IL2 Targeted to CD8+ T Cells Promotes Robust Effector T-cell Responses and Potent Antitumor Immunity.

IL2 signals pleiotropically on diverse cell types, some of which contribute to therapeutic activity against tumors, whereas others drive undesired activity, such as immunosuppression or toxicity. We explored the theory that targeting of IL2 to CD8+ T cells, which are key antitumor effectors, could enhance its therapeutic index. To this aim, we developed AB248, a CD8 cis-targeted IL2 that demonstrates over 500-fold preference for CD8+ T cells over natural killer and regulatory T cells (Tregs), which may contribute to toxicity and immunosuppression, respectively. AB248 recapitulated IL2's effects on CD8+ T cells in vitro and induced selective expansion of CD8+T cells in primates. In mice, an AB248 surrogate demonstrated superior antitumor activity and enhanced tolerability as compared with an untargeted IL2Rßγ agonist. Efficacy was associated with the expansion and phenotypic enhancement of tumor-infiltrating CD8+ T cells, including the emergence of a "better effector" population. These data support the potential utility of AB248 in clinical settings. Significance: The full potential of IL2 therapy remains to be unlocked. We demonstrate that toxicity can be decoupled from antitumor activity in preclinical models by limiting IL2 signaling to CD8+ T cells, supporting the development of CD8+ T cell-selective IL2 for the treatment of cancer. See related article by Kaptein et al. p. 1226.

Histoplasma tympanomastoiditis: Case report and literature review.

Histoplasma is a dimorphic fungus capable of producing a diverse array of clinical pathology in humans dependent upon the host immune status. Acute symptomatic infection typically presents as an isolated pulmonary or nodal disease in immunocompetent patients with extra-thoracic manifestations rarely seen in this population. In this report, we describe a novel case of Histoplasma capsulatum tympanomastoiditis in an immunocompetent patient who presented with progressively worsening purulent otorrhea, vertigo, and facial nerve palsy. He was successfully managed with surgical debridement and a prolonged antifungal course.

An Engineered IL15 Cytokine Mutein Fused to an Anti-PD1 Improves Intratumoral T-cell Function and Antitumor Immunity.

The use of cytokines for immunotherapy shows clinical efficacy but is frequently accompanied by severe adverse events caused by excessive and systemic immune activation. Here, we set out to address these challenges by engineering a fusion protein of a single, potency-reduced, IL15 mutein and a PD1-specific antibody (anti-PD1-IL15m). This immunocytokine was designed to deliver PD1-mediated, avidity-driven IL2/15 receptor stimulation to PD1+ tumor-infiltrating lymphocytes (TIL) while minimally affecting circulating peripheral natural killer (NK) cells and T cells. Treatment of tumor-bearing mice with a mouse cross-reactive fusion, anti-mPD1-IL15m, demonstrated potent antitumor efficacy without exacerbating body weight loss in B16 and MC38 syngeneic tumor models. Moreover, anti-mPD1-IL15m was more efficacious than an IL15 superagonist, an anti-mPD-1, or the combination thereof in the B16 melanoma model. Mechanistically, anti-PD1-IL15m preferentially targeted CD8+ TILs and single-cell RNA-sequencing analyses revealed that anti-mPD1-IL15m treatment induced the expansion of an exhausted CD8+ TIL cluster with high proliferative capacity and effector-like signatures. Antitumor efficacy of anti-mPD1-IL15m was dependent on CD8+ T cells, as depletion of CD8+ cells resulted in the loss of antitumor activity, whereas depletion of NK cells had little impact on efficacy. The impact of anti-hPD1-IL15m on primary human TILs from patients with cancer was also evaluated. Anti-hPD1-IL15m robustly enhanced the proliferation, activation, and cytotoxicity of CD8+ and CD4+ TILs from human primary cancers in vitro, whereas tumor-derived regulatory T cells were largely unaffected. Taken together, our findings showed that anti-PD1-IL15m exhibits a high translational promise with improved efficacy and safety of IL15 for cancer immunotherapy via targeting PD1+ TILs.See related Spotlight by Felices and Miller, p. 1110.

An Unusual Case of Evolving Localized Tetanus Despite Prior Immunization and Protective Antibody Titer.

Centers for Disease Control and Prevention has reported that tetanus infection in a fully immunized person with the last dose within 10 years is extremely rare. The prevalence of localized tetanus in such a scenario is unknown. Only two case reports of localized tetanus in previously immunized patients have been reported so far, making this the third one. Also, this is the first case of its kind to demonstrate evolving localized tetanus. Our patient is a 19-year-old man who presented with shortness of breath, pain in right upper extremity, shoulder, and neck. His chest X-ray and creatine kinase were normal. The patient was sent home. He presented again to our hospital two days later with difficulty swallowing and speaking as well as chest tightness. Routine blood tests, electrocardiogram, CT angiography of the chest, and transthoracic echocardiogram were normal. He gave a history of a cut in the right middle finger while removing the carpet a week before his presentation. His immunization history was complete with documented last tetanus shot nine years and two months ago. He was treated with tetanus vaccine and penicillin. His tetanus antitoxoid titer came out protective.

Characterization and Comparison of GITR Expression in Solid Tumors.

PURPOSE: Determine the differential effect of a FcγR-binding, mIgG2a anti-GITR antibody in mouse tumor models, and characterize the tumor microenvironment for the frequency of GITR expression in T-cell subsets from seven different human solid tumors.Experimental Design: For mouse experiments, wild-type C57BL/6 mice were subcutaneously injected with MC38 cells or B16 cells, and BALB/c mice were injected with CT26 cells. Mice were treated with the anti-mouse GITR agonist antibody 21B6, and tumor burden and survival were monitored. GITR expression was evaluated at the single-cell level using flow cytometry (FC). A total of 213 samples were evaluated for GITR expression by IHC, 63 by FC, and 170 by both in seven human solid tumors: advanced hepatocellular carcinoma, non-small cell lung cancer (NSCLC), renal cell carcinoma, pancreatic carcinoma, head and neck carcinoma, melanoma, and ovarian carcinoma. RESULTS: The therapeutic benefit of 21B6 was greatest in CT26 followed by MC38, and was least in the B16 tumor model. The frequency of CD8 T cells and effector CD4 T cells within the immune infiltrate correlated with response to treatment with GITR antibody. Analysis of clinical tumor samples showed that NSCLC, renal cell carcinoma, and melanoma had the highest proportions of GITR-expressing cells and highest per-cell density of GITR expression on CD4+ Foxp3+ T regulatory cells. IHC and FC data showed similar trends with a good correlation between both techniques. CONCLUSIONS: Human tumor data suggest that NSCLC, renal cell carcinoma, and melanoma should be the tumor subtypes prioritized for anti-GITR therapy development.

Continuous infusion of furosemide combined with low-dose dopamine compared to intermittent boluses in acutely decompensated heart failure is less nephrotoxic and carries a lower readmission at thirty days.

INTRODUCTION: Furosemide is a potent loop diuretic that is widely used in the management of heart failure. Several reports have suggested that continuous intravenous administration of loop diuretics may be superior to intermittent administration. In addition the effect of low-dose dopamine to improve renal perfusion might be of benefit to this patient cohort. METHODS: We retrospectively evaluated 116 consecutive cardiac care unit patients, who were admitted with acute decompensated heart failure and were divided into two equal groups according to diuretic protocol. Group A patients received furosemide by continuous infusion combined with low-dose dopamine infusion. Group B patients received bolus therapy of intravenous furosemide. The effect on renal function and readmission rate was recorded. RESULTS: Among 116 patients (60% males, average age 71, range 46-96 years) 41% had ischemic cardiomyopathy, NYHA functional Class was 3.5 ± 0.5 and average EF was 21% ± 7%. On admission, patients in Group A had creatinine (Cr) 2.3 ± 0.2 mg/dL, blood urea nitrogen (BUN) 49.2 ± 25 mg/100 ml and median b-type natriuretic peptid (BNP) 1340 pg/mL, compared to group B patients with Cr 1.7 ± 1.2 mg/dL, BUN 32 ± 22 mg/100 ml and median BNP 1106 pg/mL. The average furosemide dose in group A was 7.9 ± 3.5 mg/hr compared to 7.6 ± 2.7 mg/hr for group B (p=NS). At the end of the study, patients in group A had lower Cr 1.8 ± 0.9 (p=0.0001), lower BUN 43.6 ± 22.9 (p=NS), an increase in estimated glomerular filtration rate 57.4 ± 27.4, a shorter hospital stay (p=0.015) and lower readmission rates at 30 days (p=0.0003). CONCLUSIONS: Continuous infusion of furosemide in addition to low-dose dopamine is safe, effective and less nephrotoxic than intermittent boluses in patients admitted with acute decompensated heart failure and portends a shorter hospital stay and lower readmission rates at 30 days.