Factors associated with the clinical outcome of patients with relapsed/refractory CD19<sup>+</sup> acute lymphoblastic leukemia treated with ARI-0001 CART19-cell therapy
Valentín Ortiz‐Maldonado, Susana Rives, Marta Español‐Rego, Anna Alonso‐Saladrigues, Mercedes Montoro, Laura Magnano, Eva Giné, Mariona Pascal, Marina Díaz‐Beyá, María Castellà, Albert Català, Anna Faura, Luis Gerardo Rodríguez‐Lobato, Aina Oliver‐Caldés, Alexandra Martínez‐Roca, Montserrat Rovira, Europa Azucena González‐Navarro, Juan Ramón Granados Ortega, Joan Cid, Miquel Lozano, Enric García‐Rey, Sara Fernández, Pedro Castro, Iolanda Jordán, Neus Villamor, Marta Aymerich, Montserrat Torrebadell, Àngela Deyà‐Martínez, Carlos Fernández de Larrea, Daniel Benítez‐Ribas, Esteve Trias, Sara Varea, Gonzalo Calvo, Jordi Esteve, Álvaro Urbano-Ispizúa, Manel Juan, Julio Delgado
Abstract
<h3>Abstract</h3> Serum antibodies IgM and IgG are elevated during COVID-19 to defend against viral attack. Atypical results such as negative and abnormally high antibody expression were frequently observed whereas the underlying molecular mechanisms are elusive. In our cohort of 144 COVID-19 patients, 3.5% were both IgM and IgG negative whereas 29.2% remained only IgM negative. The remaining patients exhibited positive IgM and IgG expression, with 9.3% of them exhibiting over 20-fold higher titers of IgM than the others at their plateau. IgG titers in all of them were significantly boosted after vaccination in the second year. To investigate the underlying molecular mechanisms, we classed the patients into four groups with diverse serological patterns and analyzed their two-year clinical indicators. Additionally, we collected 111 serum samples for TMTpro-based longitudinal proteomic profiling and characterized 1494 proteins in total. We found that the continuously negative IgM and IgG expression during COVID-19 were associated with mild inflammatory reactions and high T cell responses. Low levels of serum IgD, inferior complement 1 activation of complement cascades, and insufficient cellular immune responses might collectively lead to compensatory serological responses, causing overexpression of IgM. Serum CD163 was positively correlated with antibody titers during seroconversion. This study suggests that patients with negative serology still developed cellular immunity for viral defense, and that high titers of IgM might not be favorable to COVID-19 recovery.