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2 results on '"Chiara Cassarino"'

1. Venetoclax resistance induced by activated T cells can be counteracted by sphingosine kinase inhibitors in chronic lymphocytic leukemia

Author

Valeria J. Sarapura Martinez, Brenda Buonincontro, Chiara Cassarino, Juliana Bernatowiez, Ana Colado, Gregorio Cordini, Maria del Rosario Custidiano, Carolina Mahuad, Miguel A. Pavlovsky, Raimundo F. Bezares, Nicolás O. Favale, Mónica Vermeulen, Mercedes Borge, Mirta Giordano, and Romina Gamberale

Subjects
sphingosine kinases, activated T cells, Bcl-XL, CLL (chronic lymphocytic leukemia), venetoclax resistance, SKI-II, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

The treatment of chronic lymphocytic leukemia (CLL) patients with venetoclax-based regimens has demonstrated efficacy and a safety profile, but the emergence of resistant cells and disease progression is a current complication. Therapeutic target of sphingosine kinases (SPHK) 1 and 2 has opened new opportunities in the treatment combinations of cancer patients. We previously reported that the dual SPHK1/2 inhibitor, SKI-II enhanced the in vitro cell death triggered by fludarabine, bendamustine or ibrutinib and reduced the activation and proliferation of chronic lymphocytic leukemia (CLL) cells. Since we previously showed that autologous activated T cells from CLL patients favor the activation of CLL cells and the generation of venetoclax resistance due to the upregulation of BCL-XL and MCL-1, we here aim to determine whether SPHK inhibitors affect this process. To this aim we employed the dual SPHK1/2 inhibitor SKI-II and opaganib, a SPHK2 inhibitor that is being studied in clinical trials. We found that SPHK inhibitors reduce the activation of CLL cells and the generation of venetoclax resistance induced by activated T cells mainly due to a reduced upregulation of BCL-XL. We also found that SPHK2 expression was enhanced in CLL cells by activated T cells of the same patient and the presence of venetoclax selects resistant cells with high levels of SPHK2. Of note, SPHK inhibitors were able to re-sensitize already resistant CLL cells to a second venetoclax treatment. Our results highlight the therapeutic potential of SPHK inhibitors in combination with venetoclax as a promising treatment option for the patients.

Published
2023
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2. ­­­­­COVID-19 vaccination responses with different vaccine platforms in patients with inborn errors of immunity

Author

Lorenzo Erra, Ignacio Uriarte, Ana Colado, María Virginia Paolini, Gisela Seminario, Julieta Belén Fernández, Lorena Tau, Juliana Bernatowiez, Ileana Moreira, Sebastián Vishnopolska, Martín Rumbo, Chiara Cassarino, Gustavo Vijoditz, Ana Laura López, Renata Curciarello, Diego Rodríguez, Gastón Rizzo, Malena Ferreyra, Leila Romina Ferreyra Mufarregue, María Noel Badano, María Inés Pérez Millán, María Florencia Quiroga, Patricia Baré, Itatí Ibañez, Roberto Pozner, Mercedes Borge, Guillermo Docena, Liliana Bezrodnik, and María Belén Almejun

Subjects
Immunology, Immunology and Allergy
Abstract

Patients with inborn errors of immunity (IEI) in Argentina were encouraged to receive licensed Sputnik, AstraZeneca, Sinopharm, Moderna, and Pfizer vaccines, even though most of the data of humoral and cellular responses combination on available vaccines comes from trials conducted in healthy individuals. We aimed to evaluate the safety and immunogenicity of the different vaccines in IEI patients in Argentina. The study cohort included adults and pediatric IEI patients (n = 118) and age-matched healthy controls (HC) (n = 37). B cell response was evaluated by measuring IgG anti-spike/receptor binding domain (S/RBD) and anti-nucleocapsid(N) antibodies by ELISA. Neutralization antibodies were also assessed with an alpha-S protein-expressing pseudo-virus assay. The T cell response was analyzed by IFN-γ secretion on S- or N-stimulated PBMC by ELISPOT and the frequency of S-specific circulating T follicular-helper cells (TFH) was evaluated by flow cytometry.No moderate/severe vaccine-associated adverse events were observed. Anti-S/RBD titers showed significant differences in both pediatric and adult IEI patients versus the age-matched HC cohort (p 0.05). Neutralizing antibodies were also significantly lower in the patient cohort than in age-matched HC (p 0.01). Positive S-specific IFN-γ response was observed in 84.5% of IEI patients and 82.1% presented S-specific TFH cells. Moderna vaccines, which were mainly administered in the pediatric population, elicited a stronger humoral response in IEI patients, both in antibody titer and neutralization capacity, but the cellular immune response was similar between vaccine platforms. No difference in humoral response was observed between vaccinated patients with and without previous SARS-CoV-2 infection.In conclusion, COVID-19 vaccines showed safety in IEI patients and, although immunogenicity was lower than HC, they showed specific anti-S/RBD IgG, neutralizing antibody titers, and T cell-dependent cellular immunity with IFN-γ secreting cells. These findings may guide the recommendation for a vaccination with all the available vaccines in IEI patients to prevent COVID-19 disease.

Published
2022

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