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.

Abstract

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.

• Authors: Hans D Menssen, Ulf Harnack, Ulrike Erben, Dario Neri, Burkhard Hirsch, Horst Dürkop
• Journal: Journal of cancer research and clinical oncology (J Cancer Res Clin Oncol) Vol. 144 Issue 3 Pg. 499-507 (Mar 2018) ISSN: 1432-1335 [Electronic] Germany
• PMID: 29327244 (Publication Type: Journal Article)

Chemical References

• Angiogenesis Inhibitors
• Antibodies, Monoclonal
• Cancer Vaccines
• Immunotoxins
• Interleukin-2
• Tumor Necrosis Factor-alpha

Topics

• Angiogenesis Inhibitors (therapeutic use)
• Animals
• Antibodies, Monoclonal (therapeutic use)
• Cancer Vaccines (therapeutic use)
• Cell Line, Tumor
• Drug Delivery Systems
• Female
• Immunotherapy (methods)
• Immunotoxins (therapeutic use)
• Interleukin-2 (therapeutic use)
• Mice
• Mice, Inbred BALB C
• Multiple Myeloma (immunology, pathology, therapy)
• Neovascularization, Pathologic (drug therapy)
• T-Lymphocytes, Regulatory (drug effects, immunology)
• Transplantation, Isogeneic
• Tumor Necrosis Factor-alpha (therapeutic use)