Identification of new markers associated with long-term efficacy in patients treated with CAR T cells is a current medical need, particularly in diseases such as multiple myeloma. In this study we address the impact of CAR density on the functionality of BCMA-CAR T cells. Functional and transcriptional studies demonstrate that CAR T cells with high expression of the CAR construct show an increased tonic signaling with upregulation of exhaustion markers, increased in vitro cytotoxicity but a decrease in in vivo BM infiltration. Characterization of Gene Regulatory Networks using scRNA-seq identified regulons associated to activation and exhaustion upregulated in CARHigh T cells, providing mechanistic insights behind differential functionality of these cells. Finally, we demonstrate that patients treated with CAR T cell products enriched in CARHigh T cells show a significantly worse clinical response in several hematological malignancies. In summary, our work demonstrates that CAR density plays an important role in CAR T activity with significant impact on clinical response.
We evaluated outcomes of 18 patients with isolated extramedullary disease (iEMD) relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) treated with the CD19-directed CAR T cells ARI-0001 in two centers (adult and pediatric), including patients treated in the CART19-BE-01 trial and the consecutive compassionate use program.
To the Editor, Since early start of coronavirus disease (COVID-19) pandemic, an outbreak of chilblains-like lesions was largely recognized worldwide. [1][2][3][4] Pernio or chilblains is characterized by erythema and swelling at acral sites, most commonly on the toes and fingers, and typically triggered by cold exposure. [1][2][3][4] A form of COVID-19-associated chilblains (also called COVID-toes) has mainly affected the feet of young patients with mild or no other symptoms of COVID-19. 2 The temporal relationship between the appearance of these lesions amidst coronavirus pandemic and their similarities with the skin lesions observed in some monogenic type-I interferonopathies prompted dermatologists and scientists around the world to hypothesize that these lesions might have been provoked by SARS-CoV-2 infection and by an exaggerated up-regulation of type-I interferon (IFN) pathway triggered by the virus. 3 Previous studies in skin biopsies of patients with COVID-toes have demonstrated the presence of SARS-CoV-2 by immunohistochemistry and electron microscopy. 4,5 However, a direct link between COVID-toes and SARS-CoV-2 infection could not be made since all tests including nasopharyngeal swab (NPS) polymerase chain reaction (PCR) and serum antibodies against SARS-CoV-2 have been negative in most of previously reported patients. 3-5 To date, the contribution of type-I IFN response to the viral control and inflammation in COVID-toes has not yet been fully evaluated. Herein, we describe a cohort of 28 consecutive children (median age 14 years; range 4-18) with COVID-toes seen in a Pediatric Dermatology Department in a tertiary care hospital during the COVID-19 outbreak peak occurring in Barcelona in March-May 2020. The aim of this study was to investigate the role of type-I IFN signature in peripheral blood of pediatric patients with COVID-toes and to demonstrate an association between COVID-toes and SARS-CoV-2 infection.
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