title: A novel non-Hodgkin lymphoma murine model closer to the standard clinical scenario.
abstract: Non-Hodgkin lymphomas (NHL) are the most frequent hemato-oncological malignancies. Despite recent major advances in treatment, a substantial proportion of patients relapses highlighting the need for new therapeutic modalities. Promissory results obtained in pre-clinical studies are usually not translated when moving into clinical trials. Pre-clinical studies are mainly conducted in animals with high tumor burden; instead patients undergo chemotherapy as first line of treatment and most likely are under remission when immunotherapies are applied. Thus, an animal model that more closely resembles patients' conditions would be a valuable tool.
  
  
  
  BALB/c mice were injected subcutaneously with A20 lymphoma cells and after tumor development different doses of chemotherapy were assessed to find optimal conditions for minimal residual disease (MRD) establishment. Tumor growth and survival, as well as drugs side effects, were all evaluated. Complete lymphoma remission was monitored in vivo using positron emission tomography (PET), and the results were correlated with histology. Immunological status was assessed by splenocytes proliferation assays in NHL-complete remission mice and by analyzing tumor cell infiltrates and chemokines/cytokines gene expression in the tumor microenvironment of animals with residual lymphoma.
  
  
  
  Two cycles of CHOP chemotherapy at days 25 and 35 post-tumor implantation induced complete remission for around 20 days. PET showed to be a suitable follow-up technique for MRD condition with 85.7 and 75% of sensibility and specificity respectively. Proliferative responses upon mitogen stimulation were similar in animals that received chemotherapy and wild type mice. Tumors from animals with residual lymphoma showed higher numbers of CD4+and CD8+and similar numbers of NK, neutrophils and Tregs infiltrating cells as compared with non-treated animals. Gene expression of several cytokines as well as an array of chemokines associated with migration of activated T cells to tumor sites was upregulated in the tumor microenvironment of animals that received chemotherapy treatment.
  
  
  
  We established a NHL-B pre-clinical model using standard chemotherapy to achieve MRD in immunocompetent animals. The MRD condition is maintained for approximately 20 days providing a therapeutic window of time where new immunotherapies can be tested in conditions closer to the clinics.
authors.affiliation: Departamento de Desarrollo Biotecnológico, Instituto de Higiene, Facultad de Medicina, UdelaR, Montevideo, Uruguay.
authors.forename: Thais
authors.initials: T
authors.lastname: Bascuas
authors.affiliation: Departamento de Desarrollo Biotecnológico, Instituto de Higiene, Facultad de Medicina, UdelaR, Montevideo, Uruguay.
authors.forename: María
authors.initials: M
authors.lastname: Moreno
authors.affiliation: Departamento de Desarrollo Biotecnológico, Instituto de Higiene, Facultad de Medicina, UdelaR, Montevideo, Uruguay.
authors.forename: Amy
authors.initials: A
authors.lastname: Mónaco
authors.affiliation: Área de Investigación y Desarrollo, Departamento Biomédico, Centro Uruguayo de Imagenología Molecular (CUDIM), Montevideo, Uruguay.
authors.forename: Laura
authors.initials: L
authors.lastname: Reyes
authors.affiliation: Área de Investigación y Desarrollo, Departamento Biomédico, Centro Uruguayo de Imagenología Molecular (CUDIM), Montevideo, Uruguay.
authors.forename: Andrea
authors.initials: A
authors.lastname: Paolino
authors.affiliation: Área de Investigación y Desarrollo, Departamento Biomédico, Centro Uruguayo de Imagenología Molecular (CUDIM), Montevideo, Uruguay.
authors.forename: Patricia
authors.initials: P
authors.lastname: Oliver
authors.affiliation: Departamento de Desarrollo Biotecnológico, Instituto de Higiene, Facultad de Medicina, UdelaR, Montevideo, Uruguay.
authors.forename: María G
authors.initials: MG
authors.lastname: Kramer
authors.affiliation: Área de Investigación y Desarrollo, Departamento Biomédico, Centro Uruguayo de Imagenología Molecular (CUDIM), Montevideo, Uruguay.
authors.forename: Henry
authors.initials: H
authors.lastname: Engler
authors.affiliation: Área de Patología Funcional y Morfológica, Departamento de Patología, Facultad de Veterinaria, UdelaR, Montevideo, Uruguay.
authors.forename: José P
authors.initials: JP
authors.lastname: Pacheco
authors.affiliation: Cátedra de Hematología, Hospital de Clínicas, Facultad de Medicina, UdelaR, Montevideo, Uruguay.
authors.forename: Sofía
authors.initials: S
authors.lastname: Grille
authors.affiliation: Departamento de Desarrollo Biotecnológico, Instituto de Higiene, Facultad de Medicina, UdelaR, Montevideo, Uruguay. jachabal@higiene.edu.uy.
authors.forename: José A
authors.initials: JA
authors.lastname: Chabalgoity
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D049109:Cell Proliferation; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D008807:Mice, Inbred BALB C; D018365:Neoplasm, Residual / Q000188:drug therapy / Q000473:pathology; D000072078:Positron Emission Tomography Computed Tomography; D012015:Reference Standards; D012074:Remission Induction; D013154:Spleen / Q000473:pathology; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D018925:Chemokines
keywords: CHOP; Chemotherapy; Clinical; Immunotherapy; Minimal residual disease (MRD); Non-Hodgkin lymphoma (NHL); Positron emission tomography (PET)