Off-the-shelf CAR-T cells could prove paradigm shifting for autoimmune diseases.

Early reports suggest that chimeric antigen receptor (CAR)-T therapy has remarkable potential for treating autoimmune disease. Current approaches rely on autologous CAR-T cells, creating a bottleneck to the broad deployment of this therapy. In this issue of Cell, Wang et al.1 report the first use of allogeneic CAR-T cells in three patients with systemic autoimmune disease.

CAR T therapy beyond cancer: the evolution of a living drug.

Engineering a patient's own T cells to selectively target and eliminate tumour cells has cured patients with untreatable haematologic cancers. These results have energized the field to apply chimaeric antigen receptor (CAR) T therapy throughout oncology. However, evidence from clinical and preclinical studies underscores the potential of CAR T therapy beyond oncology in treating autoimmunity, chronic infections, cardiac fibrosis, senescence-associated disease and other conditions. Concurrently, the deployment of new technologies and platforms provides further opportunity for the application of CAR T therapy to noncancerous pathologies. Here we review the rationale behind CAR T therapy, current challenges faced in oncology, a synopsis of preliminary reports in noncancerous diseases, and a discussion of relevant emerging technologies. We examine potential applications for this therapy in a wide range of contexts. Last, we highlight concerns regarding specificity and safety and outline the path forward for CAR T therapy beyond cancer.

CAR T therapy extends its reach to autoimmune diseases.

CAR T therapy has revolutionized the treatment of hematologic cancers. In their recent Nature Medicine paper, Mackensen et al. report the use of CAR T cells to treat systemic lupus erythematosus in five patients. This provides enthusiasm to further explore CAR T therapy beyond oncology.

Thermogenic T cells: a cell therapy for obesity?

Obesity is a widespread public health problem with profound medical consequences and its burden is increasing worldwide. Obesity causes significant morbidity and mortality and is associated with conditions including cardiovascular disease and diabetes mellitus. Conventional treatment options are insufficient, or in the case of bariatric surgery, quite invasive. The etiology of obesity is complex, but at its core is often a caloric imbalance with an inability to burn off enough calories to exceed caloric intake, resulting in storage. Interventions such as dieting often lead to decreased resting energy expenditure (REE), with a rebound in weight ("yo-yo effect" or weight cycling). Strategies that increase REE are attractive treatment options. Brown fat tissue engages in nonshivering thermogenesis whereby mitochondrial respiration is uncoupled from ATP production, increasing REE. Medications that replicate brown fat metabolism by mitochondrial uncoupling (e.g., 2,4-dinitrophenol) effectively promote weight loss but are limited by toxicity to a narrow therapeutic range. This review explores the possibility of a new therapeutic approach to engineer autologous T cells into acquiring a thermogenic phenotype like brown fat. Engineered autologous T cells have been used successfully for years in the treatment of cancers (chimeric antigen receptor T cells), and the principle of engineering T cells ex vivo and transferring them back to the patient is established. Engineering T cells to acquire a brown fat-like metabolism could increase REE without the risks of pharmacological mitochondrial uncoupling. These thermogenic T cells may increase basal metabolic rate and are therefore a potentially novel therapeutic strategy for obesity.

Patient-Reported Outcomes following Surgical Treatment of Symptomatic Digital Neuromas.

BACKGROUND: Many surgical techniques are used to treat symptomatic neuroma, but options are limited for digital neuromas because of a paucity of soft-tissue coverage and/or the absence of the terminal nerve end. The authors assessed factors that influence patient-reported outcomes after surgery for symptomatic digital neuroma. METHODS: The authors retrospectively identified 29 patients with 33 symptomatic digital neuromas that were treated surgically. Patients completed the Patient-Reported Outcomes Measurement Information System (PROMIS) Upper Extremity and Pain Interference scales, a numeric rating scale for pain, and the PROMIS Depression scale at a median follow-up of 7.6 years postoperatively (range, 3.2 to 16.8 years). Surgical treatment for neuroma included excision with nerve repair/reconstruction (n =13; 39 percent), neuroma excision alone (n =10; 30 percent), and excision and implantation (n =10; 30 percent). Multivariable linear regression was performed to identify the factors that independently influenced patient-reported outcomes. RESULTS: The mean postoperative PROMIS Upper Extremity score was 45.2 ± 11.2, the mean Pain Interference score was 54.3 ± 10.7, and the mean numeric rating scale pain score was 3 (interquartile range, 1 to 5). Compared with other treatment techniques, neuroma excision with nerve repair/reconstruction was associated with lower numeric rating scale pain scores; lower Pain Interference scores, corresponding to less daily impact of pain; and higher Upper Extremity scores, reflecting better upper extremity function. Older age and higher Depression scores were associated with lower Upper Extremity scores and higher Pain Interference scores. Smoking was associated with higher Pain Interference and numeric rating scale pain scores. CONCLUSIONS: Neuroma excision followed by nerve repair/reconstruction resulted in better outcomes compared with neuroma excision alone with or without implantation. Patient age and psychosocial factors influenced patient-reported outcomes. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.