Yong Gu Lee

Abstract Primary resistance to CD19-directed chimeric antigen receptor T-cell therapy (CART19) occurs in 10% to 20% of patients with acute lymphoblastic leukemia (ALL); however, the mechanisms of this resistance remain elusive. Using a genome-wide loss-of-function screen, we identified that impaired death receptor signaling in ALL led to rapidly progressive disease despite CART19 treatment. This was mediated by an inherent resistance to T-cell cytotoxicity that permitted antigen persistence and was subsequently magnified by the induction of CAR T-cell functional impairment. These findings were validated using samples from two CAR T-cell clinical trials in ALL, where we found that reduced expression of death receptor genes was associated with worse overall survival and reduced T-cell fitness. Our findings suggest that inherent dysregulation of death receptor signaling in ALL directly leads to CAR T-cell failure by impairing T-cell cytotoxicity and promoting progressive CAR T-cell dysfunction. Significance: Resistance to CART19 is a significant barrier to efficacy in the treatment of B-cell malignancies. This work demonstrates that impaired death receptor signaling in tumor cells causes failed CART19 cytotoxicity and drives CART19 dysfunction, identifying a novel mechanism of antigen-independent resistance to CAR therapy. See related commentary by Green and Neelapu, p. 492.

Most solid tumors are comprised of multiple clones that express orthogonal antigens, suggesting that novel strategies must be developed in order to adapt chimeric antigen receptor (CAR) T-cell therapies to treat heterogeneous solid tumors. Here, we utilized a cocktail of low-molecular-weight bispecific adapters, each comprised of fluorescein linked to a different tumor-specific ligand, to bridge between an antifluorescein CAR on the engineered T cell and a unique antigen on the cancer cell. This formation of an immunologic synapse between the CAR T cell and cancer cell enabled use of a single antifluorescein CAR T cell to eradicate a diversity of antigenically different solid tumors implanted concurrently in NSG mice. Based on these data, we suggest that a carefully designed cocktail of bispecific adapters in combination with antifluorescein CAR T cells can overcome tumor antigen escape mechanisms that lead to disease recurrence following many CAR T-cell therapies. SIGNIFICANCE: A cocktail of tumor-targeted bispecific adapters greatly augments CAR T-cell therapies against heterogeneous tumors, highlighting its potential for broader applicability against cancers where standard CAR T-cell therapy has failed.

OBJECTIVE: To evaluate magnetic resonance imaging (MRI) findings of medial meniscal root tear and the correlation of medial meniscal root tear with other associated knee abnormalities. METHODS: We retrospectively assessed preoperative magnetic resonance images of 39 patients with arthroscopically confirmed medial meniscal root tear. Magnetic resonance imaging findings were retrospectively reviewed by 2 experienced musculoskeletal radiologists for consensus. We evaluated the configuration of meniscal root tear and the other associated knee abnormalities on MRI for direct correlation with arthroscopic findings. RESULTS: At arthroscopy, there were 36 radial tears and 3 complex tears involving the medial meniscal posterior horn roots. All 36 radial tears could be correctly diagnosed by MRI, with findings showing ghost sign on sagittal images in 100% (36/36), vertical linear defect on coronal images in 100% (36/36), and radial linear defect on axial image in 94% (34/36). However, all 3 complex tears were misdiagnosed as radial tears on MRI. Medial meniscal root tears displayed a strong association with degenerative joint disease in 97% (38/39). Medial meniscal root tears were also found in association with cartilage defects of the medial femoral condyle and medial meniscal extrusions (> or =3 mm) in 89% (34/38) and 67% (26/39), respectively. CONCLUSIONS: Medial meniscal root tears were usually posterior horn root radial tear. A high association with degenerative joint disease, cartilage defects of the medial femoral condyle, and medial meniscal extrusions (>/=3 mm) were also noted.

Although chimeric antigen receptor (CAR) T cell therapies have demonstrated considerable success in treating hematologic malignancies, they have simultaneously been plagued by a cytokine release syndrome (CRS) that can harm or even kill the cancer patient. We describe a CAR T cell strategy in which CAR T cell activation and cancer cell killing can be sensitively regulated by adjusting the dose of a low molecular weight adapter that must bridge between the CAR T cell and cancer cell to initiate tumor eradication. By controlling the concentration and dosing schedule of adapter administration, we document two methods that can rapidly terminate (<3 h) a pre-existing CRS-like toxicity and two unrelated methods that can pre-emptively prevent a CRS-like toxicity that would have otherwise occurred. Because all four methods concurrently enhance CAR T cell potency, we conclude that proper use of bispecific adapters could potentially avoid a life-threatening CRS while enhancing CAR T cell tumoricidal activity.