Engineering CAR-NK cells to secrete IL-15 sustains their anti-AML functionality but is associated with systemic toxicities.

BACKGROUND: The prognosis of patients with recurrent/refractory acute myelogenous leukemia (AML) remains poor and cell-based immunotherapies hold promise to improve outcomes. Natural Killer (NK) cells can elicit an antileukemic response via a repertoire of activating receptors that bind AML surface ligands. NK-cell adoptive transfer is safe but thus far has shown limited anti-AML efficacy. Here, we aimed to overcome this limitation by engineering NK cells to express chimeric antigen receptors (CARs) to boost their anti-AML activity and interleukin (IL)-15 to enhance their persistence. METHODS: We characterized in detail NK-cell populations expressing a panel of AML (CD123)-specific CARs and/or IL-15 in vitro and in AML xenograft models. RESULTS: CARs with 2B4.ζ or 4-1BB.ζ signaling domains demonstrated greater cell surface expression and endowed NK cells with improved anti-AML activity in vitro. Initial in vivo testing revealed that only 2B4.ζ Chimeric Antigen Receptor (CAR)-NK cells had improved anti-AML activity in comparison to untransduced (UTD) and 4-1BB.ζ CAR-NK cells. However, the benefit was transient due to limited CAR-NK-cell persistence. Transgenic expression of secretory interleukin (sIL)-15 in 2B4.ζ CAR and UTD NK cells improved their effector function in the setting of chronic antigen simulation in vitro. Multiparameter flow analysis after chronic antigen exposure identified the expansion of unique NK-cell subsets. 2B4.ζ/sIL-15 CAR and sIL-15 NK cells maintained an overall activated NK-cell phenotype. This was confirmed by transcriptomic analysis, which revealed a highly proliferative and activated signature in these NK-cell groups. In vivo, 2B4.ζ/sIL-15 CAR-NK cells had potent anti-AML activity in one model, while 2B4.ζ/sIL-15 CAR and sIL-15 NK cells induced lethal toxicity in a second model. CONCLUSION: Transgenic expression of CD123-CARs and sIL-15 enabled NK cells to function in the setting of chronic antigen exposure but was associated with systemic toxicities. Thus, our study provides the impetus to explore inducible and controllable expression systems to provide cytokine signals to AML-specific CAR-NK cells before embarking on early-phase clinical testing.

How I Do It: Pilot Study of Video-Based Feedback as an Educational Tool for Medical Students' Presentations on Morning Rounds.

OBJECTIVE: Morning rounds are a bedrock learning opportunity during clinical rotations in medical school. Specific feedback is critical for students to improve presentation skills and build confidence, however, current feedback mechanisms are fragmented and nonstandard. We aimed to assess whether video-based coaching of morning rounds could improve student feedback and self-awareness without increasing anxiety during patient presentations. DESIGN: Medical students during core clinical clerkships were filmed presenting on morning rounds during their surgery clerkship. A designated faculty coach reviewed the video prior to an in-person coaching session. Students reviewed the video with faculty and were coached on content, presentation style, and presence. A short survey assessed students' pre- and postcoaching confidence, skill, and the utility of the coaching session. SETTING: University of Michigan Health System, Department of Surgery, Division of General Surgery, Ann Arbor, Michigan PARTICIPANTS: Eight medical student volunteers during their core clinical clerkships at University of Michigan Medical School during the surgery clerkship. RESULTS: Comparison of pre- and post self-assessments showed that students underestimated their knowledge of basic and clinical science and overestimated their clinical assessment skills and ability to appropriately address the core components of a presentation. Most students (75%) did not think that the filming process altered their performance and only 25% of students felt increased anxiety due to filming. All students agreed that the feedback session was useful and helped them understand how to improve their oral presentations. CONCLUSION: This pilot demonstrates the feasibility and value of video-based coaching as an educational tool for medical students on clerkships. A larger sample size is needed to further evaluate the effectiveness of video-based coaching in establishing baseline clinical abilities and identifying potential areas for improvement.