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Chimeric antigen receptor (CAR) T cell therapies have demonstrated remarkable efficacy in hematologic malignancies; however, their clinical benefit in solid tumors remains limited. A major barrier is T cell dysfunction, particularly exhaustion and senescence, which impair persistence, effector function, and durable tumor control. Targeting these dysfunctional states is therefore essential in order to improve CAR T cell efficacy in solid tumors.This review summarizes recent preclinical strategies aimed at preventing or reversing CAR T cell exhaustion and senescence in solid malignancies. While both exhaustion and senescence are relevant dysfunctional states, the preclinical evidence summarized in this review is currently more extensive for modulation of exhaustion-associated programs than for direct reversal of canonical T cell senescence. Approaches are organized according to their primary mechanistic focus, including gene editing, metabolic modulation, receptor redesign, and remodeling of the tumor microenvironment.Across these mechanistic categories, reported benefits include enhanced CAR T cell persistence, reduced expression of inhibitory receptors, such as PD-1, LAG-3, and TIM-3, preservation or restoration of memory-like phenotypes, and improved antitumor cytotoxicity. Notably, combinatorial strategies targeting multiple dysfunction pathways consistently demonstrate superior efficacy in preclinical models. Despite these advances, important translational challenges remain, including the limited predictive value of current preclinical systems, potential safety concerns, and the manufacturing complexity associated with increasingly engineered cell products.Collectively, preclinical evidence supports the rational integration of complementary approaches to generate next-generation CAR T cells capable of resisting dysfunction and maintaining activity within immunosuppressive solid tumor microenvironments. Further validation in clinically relevant models will be critical to facilitate translation into safe and durable cancer immunotherapies.
BACKGROUND AND AIMS:Evidence regarding the influence of vedolizumab (VDZ) on extraintestinal manifestations (EIMs) of inflammatory bowel disease (IBD) is limited. Our aim was to analyze the effectiveness of VDZ in preexisting EIMs and the occurrence of de novo EIMs during VDZ therapy for IBD. METHODS:This observational, multicenter, retrospective cohort study included patients from the Spanish ENEIDA registry. All EIMs were assessed at baseline, and clinical response and worsening of IBD and EIMs were evaluated at 3 and 12 months after VDZ initiation, according to the physician's assessment. RESULTS:We retrospectively identified 551 patients with IBD treated with VDZ. At baseline, 133 patients (24.1%) had preexisting EIMs, with 77 having active EIMs. At 3 months, 29.9% of these patients showed clinical improvement, 16.9% experienced worsening, and 53.2% remained unchanged. Clinical response of IBD at 3 months was the only factor associated with EIM improvement (OR 3.72; 95% CI 1.08-12.83). Among 56 patients with inactive EIMs at baseline, 13.5% experienced worsening after 12 months. During follow-up, 25 patients (4.5%) developed 27 de novo EIMs. The presence of 2 preexisting EIMs was the only factor associated with de novo EIM onset (OR 16.2; 95% CI 4.3-60.9). Worsening of preexisting EIMs or de novo EIMs led to VDZ discontinuation in 15 patients (5.8% of all patients who discontinued VDZ and 2.7% of the entire cohort). CONCLUSIONS:VDZ achieved clinical response of active EIMs in nearly one-third of patients after 3 months. Although infrequent, VDZ may exacerbate inactive EIMs and induce de novo EIMs during therapy, potentially leading to treatment discontinuation.
AIMS:To determine the level of knowledge about HIV, HIV transmission, Sexually Transmitted Infections (STIs), hepatitis, Pre-Exposure Prophylaxis (PrEP), and Post-Exposure Prophylaxis (PEP) in heterosexual, homosexual, and bisexual-other individuals attending a hospital-based nursing STI consultation. To analyze sociodemographic, clinical, sexual behavior, substance use, social support, and stigma factors associated with the level of knowledge about these infections. METHODS:Observational, cross-sectional, analytical, single-center study in a hospital in Spain, with 259 patients consecutively recruited between November 2021 and July 2022. The European Men to Men Internet Survey (EMIS) was used, and bivariate and multivariate statistical analysis was applied. RESULTS:66.0% of the participants were heterosexual, 25.5% homosexual, and 8.5% bisexual-other. The median age was 52 years [41.5-59.0]. The highest level of HIV knowledge was observed in homosexual individuals (69.7%). 93% of heterosexuals were unaware of PrEP and PEP. Factors associated with lower knowledge were: heterosexual orientation, age over 40, female gender, lower educational level and income, unemployment, alcohol and drug use, limited internet use, fewer sexual partners, lack of safe sex, and lower social integration. CONCLUSIONS:It is necessary to strengthen education on HIV and STIs, especially among heterosexuals, women, older adults, and bisexual-other individuals. Interventions should be adapted to each group, demystify HIV transmission, promote PrEP and PEP, and reduce stigma, contributing to the design of more inclusive and effective educational strategies to reduce the prevalence of STIs and HIV.
