Faculty Bibliography

T cell co-stimulation is important for the maintenance of immunologic tolerance. Co-inhibitory receptors including programmed cell death-1 (PD-1) confer peripheral tolerance to prevent autoimmunity. SAP (SH2D1A) is an adaptor molecule that is important in T cell signaling and has been shown to interact with signaling lymphocytic activation molecule (SLAM) family receptors also in the context of self-tolerance. We recently reported that SAP interferes with PD-1 function. In the current study, we investigated the levels of SAP and PD-1 in patients with rheumatoid arthritis (RA) to further understand what role they play in disease activity. We observed increased SAP levels in lymphocytes of RA patients and found that PD-1 levels correlated positively with RA disease activity. Additionally, we found that SAP interacts with CD28 to inhibit T cell signaling in vitro. This work demonstrates a putative molecular mechanism for SAP mediated PD-1 inhibition.

In the past 10 years, immune checkpoint inhibitors (ICIs) have become an additional pillar of cancer therapy by activating the immune system to treat a number of different malignancies. Many patients receiving ICIs develop immune-related adverse events (irAEs) that mimic some features of classical autoimmune diseases. Unfortunately, patients with underlying autoimmune conditions, many of whom have an increased risk for malignancy, have been excluded from clinical trials of ICIs due to a concern that they will have an increased risk of irAEs. Retrospective data from patients with autoimmune diseases and concomitant malignancy treated with ICIs are encouraging and suggest that ICIs may be tolerated safely in patients with specific autoimmune diseases, but there are no prospective data to guide management. In this manuscript, we review the relationship between pre-existing autoimmune disease and irAEs from checkpoint inhibitors. In addition, we assess the likelihood of autoimmune disease exacerbations in patients with pre-existing autoimmunity receiving ICI.

PURPOSE OF REVIEW/OBJECTIVE:Clinical use of immune checkpoint inhibitor (ICI) therapy has revolutionized the therapeutic landscape of cancer. By activating the immune system using monoclonal anti-CTLA-4 and PD(L)-1 antibodies, remission can be induced in previously terminal cancers. However, these breakthroughs come at a price. Multiple de-novo autoimmune illnesses, termed immune-related adverse events (irAEs), have been reported with patients increasingly being referred to rheumatologists with varying diagnoses. Among these are vasculitic syndromes, which may be limited to an organ or systemic and potentially-life threatening. Relatively little is known about the prevalence, mechanisms, and phenotypes of vasculitis occurring in response to ICIs. Here, we review the literature and describe the frequency and patterns of presentation. RECENT FINDINGS/RESULTS:Vasculitis, while infrequent, has been described as an irAE in patients treated with ICI therapy with resultant morbidity and mortality. SUMMARY/CONCLUSIONS:Recognizing the risk and management of immune checkpoint inhibitor induced vasculitis in patients with cancer is important in the daily practice of rheumatology.

Background: The prevalence of autoimmune diseases (AIDs) in patients with lung cancer is approximately 14%. However, patients with pre-existing AIDs have been excluded from trials of immune checkpoint inhibitors (ICIs) known to cause immune activation and lead to immune related adverse events (irAEs) limiting the data on safety and efficacy of these agents. Oncologists are therefore wary to use them in this at-risk population.
Method(s): We conducted a single institution IRB-approved retrospective study to evaluate the safety and efficacy of combination and single agent ICI therapy in patients with pre-existing AIDs and concomitant advanced lung cancer that were treated with ICI from 2011 to 2018. Primary endpoints were incidence of irAEs and AID flares. The secondary endpoint was overall survival (OS).
Result(s): We evaluated records from 29 patients with lung cancer of which 17 (59%) had adenocarcinoma, 10 (34%) had squamous cell carcinoma, two (7%) had small cell cancer, and one (3%) had undifferentiated non-small cell lung cancer. AIDs included rheumatic (72%), gastrointestinal (10%), endocrine (10%) and neurologic (7%). 34% of patients experienced an irAE, though only 7% were severe (grade 3-4 colitis and hepatitis). 66% of patients reported no irAEs at all. The most common irAEs were dermatitis (14%) and colitis (10%). 10% of patients had to permanently discontinue ICIs due to an irAE while 17% temporarily held their ICI. 96% of patients with AIDs were either stable or in remission. AID flares were observed in 28% of patients with 24% requiring treatment. None of the AID flares resulted in permanent discontinuation of ICI therapy. 21% of patients were on immunomodulatory therapies at start of ICI treatment. The use of immunomodulatory medications was not associated with an increased incidence of either irAEs or AID flares. Median OS from ICI initiation was 8.5 months and median PFS was 6 months. There was no statistically significant difference for OS or PFS by presence of irAE or presence of immunomodulatory therapy at start of ICI use.
Conclusion(s): In this cohort, patients with pre-existing AIDs and advanced lung cancer reported fewer AID flares (28%) than has been cited in the literature (approximately 50%). IrAEs were seen at an incidence similar to that observed in patients without AIDs. In our cohort, the majority of adverse reactions were manageable and did not require permanent discontinuation of ICI therapy. Furthermore, the presence of irAEs did not detrimentally affect patients' OS or PFS. Based on these findings, we would consider ICI therapy as an option in select patients with pre-existing autoimmunity. Keywords: toxicity, pre-existing autoimmune disease, Immunotherapy
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PURPOSE OF REVIEW/OBJECTIVE:With the advent of cancer immunotherapy and immune checkpoint inhibitors, patients with malignancies can now achieve durable remissions for conditions previously described as terminal. However, immune-related adverse events (irAEs) associated with cancer immunotherapy have become an anticipated consequence of enhanced T cell activation. Through an extensive literature review, we assess the most recent clinical and basic research data concerning immune checkpoint blockade and describe the spectrum of associated irAEs as well as their management. RECENT FINDINGS/RESULTS:Anti-PD-1, anti-PD-L1, and anti-CTLA-4 antibodies are widely used in the management of an array of tumors with incredible clinical remissions. However, irAEs cause significant morbidity and mortality and in some cases, result in withdrawal of cancer therapy and initiation of immunosuppression. While this is an exciting time in oncology, irAEs are a barrier to adequate care and therefore deserve close attention and improved capacity to predict and prevent toxicity. Rheumatologists should be familiar with these topics in the eventuality of patient evaluation and management.

Background/Purpose: T cells play a major role in the pathogenesis of Rheumatoid Arthritis (RA). These cells are regulated by signals provided via the T cell receptor (TCR) complex as well as by a set of co-receptors, which can propagate either stimulatory or inhibitory signals. CD28, a co-stimulatory receptor, and PD-1, a co-inhibitory receptor, are two essential T cell co-receptors whose ligands belong to the B7 family, but have opposing functions. Interestingly, both coreceptors play a role in the pathogenesis of RA and recent studies have shown that CD28 is targeted directly by PD-1. Accordingly, understanding the interplay between CD28 and PD-1 in the context of RA may provide novel approaches to better understand or treat autoimmunity. We hypothesize that PD-1 regulates CD28 function by dephosphorylating specific motifs in the tail of CD28 resulting in impaired downstream T cell function.
Method(s): Genetically modified T cell lines were used to study the contribution of different versions of CD28 to TCR signaling. Western blotting and cytokine levels were used to measure the role of CD28 on T cell function. The inhibitory effect of the PD-1 was examined by plating T cells on PD-1 ligand coated surfaces. Mass spectrometry was used to uncover additional proteins that regulate the interaction between PD-1 and CD28. To translate our finding to RA, blood and synovial fluid were collected from active RA patients (disease activity score (DAS)>5.1) to analyze expression of PD-1, CD28 and other signaling mediators. Peripheral blood mononuclear cells (PBMCs) and synovial fluid mononuclear cells (SFMCs) were analyzed by flow cytometry.
Result(s): We discovered that signaling downstream of PD-1 dephosphorylates tyrosine 173 of CD28 and that this event was absolutely required for the ability of PD-1 to inhibit interleukin 2 (IL-2) secretion. Mass spectrometry results identified SAP, a hematopoietic-restricted adaptor protein found to be associated with autoimmunity, as a regulator of the functional interaction between PD-1 and CD28. SAP co-localized and physically interacted with CD28 to counter PD-1 mediated dephosphorylation. More specifically, SAP bound to tyrosine 173, but not to tyrosine 190 of the cytoplasmic tail CD28, and by doing so blocked the ability of PD-1 to dephosphorylate this site. Additionally, serine at position 171 of CD28 was required to stabilize the interaction between SAP and CD28. Finally, we also learned that SAP levels were elevated in synovial fluid and peripheral blood RA T cells, concordant with PD-1 levels and DAS.
Conclusion(s): Our results demonstrate that SAP binds to phosphorylated CD28 at tyrosine 173 to interfere with PD-1 activity. It has been suggested that RA T cells are in a state of dysfunction with limited ability to regulate IL-2 production. Our finding of elevated SAP levels in these cells provides a mechanistic explanation for these observations whereby SAP interferes with PD-1 signaling by shielding phosphorylated CD28 and leading to persistent activation in acute disease followed by dysfunction in chronic disease. Therefore, SAP has potential to be utilized as a biomarker for RA disease activity. Manipulation of the PD-1/CD28 axis may prove to be a promising therapeutic target in autoimmunity