T cell exhaustion limits immune responses against cancer and is a major cause of resistance to chimeric antigen receptor (CAR)–T cell therapeutics. Using murine xenograft models and an in vitro model wherein tonic CAR signaling induces hallmark features of exhaustion, we tested the effect of transient cessation of receptor signaling, or rest, on the development and maintenance of exhaustion. Induction of rest through enforced down-regulation of the CAR protein using a drug-regulatable system or treatment with the multikinase inhibitor dasatinib resulted in the acquisition of a memory-like phenotype, global transcriptional and epigenetic reprogramming, and restored antitumor functionality in exhausted CAR-T cells. This work demonstrates that rest can enhance CAR-T cell efficacy by preventing or reversing exhaustion, and it challenges the notion that exhaustion is an epigenetically fixed state.

Adenosine (Ado) mediates immune suppression in the tumor microenvironment and exhausted CD8+ CAR T cells mediate Ado-induced immunosuppression through CD39/73-dependent Ado production. Knockout of CD39, CD73 or A2aR had modest effects on exhausted CAR T cells, whereas overexpression of Ado deaminase (ADA), which metabolizes Ado to inosine (INO), induced stemness features and potently enhanced functionality. Similarly, and to a greater extent, exposure of CAR T cells to INO augmented CAR T cell function and induced hallmark features of T cell stemness. INO induced a profound metabolic reprogramming, diminishing glycolysis and increasing oxidative phosphorylation, glutaminolysis and polyamine synthesis, and modulated the epigenome toward greater stemness. Clinical scale manufacturing using INO generated enhanced potency CAR T cell products meeting criteria for clinical dosing. These data identify INO as potent modulator of T cell metabolism and epigenetic stemness programming and deliver a new enhanced potency platform for immune cell manufacturing.

Epidural abscesses can be caused by a number of different organisms, including atypical Mycobacterium. This is a rare case report of an atypical Mycobacterium epidural abscess requiring surgical decompression. Here, we present Mycobacterium abscessus causing a nonpurulent epidural collection surgically treated with laminectomy and washout and discuss clinical clues and radiologic characteristics associated with this condition.A 51-year-old male with a past medical history of chronic intravenous (IV) drug use presented with a threeday history of falls and three-month history of progressively worsening bilateral lower extremity radiculopathy, paresthesias, and numbness. MRI demonstrated an enhancing collection at L2-3 ventral and to the left of the spinal canal causing severe compression of the thecal sac, along with heterogenous contrast enhancement of the L2-3 vertebral bodies and intervertebral disc. The patient was taken for an L2-3 laminectomy and left medial facetectomy, where a fibrous, nonpurulent mass was discovered. Cultures ultimately demonstrated Mycobacterium abscessus subspecies massiliense, and the patient was discharged on IV levofloxacin, azithromycin, and linezolid with complete symptomatic relief.Unfortunately, despite surgical washout and antibiotic coverage, the patient presented twice more, the first time with a recurrent epidural collection requiring repeat drainage and the second time with a recurrent epidural collection with discitis and osteomyelitis with pars fractures requiring repeat epidural drainage and interbody fusion.It is important to recognize that atypical Mycobacterium abscessus can cause a nonpurulent epidural collection, especially in high-risk patients such as those with a history of chronic IV drug use. Additionally, our initial intraoperative findings of a fibrous, adherent mass suggest that in cases where this entity is suspected, surgical decompression should be carefully considered. To this end, the radiologic findings associated with this condition, namely, an enhancing ventral epidural mass involving the disc space, should also be recognized. The notable postoperative course consisting of recurrent collections and osteomyelitis with a pars fracture suggests that early fusion should be considered as an option in these patients. This case report presents clinical and radiologic findings associated with an atypical Mycobacterium discitis and osteomyelitis. The clinical course described herein suggests that early fusion in these patients may provide superior results to decompression alone.

Background: Previous studies suggest that wide area circumferential pulmonary vein ablation (WACA) is more effective than segmental pulmonary vein ablation (SPVA) for pulmonary vein isolation (PVI) for treatment of atrial fibrillation. Whether this is true in patients (pts) with very short duration paroxysmal atrial fibrillation (PAF) is unknown. Objective: To compare WACA to SPVA in pts with PAF lasting <48 hours. Methods: One hundred pts with PAF <48 hours were randomized to either WACA vs SPVA (45 and 53 pts respectively, with 2 withdrawals), and followed up for 24 months with 14-day ECGs every 6 months. Results: Among 97 pts at an average of 22.1±4.8 months followup, 26 (57.8%) remained free of any atrial arrhythmias after WACA versus 29 (55.86%) after SPVA (p=0.64). Sixteen pts (35.6%) had recurrent PAF after WACA versus 20 pts (38.5%) after SPVA (p=0.79). Seven pts (15.6%) had atrial flutter after WACA versus 5 pts (9.64%) after SPVA (p=0.376) and 1 pt (2.2%) had atrial tachycardia after WACA vs 1 pt (1.9%) after SPVA (p=0.918). Total procedure time was lower for SPVA vs WACA (242.9 vs 271.1 minutes, p= 0.047), and fluoroscopy time similar for WACA vs SPVA (50.8 vs 53.4 minutes, p=0.555). Conclusions: As an initial ablation approach in pts with PAF <48 hours, SPVA was similarly effective to WACA with respect to arrhythmia recurrence, supporting the central role of the pulmonary veins for maintaining AF in these pts. Future therapies using alternative ablation energies may incorporate these insights to reduce risk to gastroesophageal structures.