Emerging approaches for preventing cytokine release syndrome in CAR-T cell therapy.

Chimeric antigen receptor (CAR) T cells have demonstrated remarkable anti-tumor efficacy against hematological malignancies, such as leukemia and lymphoma. However, patients treated with CAR-T cells frequently experience cytokine release syndrome (CRS), one of the most life-threatening adverse events of the therapy induced by systemic concentrations of pro-inflammatory cytokines throughout the body. Immunosuppressants such as tocilizumab are currently administered to treat the onset and progression of CRS symptoms. In order to reduce the risk of CRS, newly designed next-generation CAR-T treatments are being developed for both hematopoietic malignancies and solid tumors. In this review, we discuss six classes of interesting approaches that control cytokine production of CAR-T cell therapy: adaptor-based strategies, orthogonal cytokine-receptor pairs, regulation of macrophage cytokine activity, autonomous neutralization of key cytokines, kill switches and methods of reversible suppression of CARs. With these strategies, future CAR-T cell therapies will be designed to preemptively inhibit CRS, minimize the patients' suffering, and maximize the number of benefiting patients.

CEACAM7 Is an Effective Target for CAR T-cell Therapy of Pancreatic Ductal Adenocarcinoma.

PURPOSE: To investigate whether CEACAM7 represents a novel therapeutic target for treating pancreatic ductal adenocarcinoma (PDAC) and to generate CEACAM7-targeting CAR T cells to test this hypothesis. EXPERIMENTAL DESIGN: We identified CEACAM7 (CGM2), a member of the CEA family of proteins with expression restricted to the colon and pancreas, as a potential CAR T-cell target for PDAC. We probed a panel of PDAC tumor sections as well as patient-derived PDAC cell cultures for CEACAM7 expression. We generated CAR-targeting CEACAM7, and assessed antitumor efficacy of CEACAM7 CAR T cells using in vitro and in vivo models. RESULTS: We show here that CEACAM7 is expressed in a large subset of PDAC tumors, with low to undetectable expression in all normal tissues tested. CEACAM7 is also expressed in primary PDAC cultures isolated from patient-derived tumors, with high expression within the cancer stem cell-enriched subset. CAR T cells targeting CEACAM7 are capable of targeting antigen-expressing tumor cells, and mediate remission in patient-derived xenograft tumors. CONCLUSIONS: We identify CEACAM7 as a potential therapeutic target in PDAC and describe the development of CEACAM7-targeted CAR T cells with efficacy against PDAC.

Mindfulness in Eating Is Inversely Related to Binge Eating and Mood Disturbances in University Students in Health-Related Disciplines.

The purpose of the study was to investigate the relationship between mindful eating, disordered eating and mood in university students in health-related disciplines. A total of 221 university students participated in the study; 102 students studied sport and exercise science (SS), 54 students pharmacy sciences (PS), and 65 students health sciences (HS). Participants completed the Binge Eating Scale (BES), the Mindful Eating Questionnaire (MEQ), and the Profile of Mood State questionnaire (POMS). 41% of the students were classified as binge eaters and 57% were above the POMS threshold of depression. Binge eaters were found to have significantly lower MEQ score and significantly higher total mood disturbance scores (TMD) compared to non-binge eaters (p < 0.01). Students with a high depression score exhibited no differences in the MEQ score but a significantly higher BES score compared to non-depressed students (p < 0.01). Gender differences were found in the MEQ with females exhibiting significantly higher scores in the MEQ score and in all MEQ subscales compared to males, with the exception of the emotional subscale that females were noted to have a lower score compared to males (p < 0.01). The MEQ score was inversely related to the BES score (r = -0.30, p < 0.01) and TMD (r = -0.21, p < 0.05). The MEQ score was a significant negative predictor of the variance of the binge eating behavior of the students (B = -3.17, p < 0.001). In conclusion, mindfulness in eating is inversely related to the binge eating behavior and mood state of university students studying health-related subjects and is a significant negative predictor of disordered eating behavior in this high risk population.

Prevalence of disordered eating in elite female athletes in team sports in Greece.

The purpose of the study was to assess (a) the prevalence of disordered eating (DE) in elite female team sports players compared to non-athletes and (b) to compare DE prevalence in elite female players in basketball, volleyball and water polo. One hundred and seventy-five females were recruited (age 23.10 ± 5.4, BMI 21.85 ± 2.3 kg/m2), 53 were elite basketball players, 42 were elite volleyball players, 34 were elite water polo players and 46 were non-athletes. Participants completed the Eating Disorders Questionnaire (EDE-Q) and a physical activity questionnaire. The EDE-Q incorporates 36 statements which relate to the occurrence and frequency of key behaviours of eating disorders, under the following four subscales: Restraint, eating concern, shape concern and weight concern and a global score of disordered eating. No differences were found in the EDE-Q subscale score and global score between athletes and non-athletes. Only 6.2% of the total number of participants exhibited DE using the global score >2.3. Water polo players had significantly higher scores in the 'eating concern' subscale and in the frequency of key behavioural features of DE such as binge eating episodes and objective and subjective bulimic episodes, compared to volleyball and basketball players. In conclusion, team sport elite female players do not exhibit greater prevalence of DE compared to non-athletes. Water polo, a sport that emphasises leanness and control of body weight for international distinctions, is associated with a higher tendency to exhibit DE, when compared to other team sports.

Effects of High Carbohydrate vs. High Protein Pre-exercise Feedings on Psychophysiological Responses to High Intensity Interval Exercise in Overweight Perimenopausal Women.

Objective: To investigate (a) the acute effect of a bout of high intensity interval exercise (HIIE) on mood, cognitive function, and blood pressure in overweight perimenopausal women and (b) to compare the effects of high carbohydrate vs. high protein pre-HIIE feedings on exercise capacity, mood and cognitive function in this population. Methods: Twelve, overweight, perimenopausal women (age; 45.5 ± 2.3 years, body fat; 32.2 ± 2.1%) completed a bout of HIIE under 3 pre-exercise feedings (HCHO: high-carbohydrate-low-protein; LCHP: low-carbohydrate-high-protein; control: fasted) in a randomized crossover design. HIIE consisted of 4 intervals of 4 min walking at 85-90% of maximum heart rate and 3 min recovery. Before and after HIIE, the shortened version of the profile of mood state questionnaire, the exercise-induced feeling inventory questionnaire and three cognitive function tests (Stroop test, Shift Stroop test, n-back test) were administered. Blood pressure was measured pre- and post-exercise. Following HIIE a performance test to volitional fatigue was conducted. Results: A single bout of HIIE resulted in significant reductions in blood pressure and improvements in cognitive capacity (p < 0.05). Both the HCHO and LCHP feedings led to significantly longer exercise performance compared to CON (422 ± 71 s and 340 ± 46 vs. 240 ± 32 s, respectively, p < 0.01), with a 1.22-fold greater increase in performance time in HCHO compared to LCHP, although not statistically significant (p > 0.05). Only the HCHO trial improved total mood disturbance and positive engagement 1 h-post-exercise compared to CON (p < 0.05). HCHO and LCHP improved physical exhaustion and revitalization feelings post-exercise vs. CON (p < 0.01). Conclusions: A single HIIE session improves cognitive function and blood pressure in overweight perimenopausal women. High-carbohydrate pre-HIIE feedings can result in greater enhancements in mood and positive engagement to exercise and may improve exercise performance compared to a high-protein meal.