Aberrant Lck Signal via CD28 Costimulation Augments Antigen-Specific Functionality and Tumor Control by Redirected T Cells with PD-1 Blockade in Humanized Mice.

Purpose: Combination therapy of adoptively transferred redirected T cells and checkpoint inhibitors aims for higher response rates in tumors poorly responsive to immunotherapy like malignant pleural mesothelioma (MPM). Only most recently the issue of an optimally active chimeric antigen receptor (CAR) and the combination with checkpoint inhibitors is starting to be addressed.Experimental Design: Fibroblast activation protein (FAP)-specific CARs with different costimulatory domains, including CD28, Δ-CD28 (lacking lck binding moiety), or 4-1BB were established. CAR-T cells were characterized in vitro and antitumor efficacy was tested in vivo in a humanized mouse model in combination with PD-1 blockade. Finally, the Δ-CD28 CAR was tested clinically in a patient with MPM.Results: All the three CARs demonstrated FAP-specific functionality in vitro Gene expression data indicated a distinct activity profile for the Δ-CD28 CAR, including higher expression of genes involved in cell division, glycolysis, fatty acid oxidation, and oxidative phosphorylation. In vivo, only T cells expressing the Δ-CD28 CAR in combination with PD-1 blockade controlled tumor growth. When injected into the pleural effusion of a patient with MPM, the Δ-CD28 CAR could be detected for up to 21 days and showed functionality.Conclusions: Overall, anti-FAP-Δ-CD28/CD3ζ CAR T cells revealed superior in vitro functionality, better tumor control in combination with PD-1 blockade in humanized mice, and persistence up to 21 days in a patient with MPM. Therefore, further clinical investigation of this optimized CAR is warranted. Clin Cancer Res; 24(16); 3981-93. ©2018 AACR.

Influence of a nutritional intervention on dietary intake and quality of life in cancer patients: a randomized controlled trial.

OBJECTIVE: Weight loss is common in patients with malignant tumors and it can adversely affect quality of life and survival. The aim of the present study was to investigate the effects of a nutritional intervention in cancer patients in an outpatient setting. METHODS: Cancer outpatients (N = 58) who were classified as undernourished or at high risk for undernutrition by the Nutritional Risk Screening 2002 tool were randomized into two groups. One group (n = 30) received standardized individual nutritional therapy, including counseling by a dietitian, food fortification, and oral nutritional supplements if required. The second group (n = 28) received standard care. The nutritional intervention lasted 3 mo. Dietary intake (3-d dietary record), nutritional status (body weight), physical functioning (performance status, hand-grip strength) and quality of life (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire version 3.0) were assessed at baseline and after 6 wk and 3 mo. An additional follow-up assessment was carried out 3 mo post-intervention. RESULTS: Nutritional intervention led to a significantly higher average energy and protein intake in the nutritional therapy group (+379 kcal; 95% confidence interval [CI], 117-642; P = 0.007, respectively; +10.4 g; 95% CI, 2.3-18.5; P = 0.016). However, the increased dietary intake was not associated with improvements in nutritional status, physical functioning, or quality of life. CONCLUSIONS: Individual nutritional counseling significantly and positively influenced energy and protein intake, but did not improve nutritional or physical outcome or quality of life. These results indicate that nutritional therapy alone is of limited efficacy in cancer patients whose nutritional status has already deteriorated.

Reversible posterior leukoencephalopathy syndrome after treatment of diffuse large B-cell lymphoma.

BACKGROUND: We report the case of a patient who experienced a severe neurologic complication after treatment of diffuse large B-cell lymphoma. CASE REPORT: A 62-year old patient was diagnosed with a diffuse large B-cell lymphoma and treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone under prophylactic G-CSF substitution. After the second cycle she developed severe neurologic complications with generalized seizures and soporous condition. The MRI showed bilateral areas of signal hyperintensity in the subcortical and cortical regions in both hemispheres, consistent with the diagnosis of a reversible posterior leukoencephalopathy syndrome. The patient was under surveillance in intensive care, and a meticulous control of the blood pressure was performed. She fully recovered within a few days, and MRI changes normalized. Antineoplastic treatment had to be continued, and we chose a combination of rituximab, doxorubicin, etoposide, and prednisone. CONCLUSIONS: The reversible posterior leukoencephalopathy syndrome is believed to be the result of altered cerebral autoregulation with impaired blood flow control and resultant endothelial damage caused by different situations and agents. Several chemotherapy agents have been described in association with the syndrome. However, little is known about the prevalence of the syndrome and the follow-up of these patients, especially their further treatment.

Unilateral uveitis induced by a nonionic iodinated contrast agent.

PURPOSE: To report recurrent unilateral uveitis after computed tomography (CT) enhanced by the contrast agent iopamidol. DESIGN: Observational case report. METHODS: A 44-year-old man with a history of mixed-cellularity Hodgkin lymphoma, Stage I B (axillar, infraclavicular, subpectoral lymphomas) was under remission after chemotherapy and radiotherapy. The contrast-enhanced CT scans performed every 3 months were within hours followed by a marked unilateral anterior uveitis, vitritis, and retinal bleedings. Symptoms resolved with topical corticosteroid treatment within a week. RESULTS: We observed recurrent unilateral uveitis after intravenously application of 150 ml of iopamidol for contrast-enhanced CT scans in a patient with lymphoma in remission. CONCLUSIONS: Iopamidol may induce uveitis under certain circumstances. We suggest a coincidence of immunologic mechanisms with predisposing discrete vascular radiation damage.