Adapter CAR T cells to counteract T-cell exhaustion and enable flexible targeting in AML.

Although the landscape for treating acute myeloid leukemia (AML) patients has changed substantially in recent years, the majority of patients will eventually relapse and succumb to their disease. Allogeneic stem cell transplantation provides the best anti-AML treatment strategy, but is only suitable in a minority of patients. In contrast to B-cell neoplasias, chimeric antigen receptor (CAR) T-cell therapy in AML has encountered challenges in target antigen heterogeneity, safety, and T-cell dysfunction. We established a Fab-based adapter CAR (AdCAR) T-cell platform with flexibility of targeting and control of AdCAR T-cell activation. Utilizing AML cell lines and a long-term culture assay for primary AML cells, we were able to demonstrate AML-specific cytotoxicity using anti-CD33, anti-CD123, and anti-CLL1 adapter molecules in vitro and in vivo. Notably, we show for the first time the feasibility of sequential application of adapter molecules of different specificity in primary AML co-cultures. Importantly, using the AML platform, we were able to demonstrate that chronic T-cell stimulation and exhaustion can be counteracted through introduction of treatment-free intervals. As T-cell exhaustion and target antigen heterogeneity are well-known causes of resistance, the AdCAR platform might offer effective strategies to ameliorate these limitations.

Effect of head orientation on the diagnostic sensitivity of posturography in patients with compensated unilateral lesions.

Patients with compensated unilateral vestibular lesions often have no detectable abnormality on conventional posturography. The purpose of this study was to determine whether a change in head orientation could improve the diagnostic sensitivity of the test for these patients. Twenty-four patients with known unilateral vestibulopathy and twenty-four normal controls were tested on the EquiTest apparatus in four head positions: head centered, head tilted right, head tilted left, and head extended. The sensory organization test was performed for each head position, using a single trial for each sensory condition. The test sequence was randomized to account for simple order effects. The subject's equilibrium was quantified by a performance index and a composite score of all sensory conditions was calculated for each head position. Patients with unilateral vestibulopathy had more postural sway with the head tilted contralateral to the side of lesion. The difference between the mean composite scores for ipsilateral and contralateral head tilts was statistically significant (p less than 0.05). When individual trials were compared, equilibrium scores were significantly different only for sensory conditions that required vestibular input. Head extension increased postural sway in both patients and controls. Equilibrium scores were significantly different for all sensory conditions in which the support was sway-referenced. We suggest that the results of head extension in patients are similar to those found in normal individuals.(ABSTRACT TRUNCATED AT 250 WORDS)