SUMMARY Effector memory T (Tem) cells are essential mediators of autoimmune disease and delayed-type hypersensitivity (DTH), a convenient model for two-photon imaging of Tem cell participation in an inflammatory response. Shortly (3 hr) after entry into antigen-primed ear tissue, Tem cells stably attached to antigen-bearing antigen-presenting cells (APCs). After 24 hr, enlarged Tem cells were highly motile along collagen fibers and continued to migrate rapidly for 18 hr. Tem cells rely on voltage-gated Kv1.3 potassium channels to regulate calcium signaling. ShK-186, a specific Kv1.3 blocker, inhibited DTH and suppressed Tem cell enlargement and motility in inflamed tissue but had no effect on homing to or motility in lymph nodes of naive and central memory T (Tcm) cells. ShK-186 effectively treated disease in a rat model of multiple sclerosis. These results demonstrate a requirement for Kv1.3 channels in Tem cells during an inflammatory immune response in peripheral tissues. Targeting Kv1.3 allows for effector memory responses to be suppressed while central memory responses remain intact.

These three cases suggest that anti-IL-6 receptor antibody may be an effective alternative to corticosteroids or TNFαi for the treatment of arthritis irAEs.

BackgroundImmune-related enterocolitis (irEC) is the most common serious complication from checkpoint inhibitors (CPIs). The current front-line treatment for irEC, high-dose corticosteroids (CS), have significant side effects and prolonged therapy may reduce CPI-anti-tumor activity. Early addition of TNF-α inhibitors such as infliximab (IFX) may expedite symptom resolution and shorten CS duration. Thus, we conducted the first retrospective study, to our knowledge, evaluating symptom resolution in patients with irEC treated with and without IFX.MethodsData were collected from the medical records of patients diagnosed with irEC. The primary endpoint was time to symptom resolution for irEC for cases managed with IFX plus CS (IFX group) versus CS alone (CS group). Duration of CS, overall survival (OS), and time to treatment failure (TTF) were secondary endpoints.ResultsAmong 75 patients with irEC, 52% received CS alone, and 48% received IFX. Despite higher grade colitis in the IFX group (grade 3/4: 86% vs. 34%; p < 0.001), median times to diarrhea resolution (3 vs. 9 days; p < 0.001) and to steroid titration (4 vs. 13 days; p < 0.001) were shorter in the IFX group than in the CS group without a negative impact on TTF or OS. Total steroid duration (median 35 vs. 51 days; p = 0.150) was numerically lower in the IFX group.ConclusionsDespite higher incidence of grade 3/4 colitis, IFX added to CS for the treatment of patients with irEC was associated with a significantly shorter time to symptom resolution. The data suggest that early introduction of IFX should be considered for patients with irEC until definitive prospective clinical trials are conducted.Electronic supplementary materialThe online version of this article (10.1186/s40425-018-0412-0) contains supplementary material, which is available to authorized users.

BackgroundNovel immunotherapies, or checkpoint inhibitors, targeting programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) have significantly improved outcomes for patients with numerous different cancer types. However, owing to their exclusion from clinical trials and risk for autoimmune exacerbation on these treatments, the impact on safety and degree of toxicity of these potentially life-prolonging therapies is not well characterized in patients with an underlying autoimmune disease or previous organ transplant.Case presentationWe report a case of a patient with advanced melanoma and refractory Crohn’s disease who was treated concurrently with pembrolizumab (anti-PD-1 antibody) and tocilizumab (anti-interluekin-6 receptor antibody). This novel treatment strategy was well tolerated and did not result in Crohn’s disease exacerbation for at least 16 weeks. Importantly, this treatment resulted in marked, durable antitumor responses.ConclusionsThis outcome suggests that targeted immunosuppression combined with checkpoint inhibitors may hold promise as a treatment strategy for this unique patient population and may warrant additional study.

Purpose: Molecular profiling has been used to select patients for targeted therapy and determine prognosis. Noninvasive strategies are critical to hepatocellular carcinoma (HCC) given the challenge of obtaining liver tissue biopsies.Experimental Design: We analyzed blood samples from 206 patients with HCC using comprehensive genomic testing (Guardant Health) of circulating tumor DNA (ctDNA).Results: A total of 153/206 (74.3%) were men; median age, 62 years (range, 18-91 years). A total of 181/206 patients had 1 alteration. The total number of alterations was 680 (nonunique); median number of alterations/ patient was three (range, 1-13); median mutant allele frequency (% cfDNA), 0.49% (range, 0.06%-55.03%). TP53 was the common altered gene [>120 alterations (non-unique)] followed by EGFR, MET, ARID1A, MYC, NF1, BRAF, and ERBB2 [20-38 alterations (nonunique)/gene]. Of the patients with alterations, 56.9% (103/181) had 1 actionable alterations, most commonly in MYC, EGFR, ERBB2, BRAF, CCNE1, MET, PIK3CA, ARID1A, CDK6, and KRAS. In these genes, amplifications occurred more frequently than mutations. Hepatitis B (HBV)-positive patients were more likely to have ERBB2 alterations, 35.7% (5/14) versus 8.8% HBV-negative (P ¼ 0.04).Conclusions: This study represents the first large-scale analysis of blood-derived ctDNA in HCC in United States. The genomic distinction based on HCC risk factors and the high percentage of potentially actionable genomic alterations suggests potential clinical utility for this technology.Recent technological advances in molecular diagnostics have allowed for the study of solid malignancies through noninvasive blood sampling. Importantly, intact circulating tumor cells (CTCs) and cell-free DNA (cfDNA) [leukocyte-derived and tumor-derived (circulating tumor DNA; ctDNA)] can now be interrogated through advanced sequencing methods in order to identify somatic mutations that may be druggable targets for future therapies (1, 2). Although cfDNA and ctDNA are similar in that they both derive from cell lysis and apoptosis (3), ctDNA is the fraction of cfDNA, which can range from <0.1% to >10% (4), specifically derived from primary or metastatic tumors (5). Therefore, profiling the mutational landscape of ctDNA from solid tumors may represent a particularly attractive method for identifying tumor-associated somatic mutations. Applications that can be envisioned to be of clinical utility for hepatocellular carcinoma (HCC) include detection of genomic changes, mutational analysis, prognostication, oncogenic