of adoptive T-cell therapy in a mouse model of melanoma. Based on our novel observation that CCL21 is highly chemotactic for activated OT-1 T cells in vitro and down-regulates expression of CD62L, we hypothesized that tumor cell–mediated expression of this chemokine might recruit, and retain, adoptively transferred T cells to the sites of tumor growth. Mice bearing metastatic tumors stably transduced with CCL21 survived significantly longer following adoptive T-cell transfer than mice bearing non–CCL21-expressing tumors. However, although we could not detect increased trafficking of the adoptively transferred T cells to tumors, tumor-expressed CCL21 promoted the survival and cytotoxic activity of the adoptively transferred T cells and led to the priming of antitumor immunity following T-cell transfer. To translate these observations into a protocol of real clinical usefulness, we showed that adsorption of a retrovirus encoding CCL21 to OT-1 T cells before adoptive transfer increased the therapeutic efficacy of a subsequently administered dose of OT-1 T cells, resulting in cure of metastatic disease and the generation of immunologic memory in the majority of treated mice. These studies indicate a promising role for CCL21 in enhancing the therapeutic efficacy of adoptive T-cell therapy. [Cancer Res 2007;67(1):300–8]