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[PMID]: | 29327244 |
[Au] Autor: | Menssen HD; Harnack U; Erben U; Neri D; Hirsch B; Dürkop H |
[Ad] Endereço: | Division of Hematology and Oncology, Campus Benjamin Franklin, Department of Medicine, Charité-Universitätsmedizin Berlin, Hindenburgdamm 30, 12203, Berlin, Germany. hans_dietrich.menssen@charite.de. |
[Ti] Título: | Antibody-based delivery of tumor necrosis factor (L19-TNFα) and interleukin-2 (L19-IL2) to tumor-associated blood vessels has potent immunological and anticancer activity in the syngeneic J558L BALB/c myeloma model. |
[So] Source: | J Cancer Res Clin Oncol;144(3):499-507, 2018 Mar. | [Is] ISSN: | 1432-1335 |
[Cp] País de publicação: | Germany |
[La] Idioma: | eng |
[Ab] Resumo: | PURPOSE: To analyze the impact of TNFα or IL2 on human lymphocytes in vitro and the anti-tumor and immune-modifying effects of L19-IL2 and L19-TNFα on subcutaneously growing J558L myeloma in immunocompetent mice. METHODS: PBMCs from three healthy volunteers were incubated with IL2, TNFα, or with IL2 plus addition of TNFα (final 20 h). BALB/c J558L mice with subcutaneous tumors were treated with intravenous L19-TNFα plus L19-IL2, or controls. Tumor growth and intra- and peri-tumoral tissues were analyzed for micro-vessel density, necrosis, immune cell composition, and PD1 or PD-L1 expressing cells. RESULTS: Exposure of PBMC in vitro to IL2, TNFα, or to IL2 over 3 and 5 days plus TNFα for the final 20 h resulted in an approximately 50 and 75% reduction of the CD25low effector cell/CD25high Treg cell ratio, respectively, compared to medium control. IL2 or TNFα increased the proportion of CD4- CD25low effector lymphocytes while reducing the proportion of CD4+ CD25low Teff cells. In the J558L myeloma model, tumor eradication was observed in 58, 42, 25, and 0% of mice treated with L19-TNFα plus L19-IL2, L19-TNFα, L19-IL2, and PBS, respectively. L19-TNFα/L19-IL2 combination caused tumor necrosis, capillary density doubling, peri-tumoral T cell and PD1+ T cell reduction (- 50%), and an increase in PD-L1+ myeloma cells. CONCLUSION: IL2, TNFα, or IL2 plus TNFα (final 20 h) increased the proportion of CD4- CD25low effector lymphocytes possibly indicating immune activation. L19-TNFα/L19-IL2 combination therapy eradicated tumors in J558L myeloma BALB/c mice likely via TNFα-induced tumor necrosis and L19-TNFα/L19-IL2-mediated local cellular immune reactions. |
[Mh] Termos MeSH primário: |
Inibidores da Angiogênese/uso terapêutico Anticorpos Monoclonais/uso terapêutico Imunoterapia/métodos Interleucina-2/uso terapêutico Mieloma Múltiplo/terapia Neovascularização Patológica/tratamento farmacológico Fator de Necrose Tumoral alfa/uso terapêutico
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[Mh] Termos MeSH secundário: |
Animais Vacinas Anticâncer/uso terapêutico Linhagem Celular Tumoral Sistemas de Liberação de Medicamentos Feminino Imunotoxinas/uso terapêutico Camundongos Camundongos Endogâmicos BALB C Mieloma Múltiplo/imunologia Mieloma Múltiplo/patologia Linfócitos T Reguladores/efeitos dos fármacos Linfócitos T Reguladores/imunologia Transplante Isogênico
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[Pt] Tipo de publicação: | JOURNAL ARTICLE |
[Nm] Nome de substância:
| 0 (Angiogenesis Inhibitors); 0 (Antibodies, Monoclonal); 0 (Cancer Vaccines); 0 (Immunotoxins); 0 (Interleukin-2); 0 (Tumor Necrosis Factor-alpha) |
[Em] Mês de entrada: | 1802 |
[Cu] Atualização por classe: | 180226 |
[Lr] Data última revisão:
| 180226 |
[Sb] Subgrupo de revista: | IM |
[Da] Data de entrada para processamento: | 180113 |
[St] Status: | MEDLINE |
[do] DOI: | 10.1007/s00432-017-2564-6 |
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