RESUMO
Multiple myeloma (MM) is a plasma cell neoplasm that commonly expresses CD38. Daratumumab (DARA), a human monoclonal antibody targeting CD38, has significantly improved the outcome of patients with relapsed or refractory MM, but the response is transient in most cases. Putative mechanisms of suboptimal efficacy of DARA include downregulation of CD38 expression and overexpression of complement inhibitory proteins on MM target cells as well as DARA-induced depletion of CD38high natural killer (NK) cells resulting in crippled antibody-dependent cellular cytotoxicity (ADCC). Here, we tested whether maintaining NK cell function during DARA therapy could maximize DARA-mediated ADCC against MM cells and deepen the response. We used the CRISPR/Cas9 system to delete CD38 (CD38KO) in ex vivo expanded peripheral blood NK cells. These CD38KO NK cells were completely resistant to DARA-induced fratricide, showed superior persistence in immune-deficient mice pretreated with DARA, and enhanced ADCC activity against CD38-expressing MM cell lines and primary MM cells. In addition, transcriptomic and cellular metabolic analysis demonstrated that CD38KO NK cells have unique metabolic reprogramming with higher mitochondrial respiratory capacity. Finally, we evaluated the impact of exposure to all-trans retinoic acid (ATRA) on wild-type NK and CD38KO NK cell function and highlighted potential benefits and drawbacks of combining ATRA with DARA in patients with MM. Taken together, these findings provide proof of concept that adoptive immunotherapy using ex vivo expanded CD38KO NK cells has the potential to boost DARA activity in MM.
Assuntos
ADP-Ribosil Ciclase 1/deficiência , Anticorpos Monoclonais/farmacologia , Citotoxicidade Imunológica/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Glicoproteínas de Membrana/deficiência , Mieloma Múltiplo/patologia , ADP-Ribosil Ciclase 1/genética , Transferência Adotiva , Animais , Citotoxicidade Celular Dependente de Anticorpos , Sistemas CRISPR-Cas , Linhagem Celular Tumoral , Humanos , Imunoterapia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/transplante , Masculino , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos NOD , NAD/metabolismo , Fosforilação Oxidativa , Organismos Livres de Patógenos Específicos , Tretinoína/farmacologia , Sequenciamento Completo do GenomaRESUMO
The treatment of cancer has changed significantly over the past decade, from a treatment paradigm based primarily on surgery, chemotherapy and radiotherapy, to the development of targeted therapies involving tumor-specific signaling pathways, as well as the immune system. Recent developments have demonstrated the significant clinical benefits of immunotherapy that are quickly being established as standard treatments for certain malignancies. In this study, we demonstrated that clinical practice is not keeping pace with advancing immuno-oncology principles and research. We further demonstrated that the incorporation of immunotherapeutic approaches into the treatment of cancer patients varies widely, not only between developed and developing countries, but also between countries in specific geographical areas that have experienced similar cultural and economic development. We developed a survey to assess the deficiencies in scientific understanding, access to information and treatment options and investigated the differences in clinical practice behaviors among oncologists from six European countries: France, Germany, Greece, Italy, Spain and the United Kingdom. Our data demonstrated significant differences in all the categories assessed. Therefore, we concluded that there is a need to develop similar assessment tools to identify care imbalances, so that initiatives may be developed to correct care inequities that ultimately affect patient outcomes worldwide.